TREATMENT REGIMEN FOR TREATING CANCERS

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. provisional application no. 63/426,019, which was filed on November 16, 2022, and is incorporated herein by reference in its entirety.

FIELD

[0002] The present disclosure encompasses a treatment regimen for treating haematological cancers, in particular acute myeloid leukaemia (AML) and myelodysplastic syndrome with excess blasts (MDS-EB-2), in a human subject, comprising administering an effective amount of dipeptidyl peptidase (DPP) inhibitor, particularly Talabostat or a pharmaceutically acceptable salt thereof, (e.g., Talabostat mesylate) on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each cycle is of 28-day duration. The disclosure further relates to methods of treating haematological cancers in a subject in need thereof comprising administering to the subject an effective amount of DPP inhibitor, particularly Talabostat or a pharmaceutically acceptable salt thereof in combination with other anti-cancer agents according to the regimen described herein.

BACKGROUND

[0003] Hematologic cancers are cancers that begin in blood-forming tissue, such as the bone marrow, or in the cells of the immune system. Examples of hematologic cancers include but not limited to leukemia such as acute myeloid leukemia (AML), lymphoma, Myelodysplastic syndromes and multiple myeloma. AML is a group of hematopoietic neoplasms characterized by a clonal proliferation of myeloid precursors with a reduced capacity to differentiate into mature cells. It is an aggressive myeloid malignancy that in 2015 afflicted almost 20,000 people, caused over 10,000 deaths, and led to a 5-year overall survival of almost 27%.

[0004] Myelodysplastic syndromes (MDS, or myelodysplasia) are a group of blood cancers which all affect, to a greater or lesser extent, the production of normal blood cells in the bone marrow. In MDS, abnormal bone marrow stem cells (called blast cells) produce increased numbers of immature blood cells. Myelodysplastic syndrome with excess blasts - 2 (MDS- EB-2) is the most aggressive form, often sharing similar cytogenetic and molecular mutations similar to AML

[0005] First-line treatment of such cancers consists primarily of chemotherapy and is divided into two phases: induction and post remission (or consolidation) therapy. The goal of induction therapy is to achieve a complete remission by reducing the amount of leukemic cells to an undetectable level; the goal of consolidation therapy is to eliminate any residual undetectable disease and achieve a cure. Even after complete remission is achieved, leukemic cells likely remain in numbers too small to be detected with current diagnostic techniques. If no further post remission therapy is given, almost all patients eventually relapse. The treatment of refractory relapsed and elderly AML remains a major challenge.

[0006] Despite several advances in the management of these hematologic malignancies, the development of novel targeted and immune therapies, and improvements in supportive care, the overall outcome for patients with AML or MDS remains poor due to several factors, including increased frequency in the older population, poor response to chemotherapy, high relapse rates, and limited effective therapy options in relapsed patients. Hence, clearly, the currently available treatments and regimens needs to be improved as the satisfactory treatment of this population is an unmet need. The present invention addresses this need.

SUMMARY

[0007] The inventors of present application have found that administration of dipeptidyl peptidase (DPP) inhibitors, particularly Talabostat or a pharmaceutically acceptable salt thereof, in a specific treatment regimen is safe, well-tolerated and effectively treats subjects suffering from hematological cancers. In particular the dosage amount used and the dosing schedule selected leads to a very effective treatment of hematological cancers (such as AML, MDS-EB-2).

[0008] The present disclosure provides a treatment regimen for treating cancer in a subject in need thereof, comprising administering to said subject, an effective amount of dipeptidyl peptidase (DPP) inhibitor on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration. In embodiments, said administration is followed by a rest period (no dose of DPP inhibitor is given) on days 4-7, 11-14, 18-21 and 25-28 in the 28-day treatment cycle.

[0009] The present disclosure provides a treatment regimen for treating cancer in a subject in need thereof, comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration. In embodiments, said administration is followed by a rest period (no dose of Talabostat is given) on days 4-7, 11-14, 18-21 and 25-28 in the 28-day treatment cycle.

[0010] In embodiments, there is provided a method of treating a subject having or suspected of having a cancer, the method comprising: a) measuring DNA copy number of DPP9 gene in a biological sample obtained from the subject; (b) if the DNA copy number of DPP9 gene is between about 3 and about 50, administering to the subject an effective amount of the DPP inhibitor on days 1-3, 8-10, 15- 17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0011] In embodiments, there is provided a method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor, the method comprising a), measuring level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL I 7RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 relative to an HPRT1 gene in a biological sample obtained from the subject and c) administering to the subject an effective amount of the DPP inhibitor (e.g. Talabostat) on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, when the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30; AKT3 is in the range of about 0.02 to about 30; CARD9 is in the range of about 0.004 to about 40; CXCR4 is in the range of about 0.14 to about 150; EPCAM is in the range of about 0.00 to about 10; HLA-DMA is in the range of about 0.12 to about 10; HLA-DRA is in the range of about 0.58 to about 100; HLA-DRB3 is in the range of about 0.09 to about 30; IL17RA is in the range of about 0.2 to about 50; IL4R is in the range of about 0.03 to about 30; IL6R is in the range of about 1.18 to about 60; IRF8 is in the range of about 0.03 to about 60; ITGAL is in the range of about 2.16 to about 140; ITGB2 is in the range of about 6.5 to about 400; PSMB8 is in the range of about 3.0 to about 60 and TARP is in the range of about 0.0001 to about 300 as analyzed, for example, by qRT-PCR.

[0012] In embodiments, the expression of one or more genes is measured at the mRNA level. [0013] The present disclosure provides a treatment regimen for treating haematological cancer in a subject in need thereof, comprising administering to said subject, an effective amount of a DPP inhibitor on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration. In embodiments, said administration is followed by a rest period (no dose of DPP inhibitor is given) on days 4-7, 11-14, 18-21 and 25- 28 in the 28-day treatment cycle.

[0014] The present disclosure provides a treatment regimen for treating haematological cancer in a subject in need thereof, comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration. In embodiments, said administration is followed by a rest period (no dose of Talabostat is given) on days 4-7, 11-14, 18-21 and 25-28 in the 28-day treatment cycle.

[0015] In embodiments, there is provided a method for treating haematological cancer in a subject in need thereof, comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration. In embodiments, said administration is followed by a rest period (no dose of Talabostat is given) on days 4-7, 11-14, 18-21 and 25-28 in the 28-day treatment cycle.

[0016] In embodiments, there is provided a method of treating a subject with haematological cancer using a dipeptidyl peptidase (DPP) inhibitor, the method comprising a) measuring DNA copy number of DPP9 gene in a biological sample obtained from the subject and b) administering to the subject an effective amount of the DPP inhibitor on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, if the DNA copy number of the DPP9 gene is equal to or higher than 3.

[0017] In embodiments, there is provided a method of treating a subject with a haematological cancer using a dipeptidyl peptidase (DPP) inhibitor, the method comprising a) measuring level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 relative to an HPRT1 gene in a biological sample obtained from the subject and (b) administering to the subject an effective amount of the DPP inhibitor (e.g. Talabostat) on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, when the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30; AKT3 is in the range of about 0.02 to about 30; CARD9 is in the range of about 0.004 to about 40; CXCR4 is in the range of about 0.14 to about 150; EPCAM is in the range of about 0.00 to about 10; HLA-DMA is in the range of about 0.12 to about 10; HLA-DRA is in the range of about 0.58 to about 100; HLA-DRB3 is in the range of about 0.09 to about 30; IL17RA is in the range of about 0.2 to about 50; IL4R is in the range of about 0.03 to about 30; IL6R is in the range of about 1.18 to about 60; IRF8 is in the range of about 0.03 to about 60; ITGAL is in the range of about 2.16 to about 140; ITGB2 is in the range of about 6.5 to about 400; PSMB8 is in the range of about 3.0 to about 60 and TARP is in the range of about 0.0001 to about 300 as analyzed, for example, by qRT-PCR.

[0018] In embodiments, the DPP inhibitor is DPP2/DPP4/DPP8/DPP9/FAP inhibitor. In embodiments, the DPP2/DPP4/DPP8/DPP9/FAP inhibitor is Talabostat or a pharmaceutically acceptable salt thereof, preferably Talabostat mesylate.

[0019] In embodiments, there is provided a method of treating a subject having or suspected of having a haematological cancer, the method comprising: a) measuring DNA copy number of DPP9 gene in the biological sample obtained from the subject, wherein if the DNA copy number of DPP9 gene between about 3 and about 50, b) administering to the subject an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0020] In embodiments, said administration is followed by a rest period (no dose of Talabostat is given) on days 4 -7, 11-14, 18-21 and 25-28 in the 28-day treatment cycle.

[0021] In embodiments, there is provided a method of enhancing an immune response in a subject suffering from myelodysplastic syndrome, the method comprising administering to said subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0022] In embodiments, there is provided a method of enhancing an immune response in a subject suffering from hematological cancer (e.g. AML), the method comprising administering to said subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0023] In embodiments, the enhanced innate immune response is associated with increased T- cells, tumoricidal natural killer cells (NK cells), macrophages, and monocyte/myeloid cells, as well as the activity NK cells and CD8+ T cell. In embodiments, the enhanced immune response is associated with suppression of T-regul tory cells.

[0024] In embodiments, the present disclosure provides a method of enhancing proinfl ammatory cytokine release (e.g. IL-18, IL- 1 and ZFN-y) in a subject afflicted with hematological cancer, the method comprising administering to said subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration. In embodiments, the haematological cancer is selected from a group consisting of leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, acute myeloid leukemia (AML) (e.g. relapsed AML, refractory AML), chronic myeloid leukemia, Hodgkin lymphoma, nonHodgkin lymphoma, myelodysplastic syndrome (MDS); myeloproliferative neoplasms (MPN) and multiple myeloma.

[0025] In embodiments, the hematological cancer is acute myeloid leukemia.

[0026] In embodiments, the hematological cancer is myelodysplastic syndrome.

[0027] In embodiments, the myelodysplastic syndrome includes MDS with multilineage dysplasia (MDS-MLD), MDS with single lineage dysplasia (MDS-SLD), MDS with excess blasts (MDS-EB-1 and MDS-EB-2), MDS with ring sideroblasts (MDS-RS), MDS with isolated del (5q) and MDS, unclassifiable (MDS-U). In embodiments, the myelodysplastic syndrome is MDS-EB-2.

[0028] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is Talabostat mesylate.

[0029] In embodiments, the subj ect maintains a sustained response to progression of the cancer after cessation of treatment.

[0030] In embodiments, the present disclosure provides a treatment regimen for treating AML in a subject in need thereof, the regimen comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration. In embodiments, the said administration is followed by a rest period on days 4- 7, 11-14, 18-21 and 25-28 in a 28-day treatment cycle. [0031] In embodiments, there is provided a method of treating a subject having or suspected of having acute myeloid leukemia (AML), the method comprising: a) measuring DNA copy number of DPP9 gene in the biological sample obtained from the subject, (b)if the DNA copy number of DPP9 gene is about 3 to about 13, administering to the subject an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0032] In embodiments, the DNA copy number of DPP9 gene is measured by RT-PCR, Multiplex ligation-dependent probe amplification (MLPA), Multiplex amplifiable probe hybridization (MAPH), Dynamic allele-specific hybridization (DASH), Comparative genomic hybridization (CGH), Oligonucleotides arrays, Genotype arrays or the like.

[0033] In embodiments, the assay comprises PCR amplifying a gene and determining the DNA copy number.

[0034] In embodiments, there is provided a method of treating a subject having or suspected of having acute myeloid leukemia (AML), the method comprising a) measuring level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 relative to an HPRT1 gene in a biological sample obtained from the subject and (b) administering to the subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, when the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30; AKT3 is in the range of about 0.02 to about 30; CARD9 is in the range of about 0.004 to about 40; CXCR4 is in the range of about 0.14 to about 150; EPCAM is in the range of about 0.00 to about 10; HLA-DMA is in the range of about 0.12 to about 10; HLA-DRA is in the range of about 0.58 to about 100; HLA-DRB3 is in the range of about 0.09 to about 30; IL17RA is in the range of about 0.2 to about 50; IL4R is in the range of about 0.03 to about 30; IL6R is in the range of about 1.18 to about 60; IRF8 is in the range of about 0.03 to about 60; ITGAL is in the range of about 2.16 to about 140; ITGB2 is in the range of about 6.5 to about 400; PSMB8 is in the range of about 3.0 to about 60 and TARP is in the range of about 0.0001 to about 300 as analyzed, for example, by qRT-PCR. [0035] In embodiments, the biological sample from the subject comprises nucleic acid molecules.

[0036] In embodiments, the present disclosure provides a method of treating AML in a subject in need thereof, the method comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration. In embodiments, the said administration is followed by a rest period on days 4-7, 11-14, 18-21 and 25-28 in a 28-day treatment cycle.

[0037] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered to a subject suffering from AML (e.g., relapsed/refractory AML) in any desired number of treatment cycles as long as a clinical benefit is observed or until there is a complete remission (CR) or unmanageable toxicity.

[0038] In embodiments, the treatment is administered for at least 12 weeks (e.g. three 4-week cycles), at least 14 weeks, at least 16 weeks or at least 24 weeks (e.g. six 4-week cycles).

[0039] In embodiments, the subject achieves a complete response within 2-4 weeks after treatment.

[0040] In embodiments, there is provided a treatment regimen for treating myelodysplastic syndrome (MDS) in a subject in need thereof, the regimen comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0041] In embodiments, there is provided a method of treating a subject having or suspected of having myelodysplastic syndrome (MDS), the method comprising: a) measuring DNA copy number of DPP9 gene in the biological sample obtained from the subject, (b)if the DNA copy number of DPP9 gene is about 3 to about 13, administering to the subject an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0042] In embodiments, there is provided a method of treating a subject having or suspected of having myelodysplastic syndrome, the method comprising a) measuring level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 relative to an HPRT1 gene in a biological sample obtained from the subject and (b) administering to the subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, when the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30; AKT3 is in the range of about 0.02 to about 30; CARD9 is in the range of about 0.004 to about 40; CXCR4 is in the range of about 0.14 to about 150; EPCAM is in the range of about 0.00 to about 10; HLA-DMA is in the range of about 0.12 to about 10; HLA-DRA is in the range of about 0.58 to about 100; HLA-DRB3 is in the range of about 0.09 to about 30; IL17RA is in the range of about 0.2 to about 50; IL4R is in the range of about 0.03 to about 30; IL6R is in the range of about 1.18 to about 60; IRF8 is in the range of about 0.03 to about 60; ITGAL is in the range of about 2.16 to about 140; ITGB2 is in the range of about 6.5 to about 400; PSMB8 is in the range of about 3.0 to about 60 and TARP is in the range of about 0.0001 to about 300 as analyzed, for example, by qRT-PCR.

[0043] In embodiments, there is provided a method of treating myelodysplastic syndrome in a subject in need thereof, said method comprising administering to said subject an effective amount of Talabostat mesylate wherein Talabostat mesylate is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration. In embodiments, the said administration is followed by a rest period on days 4- 7, 11-14,18-21 and 25-28 in a 4-week treatment cycle.

[0044] In embodiments, the myelodysplastic syndrome is high-risk MDS-EB-2.

[0045] In embodiments, said treatment is administered for at least 12 weeks (e.g. three 4-week cycles), or at least 24 weeks (e.g. six 4-week cycles). In embodiments, said treatment is administered for at least 14 weeks, or at least 16 weeks. In embodiments, the subject achieves a complete response within 2-4 weeks after treatment.

[0046] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered to a subject suffering from MDS-EB-2 (e.g., relapsed/refractory MDS-EB-2) in any desired number of treatment cycles as long as a clinical benefit is observed or until there is a complete remission (CR) or unmanageable toxicity.

[0047] A suitable time period of therapy can be determined by one skilled in the art (e.g., a physician). As can be appreciated in the art, a suitable period of time can be determined by one skilled in the art based on one or more of: the stage of disease in the patient, the mass and sex of the patient, clinical trial guidelines (e.g., those on the fda.gov website), and information on the approved drug label. For example a suitable time period of therapy can be, e.g., from 1 week to 2 years, 1 week to 22 months, 1 week to 20 months, 1 week to 18 months, 1 week to 16 months, 1 week to 14 months, 1 week to 12 months, 1 week to 10 months, 1 week to 8 months, 1 week to 6 months, 1 week to 4 months 1 week to 2 months, 1 week to 1 month, 2 weeks to 2 years, 2 weeks to 22 months, 2 weeks to 20 months, 2 weeks to 18 months, 2 weeks to 16 months, 2 weeks to 14 months, 2 weeks to 12 months, 2 weeks to 10 months, 2 weeks to 8 months, 2 weeks to 6 months, 2 weeks to 4 months, 2 weeks to 2 months, 2 weeks to 1 month, 1 month to 2 years, 1 month to 22 months, 1 month to 20 months, 1 month to 18 months,

1 month to 16 months, 1 month to 14 months, 1 month to 12 months, 1 month to 10 months, 1 month to 8 months, 1 month to 6 months, 1 month to 4 months, 1 month to 2 months, 2 months to 2 years, 2 months to 22 months, 2 months to 20 months, 2 months to 18 months, 2 months to 16 months, 2 months to 14 months, 2 months to 12 months, 2 months to 10 months, 2 months to 8 months, 2 months to 6 months, 2 months to 4 months, 3 months to 2 years, 3 months to 22 months, 3 months to 20 months, 3 months to 18 months, 3 months to 16 months, 3 months to 14 months, 3 months to 12 months, 3 months to 10 months, 3 months to 8 months, 3 months to 6 months, 4 months to 2 years, 4 months to 22 months, 4 months to 20 months, 4 months to 18 months, 4 months to 16 months, 4 months to 14 months, 4 months to 12 months, 4 months to 10 months, 4 months to 8 months, 4 months to 6 months, 6 months to 2 years, 6 months to 22 months, 6 months to 20 months, 6 months to 18 months, 6 months to 16 months, 6 months to 14 months, 6 months to 12 months, 6 months to 10 months, 6 months to 8 months, 8 months to

2 years, 8 months to 22 months, 8 months to 20 months, 8 months to 18 months, 8 months to 16 months, 8 months to 14 months, 8 months to 12 months, 8 months to 10 months, 10 months to 2 years, 10 months to 22 months, 10 months to 20 months, 10 months to 18 months, 10 months to 16 months, 10 months to 14 months, 10 months to 12 months, 12 months to 2 years, 12 months to 22 months, 12 months to 20 months, 12 months to 18 months, 12 months to 16 months, or 12 months to 14 months, inclusive

[0048] In embodiments, the subject has not been previously treated with a biotherapeutic or chemotherapeutic agent, i.e., is treatment- naive. In embodiments, the subject has experienced little or no improvement after prior therapy with a biotherapeutic or chemotherapeutic agent. In embodiments, the subject has relapsed or progressed after treatment with previous therapies. In embodiments, the subject has failed to achieve a sustained response after prior therapy with a biotherapeutic or chemotherapeutic agent or like, i.e., is treatment- experienced. In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered orally (e.g. as a tablet) in the morning and evening. [0049] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of from about 0.4 mg to about 2.0 mg.

[0050] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of from about 0.6 mg to about 1.6 mg.

[0051] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of from about 0.8 mg to about 1.6 mg.

[0052] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of from about 1.2 mg to about 1.6 mg.

[0053] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.2 mg twice daily, about 0.3 mg twice daily, about 0.4 mg twice daily, about 0.6 mg twice daily or about 0.8 mg of Talabostat twice daily.

[0054] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional anticancer agents. In embodiments, the additional anticancer agents are selected from hypomethylating agents (e g. 5-Azacitidine, Decitabine, Guadecitabine), BCL-2 inhibitors (e.g. Venetoclax, Navitoclax, Obatoclax, Subatoclax, Maritoclax, Gossypol, Apogossypol, TW-37, UMI-77, and BDA-366) or combinations thereof.

[0055] In embodiments, the hypomethylating agent is Decitabine. In embodiments, the BCL- 2 inhibitor is Venetoclax.

[0056] In embodiments, there is provided a method of treating cancer in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the 28-day treatment cycle. '

[0057] In embodiments, there is provided a method of treating haematological cancer in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond in the 28-day treatment cycle.

[0058] In embodiments, there is provided a method of treating acute myeloid leukemia in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg. once daily on day 3 and beyond in the 28-day treatment cycle.

[0059] In embodiments, there is provided a method of treating acute myeloid leukemia in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 15 mg/m ² as continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond in the 28-day treatment cycle.

[0060] In embodiments, the hypomethylating agent is Azacitidine.

[0061] In embodiments, there is provided a method of treating cancer in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 75 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg on day 3 and beyond in the 28-day treatment cycle.

[0062] In embodiments, there is provided a method of treating haematological cancer in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 75 mg/m2 daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg on day 3 and beyond in the 28-day treatment cycle.

[0063] In embodiments, there is provided a method of treating acute myeloid leukemia in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 75 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg on day 3 and beyond in the 28-day treatment cycle..

[0064] In embodiments, there is provided a method of treating acute myeloid leukemia in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 100 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg on day 3 and beyond in the 28-day treatment cycle.

[0065] In embodiments, there is provided a method of treating myelodysplastic syndrome in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days and Venetoclax is administered once daily in an amount of about 100 mg on day 1 , about 200 mg on day 2 and about 400 mg on day 3 and beyond in the 28-day treatment cycle.

[0066] In embodiments, there is provided a method of treating myelodysplastic syndrome in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 15 mg/m ² as continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg on day 3 and beyond in the 28- day treatment cycle.

[0067] In embodiments, there is provided a method of treating myelodysplastic syndrome in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 75 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg on day 3 and beyond in the 28-day treatment cycle

[0068] In embodiments, there is provided a method of treating myelodysplastic syndrome in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 100 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg on day 3 and beyond in the 28-day treatment cycle.

[0069] In embodiments, the kit includes a formulation comprising Talabostat or pharmaceutically acceptable salt thereof with or without instructions for use. In embodiments, the kit comprises a package insert comprising instructions for using Talabostat or pharmaceutically acceptable salt thereof to treat or delay progression of hematological cancer (e.g. AML/MDS-EB-2) in a subject or to enhance immune function of a subject having cancer. [0070] Other features, objects, and advantages of the disclosure will be apparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1. shows the study design for administering Talabostat mesylate to the subjects with relapsed/refractory AML.

DETAILED DESCRIPTION: [0071] In the following passages, different aspects of the disclosure are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

[0072] ABBREVIATIONS:

[0073] As used herein, the following abbreviations have the following meanings:

[0074] AE(s): Adverse Events

[0075] ALT: Alanine Aminotransferase

[0076] AML: Acute myeloid leukemia

[0077] ANC: Absolute neutrophil count

[0078] AST: Aspartate Aminotransferase

[0079] BID: Bis in Die

[0080] BDNF : Brain-derived neurotrophic factor

[0081] CARD8: Caspase Recruitment Domain Family Member 8

[0082] CD: Cluster of differentiation

[0083] CNS: Central nervous system

[0084] CNV: Copy Number Variation

[0085] CR: Complete remission

[0086] Cri: Complete response with incomplete count recovery

[0087] CPK: phosphokinase

[0088] CRF : case report form

[0089] CTCAE: Common Terminology Criteria for Adverse Events

[0090] DLT: Dose-Limiting Toxicity

[0091] DOR: Duration of response

[0092] DPP4: Dipeptidyl peptidase 4

[0093] DPP8: Dipeptidyl peptidase 8

[0094] DPP9: Dipeptidyl peptidase 9

[0095] EDTA: Ethylenediaminetetraacetic acid

[0096] FAP: Fibroblast Activation Protein

[0097] G-CSF: Granulocyte colony stimulating factor

[0098] GM-CSF: Granulocyte macrophage colony-stimulating factor

[0099] HBV: hepatitis B virus [0100] HCV: hepatitis C virus

[0101] HI: Hematologic improvement

[0102] HIV: Human Immunodeficiency Virus

[0103] ICAM-1: intercellular adhesion molecule 1

[0104] IFN-gamma: Interferon-gamma

[0105] IL-2: Interleukin 2

[0106] IL-3: Interleukin 3

[0107] IL-4: Interleukin 4

[0108] IL-5: Interleukin 5

[0109] IL-6: Interleukin 6

[0110] IL-7: Interleukin 7

[0111] IL-8: Interleukin 8

[0112] IL-10: Interleukin 10

[0113] IL-18: Interleukin 18

[0114] IL-1 alpha: Interleukin 1 alpha

[0115] IL-1 beta: Interleukin 1 beta

[0116] IL-lra: Interleukin Ira

[0117] IL-12p40: Interleukin 12p40

[0118] IL-12p70: Interleukin 12p70

[0119] IL-15: Interleukin 15

[0120] IL-17: Interleukin 17

[0121] IL-23: Interleukin 23

[0122] IV: Intravenous

[0123] LDH: Lactate Dehydrogenase

[0124] MCP-1: Monocyte chemoattractant protein- 1

[0125] MDS-EB-2: Myelodysplastic syndrome with excess blasts-2

[0126] MTP-1 alpha: Macrophage inflammatory protein-1 alpha

[0127] MIP-1 beta: Macrophage Inflammatory Protein-1 beta

[0128] MLFS: Morphologic leukemia-free state

[0129] MMP-3: Matrix metalloproteinase-3

[0130] MMP-9: Matrix metalloproteinase - 9

[0131] mRNA: messenger Ribonucleic Acid

[0132] MTD: Maximum Tolerated Dose [0133] NK: Natural killer

[0134] NLRP1: NLR Family Pyrin Domain Containing 1

[0135] OS: Overall survival

[0136] PCR: Polymerase Chain Reaction

[0137] PFS: Progression-Free Survival

[0138] PD: Pharmacodynamic

[0139] PD: Progressive disease

[0140] PK: Pharmacokinetic

[0141] PO: Per Oral

[0142] PR: Partial response

[0143] RP2D: Recommended Phase 2 Dose

[0144] SAE: Serious Adverse Event

[0145] SD: Stable disease

[0146] SCF: Stem cell factor

[0147] SGOT : serum glutamic-oxaloacetic transaminase

[0148] SGPT: serum glutamic-pyruvic transaminase

[0149] SOC: Standard of Care

[0150] TKI: Tyrosine kinase inhibitor

[0151] TLS: Tumor Lysis Syndrome

[0152] TNF-alpha: Tumor necrosis factor alpha

[0153] TNF-beta: Tumor necrosis factor beta

[0154] Treg: Regulatory T cells or T-regulatory cells

[0155] ULN: Upper Limit Normal

[0156] VEGF: Vascular endothelial growth factor

[0157] WBC: White blood cells

[0158] WNL: Within Normal Limit

[0159] DEFINITIONS:

[0160] It will be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting.

[0161] As used herein the term “about” refers to ±10% of the indicated value.

[0162] As used in this specification, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. [0163] As used herein, the term “inhibit,” refers to the ability of a compound or any agent to reduce or impede a described function, level, activity, synthesis, release, binding, etc., based on the context in which the term “inhibit” is used. The term “inhibit” is used interchangeably with “antagonize”, “reduce,” “block,” and “decrease.”

[0164] As used herein, the term “active agent” or “therapeutic agent” refers to a chemical agent capable of activity.

[0165] As used herein, the terms “comprise”, “comprising”, “includes”, “including”, “having” means “including but not limited to”. The term “consisting of means including and limited to”. [0166] As used herein, unless indicated otherwise, the terms “dosage form” "pharmaceutical composition", "composition", "formulation" and "composition of the disclosure," are used interchangeably.

[0167] As used herein, the term “effective amount” refers to an amount (quantity or concentration) sufficient to produce the desired effect (i.e. prevent, alleviate, or ameliorate symptoms of disease or condition or prolong the survival of the subject being treated) or cause an improvement in a clinically significant condition of the subject. The effective amount will depend on the particular disorder, the mode of administration, co-administered compounds, if any, and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.

[0168] As used herein, the terms “subject” or “patient” are used interchangeably and refers to human subjects in need of treatment for hematological cancer.

[0169] As used herein, "pharmaceutically acceptable salt" refers to a salt known to be nontoxic and commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like, as well as those prepared from organic acids, such as for example, aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyl alkandioic acids, aromatic acids, aliphatic (mesylate) and aromatic sulfonic acids. A preferred salt form of Talabostat is the mesylate salt.

[0170] As used herein, the terms, “administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered orally, buccally, parenterally, intravenously, intramuscularly, subcutaneously, inhalational, intranasally, transdermally, rectally, or vaginally. The administration can also be performed, for example, once, or a plurality of times per day, and/or over one or more longer periods. In embodiments, the administration includes both direct administrations, including selfadministration, and indirect administration, including the act of prescribing a drug. For example, as used herein, administration via a physician or a physician who instructs a patient to self-administer a drug, or to have the drug administered by another and/or who provides a patient with a prescription for a drug is administering the drug to the patient.

[0171] As used herein, the term, “treat” and its cognates refers to taking steps to obtain beneficial or desired results, i.e., to obtain a full or partial amelioration of hematological cancer, preferably relapsed/refractory AML, relapsed/refractory MDS-EB-2. It includes any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.

[0172] The “copy number of a gene” or the “copy number of a biomarker” refers to the number of DNA sequences in a cell encoding a particular gene product. Generally, for a given gene, a mammal has two copies of each gene. As used herein copy numbers are determined for DPP genes. In embodiments, the copy number is determined for DPP9 gene.

[0173] The term "RNA" includes mRNA transcripts, and/or specific spliced or other alternative variants of mRNA.

[0174] The term “protein” refers to proteins translated from the RNA transcripts transcribed from the biomarkers.

[0175] The term "level of expression" or "expression level" as used herein refers to a measurable level of expression of the products of biomarkers, (such as DPP9 gene). “Higher expression” or “higher level of expression” as used herein refers to higher expression of the one or more genes (protein and/or mRNA) in one or more given cells present in the sample.

[0176] The term “likelihood” generally refers to an increase in the probability of an event. The term “likelihood” when used in reference to the effectiveness of cancer response generally contemplates an increased probability that the rate of cancer progress or tumor cell growth will decrease. The term “likelihood” when used in reference to the effectiveness of a patient cancer response can also generally mean the increase of indicators, such as mRNA or protein expression, that may evidence an increase in the progress in treating the cancer.

[0177] The term "assaying" is used to refer to the act of identifying, screening, probing, testing measuring or determining, which act may be performed by any conventional means. For example, a sample may be assayed for the presence of a particular genetic marker by using an a Northern blot.

[0178] The term "obtaining" means to procure, e.g., to acquire possession of in any way, e.g., by physical intervention (e.g., biopsy) or non-physical intervention (e.g, transmittal of information via a server), etc.

[0179] 1 The term "About" and "approximately" shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.

[0180] "Dipeptidyl peptidase (DPP)" refers to a class of enzymes encoded by DPP gene (classified under EC 3.4.14). There are 9 types of DPP genes are known to date. These include Cathepsin C (DPP-1), DPP-2, DPP-3, DPP-4, DPP-6, DPP-7, DPP-8, DPP-9 and DPP- 10. The DPP also includes fibroblast activation protein (FAP). The terms " dipeptidyl peptidases" and "DPP2/DPP4/DPP-8/DPP-9/FAP" refer to a subset of DPP enzymes or genes containing one or more of DPP-2, DPP-4, DPP-8, DPP-9and/or FAP. The term " dipeptidyl peptidase inhibitor" also referred to interchangeably herein as a “DPP inhibitor” or "DPP2/DPP4/DPP8/DPP9/FAP inhibitor", is a compound that inhibits DPP2, DPP4, DPP8, DPP9 and/or FAP.

[0181] The terms “sample,” or “biological sample” and the like, encompass a variety of sample types obtained from a patient, individual, or subject and can be used in a diagnostic or monitoring assay. The patient sample may be obtained from a healthy subject or a patient having symptoms associated with or is suspected of having or likely to have or develop a disease or condition described herein. Moreover, a sample obtained from a patient can be divided and only a portion may be used for diagnosis. Further, the sample, or a portion thereof, can be stored under conditions to maintain sample for later analysis. The term “Biomarker” refers to a substance that is a distinctive indicator of a biological process, biological event and/or pathologic condition. Herein DPP genes and other target genes and genes involved in immune pathways like caspase 1, CARDS and PYCARD are the biomarkers for identifying the likelihood of cancer responsiveness to DPP inhibitors.

[0182] The term “myelodysplastic syndromes (MDS)” as used herein refers to a conglomeration of bone marrow neoplasms that are defined by ineffective hematopoiesis, peripheral cytopenias, and specific dyplastic morphology in both the peripheral smear and bone marrow. Myelodysplastic syndrome with excess blasts - 2 (MDS-EB-2) is the most aggressive form, often sharing similar cytogenetic and molecular mutations similar to AML. [0183] As used herein, the term “treatment naive” includes patient/subject who is considered ineligible for standard induction chemotherapy.

[0184] As used herein the term “refractory/resistant AML” refers to AML that has become resistant to one or more cancer therapies including, but not limited to, an anti -cancer agent, a chemotherapy (e.g., a chemotherapeutic), a radiotherapy, an immunotherapy, and/or combinations thereof. Also, subjects who have not achieved complete remission after 2 cycles of induction chemotherapy are usually diagnosed as having "refractory AML." Refractory AML as in present disclosure refer to the subject has received <2 prior induction regimens (example: patients who receive 7 + 3 followed by 5 + 2 would count as one induction regimen). [0185] As used herein in the present disclosure, the term “refractory MDS-EB-2” includes- i.e., no response achieved or is refractory after at least 4 cycles of a hypomethylating agent (e.g.Azacitidine, Decitabine , or oral Decitabine /cedazuridine).

[0186] As used herein, the term “relapsed AML/MDS-EB-2” refer to as subjects reach remission and then have a return of leukemia cells in the marrow and a decrease in normal blood cells such as evidence by >5% myeloblasts in the bone marrow, or reappearance of blasts in the peripheral blood. In the present disclosure, the relapsed MDS-EB-2 means relapsed after at least 4 cycles of a hypomethylating agent (such as Azacitidine, Decitabine, or oral Decitabine /cedazuridine).

[0187] The term “MDS-EB-2 - myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) defined as per WHO refers to blast count between 10% -19% in the bone marrow or peripheral blood blasts 5%-19% or Auer rods noted and refractory or relapsed after at least 4 cycles of a hypomethylating agent (e.g. Azacitidine, Decitabine, or oral Decitabine /cedazuridine)

[0188] As used herein, the term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals (e.g., dogs), each unit containing a predetermined quantity of active material calculated to produce the desired onset, tolerability, and/or therapeutic effects, in association with a suitable pharmaceutical excipient (e.g., tablet). [0189] The term "pharmaceutically acceptable carrier" refers to a pharmacologically inert substance to be used as a carrier. As used herein, the phrase “carrier” and “excipients” are used interchangeably, except where otherwise clearly intended to have different meanings.

[0190] As used herein, the term “rest period” or “drug-free period” refers to discontinuation or no use or administration of Talabostat or a pharmaceutically acceptable salt thereof (e.g., Talabostat mesylate) on such days. [0191] The term "statistically significant" means that the alteration is greater than what might be expected to happen by chance alone. Statistical significance can be determined by any method known in the art. For example, statistical significance can be determined by p-value.

[0192] "Optional" or "optionally" means that the subsequently described circumstance may but need not necessarily occur, so that the description includes instances where the circumstance occurs and instances where it does not.

[0193] The term “response ¹ refers to an anti-cancer response, e.g. in the sense of reduction of tumor size or inhibiting tumor growth. The terms can also refer to an improved prognosis, for example, as reflected by an increased time to recurrence, which is the period to first recurrence censoring for second primary cancer as a first event or death without evidence of recurrence, or an increased overall survival, which is the period from treatment to death from any cause. To respond or to have a response means there is a beneficial endpoint attained when exposed to a stimulus.

[0194] The term “complete remission (CR)” refers to normalization of blast percentage (<5%) with no detectable auer rods in marrow. It includes normalization in neutrophil count (>l,000/pL) and platelet count (>100,000/pL) and absence of leukemic blasts in peripheral blood. It covers absence of extramedullary disease (CNS or soft tissue).

[0195] The term “CR with incomplete blood count recovery (Cri) refers to normalization of blast percentage (<5%), absence of leukemic blasts in peripheral blood and absence of extramedullary disease (CNS or soft tissue).

[0196] The term “partial remission or PR” refers to decrease by >50% in blast percentage to 5-25% or to <5% with auer rods presence. It includes normalization in neutrophil count (>l,000/pL) and platelet count (>100,000/pL).

[0197] The term “stable disease or SD” refers to failure to achieve at least a PR, but no evidence of progression for at least 8 weeks.

[0198] The term “relapse after CR/Cri” refers to blast percentage >5% in marrow (if no peripheral blasts, then confirmation aspirate required >1 week later).

[0199] The term “relapse after PR” refers to blast percentage >25% in marrow (if no peripheral blasts, then confirmation aspirate required >1 week later).

[0200] The term “progressive disease” refers to > 50% increase in blasts from baseline in marrow. In peripheral blood, it includes one or more of the following- >50% decrease from peak remission levels in platelets or granulocytes; reduction in haemoglobin percentage by at least 2 g/dL; transfusion dependence. [0201] The term “morphologic leukemia-free state (MLFS)” refers to Bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required

[0202] The therapeutic agents intended for use in the present disclosure are described below:

THERAPEUTIC AGENTS

Talabostat or a pharmaceutically acceptable salt thereof:

[0203] Talabostat is referred to interchangeably as PT-100, Talabostat (USAN), and [(2R)- 1- I [(2S)-2-amino-3 -methyl- 1 -oxobutyl] -2 -pyrrolidinyl] boronic acid. Talabostat has a CAS registration number of 149682-77-9. Talabostat, also known as Val-boro-pro (L-vabnyl-L- boroproline), is disclosed in PCT Appl. Publication No. 1989/003223. The IUPAC name of Talabostat is [(2R)-l-[(2S)-2-amino-3-methylbutanoyl]pyrrobdin-2-yl]boroni c acid. Talabostat (PubChem ID: 6918572), or a pharmaceutically acceptable salt thereof, such as, for example, Talabostat mesylate (PubChem CID: 1152248). In embodiments, the free base may be used. In embodiments, the Talabostat or a pharmaceutically acceptable salt thereof may be a solvate. In most clinical formulations, Talabostat is provided as a salt form, e.g. Talabostat mesylate. Talabostat has two chiral centers with a R, S configuration. Talabostat or a pharmaceutically acceptable salt thereof can exist as both linear and cyclic forms (RJ Snow et al., J. Am. Chem. Soc., 1994, 116 (24), pp 10860-10869).

[0204] Other pharmaceutically acceptable salts include, for example, those prepared from typical inorganic acids such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like, as well as those prepared from organic acids, such as for example, aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyl alkandioic acids, aromatic acids, aliphatic (mesylate) and aromatic sulfonic acids, and any suitable form of Talabostat may be used in the combinations provided herein and the disclosure is not limited in this regard. A preferred salt form of Talabostat is the mesylate salt. Talabostat mesylate has a CAS registry number of 150080-09- 4 and an IUPAC name as follows: [(2R)-l-[(2S)-2-amino-3- methylbutanoyl]pyrrolidin-2- yl]boronic acid; methanesulfonic acid.

[0205] Talabostat or a pharmaceutically acceptable salt thereof is effective for the treatment of cancer by modulating multiple intracellular and extracellular dipeptidyl peptidases. More specifically, intracellular and extracellular dipeptidyl peptidases comprise Fibroblast Activation Protein, DPP 8/9, CD26/DPP4 and DPP2. Talabostat or a pharmaceutically acceptable salt thereof has a dual mechanism of action which includes stromal targeted activity via FAP inhibition and targeted immunostimulatory activity via DPP 4/8/9 inhibition. Talabostat inhibits FAP enzymatic activity thereby suppressing tumor growth. Talabostat or a pharmaceutically acceptable salt thereof also inhibits DPP 4/8/9 thereby inducing an IL lb response (via caspase-1) in the stroma of tumor and lymph nodes. Talabostat’s dual mechanism of action introduces a novel approach to the treatment of cancer because it combines both tumor-targeted and immune -stimulatory activity in a single agent.

[0206] Other small molecules are also encompassed in the scope of the present disclosure, such as, for example, analogs and prodrugs of Talabostat, as well as Talabostat-like compounds. Illustrative compounds encompass those described in at least the following documents. EP Patent No. 2,782,994 discloses Talabostat analogs, such as, for example, ARI-4175 and related compounds. PCT Appl. Publication No. W02003092605 discloses prodrugs of Talabostat, such as, for example, cyclohexyl(glycinyl)-prolinyl-valinyl-L-boroproline. PCT Appl. Publication Nos. W02018049014 and W02018049008 disclose various compounds of the boro-pro class, and other dipeptides, and are herein referred to as Talabostat-like boro-pro compounds.

[0207] Talabostat may be administered in combination therapy with at least one additional therapeutic agent. Such additional therapeutic agent can be administered prior to, concurrently with, and/or subsequently to, administration of Talabostat. In embodiments, at least one additional therapeutic agent comprises 1, 2, 3, or more therapeutic agents.

[0208] In embodiments, combination therapy comprises a therapeutic agent that affects the immune response (e.g., enhances or activates the response) and a therapeutic agent that affects (e.g., inhibits or kills) the tumor/cancer cells.

[0209] Other Agent (s) that may be used in combination with Talabostat include:

(i) Hypomethylating agents

[0210] In embodiments, hypomethylating agents are selected from 5-Azacitidine, Decitabine, Guadecitabine. In embodiments, the hypomethylating agent is Decitabine.

[0211] In embodiments, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days. In embodiments, Decitabine is administered at a dose of 15 mg/m ² by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days.

[0212] In embodiments, Decitabine is administered orally. In embodiments, Decitabine is administered as oral tablet. [0213] In embodiments, Decitabine is administered once daily in an amount of about 30 mg to about 100 mg. In embodiments, Decitabine is administered once daily in an amount of about 35 mg. In embodiments, Decitabine is administered once daily on days 1-5 of a 28-day cycle.

[0214] In embodiments, Decitabine is administered once daily in an amount of about 30 mg to about 100 mg. In embodiments, Decitabine is administered once daily in an amount of about 35 mg. In embodiments, Decitabine is administered once daily on days 1-5 of a 28-day cycle.

[0215] Decitabine (Dacogen) is an FDA-approved medication for the treatment of MDS, although it is prominently used in the treatment of AML. Dacogen is indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate- 1, intermediate-2, and high-risk International Prognostic Scoring System groups. [0216] Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine has been shown to induce hypomethylation both in vitro and in vivo.

[0217] In embodiments, the hypomethylating agent is Azacitidine.

[0218] In embodiments, Azacitidine is administered subcutaneously at a dose of 75 mg/m ² daily for seven days, every four weeks. In embodiments, Azacitidine is administered subcutaneously at a dose of 100 mg/m2 daily for seven days, every four weeks

[0219] In embodiments, Azacitidine is administered orally. In embodiments, Azacitidine is administered as oral tablet. In embodiments, Azacitidine is administered once daily in an amount of about 200 mg. In embodiments, Azacitidine is administered once daily in an amount of about 300 mg. In embodiments, Azacitidine is administered once daily on Days 1 through 14 of each 28-day cycle.

[0220] Azacitidine

[0221] Azacitidine (Vidaza) is an FDA-approved medication for the treatment of MDS, although it is prominently used in the treatment of AML. Azacitidine is a nucleoside metabolic inhibitor indicated for the treatment of patients with the following FAB myelodysplastic syndrome (MDS) subtypes: Refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).

[0222] Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of Azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms.

(ii) BCL-2 inhibitors

[0223] In embodiments, BCL-2 inhibitors are selected from the group comprising Venetoclax, Navitoclax, Obatoclax, Subatoclax, Maritoclax, Gossypol, Apogossypol, TW-37, UMI-77, and BDA-366) or combinations thereof. In embodiments, BCL-2 inhibitor is Venetoclax.

[0224] In embodiments, Venetoclax is administered orally. In embodiments, Venetoclax is administered as oral tablet. In embodiments, Venetoclax is administered in an amount of about 100 mg on day 1 of each treatment cycle. In embodiments, Venetoclax is administered in an amount of about 200 mg on day 2 a of each treatment cycle. In embodiments, Venetoclax is administered once daily in an amount of about 400 mg on day 3 and beyond of each treatment cycle. In embodiments, Venetoclax is administered in an amount of about 400 mg orally once daily of each 28- day cycle in combination with Azacitidine or Decitabine.

[0225] METHOD OF USE/TREATMENT REGIMEN:

[0226] The present disclosure is based, in part, on a treatment regimen to treat haematological cancer (specifically AML and MDS-EB-2) using effective amount of Talabostat or a pharmaceutically acceptable salt thereof to be administered according to a particular schedule. The said treatment regimen of Talabostat or a pharmaceutically acceptable salt thereof as used herein may produce, improvement in transfusion frequency, peripheral blast reduction or symptom improvement and an overall enhanced anti-cancer effect, such as improved T-cell priming, increased T cell stimulation, increased activation of natural killer cells, increase in pro-inflammatory cytokine (IL1, IL2, IL18, IFN gamma, IL6, IL12p40, IL 15, IL 7, G-CSF and GM-CSF), enhanced anti-tumor memory response, reduced metastasis and reduced toxicity.

[0227] The present disclosure provides a treatment regimen for treating cancer in a subject in need thereof, comprising administering to said subject, an effective amount of dipeptidyl peptidase (DPP) inhibitor on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration. In embodiments, said administration is followed by a rest period (no dose of DPP inhibitor is given) on days 4-7, 11-14, 18-21 and 25-28 in the 28-day treatment cycle.

[0228] In embodiments, there is provided a method of treating a subject having or suspected of having a cancer, the method comprising: a) measuring DNA copy number of DPP9 gene in the biological sample obtained from the subject, (b)if the DNA copy number of DPP9 gene between about 3 and about 50,) administering to the subject an effective amount of the DPP inhibitor on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0229] In embodiments, there is provided a method of treating a subject having or suspected of having a cancer, the method comprising: a) measuring DNA copy number of DPP9 gene in the biological sample (b)if the DNA copy number of DPP9 gene is about 3 to about 13, administering to the subject an effective amount of the DPP inhibitor or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0230] In embodiments, there is provided a method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor, the method comprising a) measuring level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 relative to an HPRT1 gene in a biological sample obtained from the subject and (b ) administering to the subject an effective amount of the DPP inhibitor (e g. Talabostat) on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, when the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30; AKT3 is in the range of about 0.02 to about 30; CARD9 is in the range of about 0.004 to about 40; CXCR4 is in the range of about 0.14 to about 150; EPCAM is in the range of about 0.00 to about 10; HLA-DMA is in the range of about 0.12 to about 10; HLA-DRA is in the range of about 0.58 to about 100; HLA-DRB3 is in the range of about 0.09 to about 30; IL17RA is in the range of about 0.2 to about 50; IL4R is in the range of about 0.03 to about 30; IL6R is in the range of about 1.18 to about 60; IRF8 is in the range of about 0.03 to about 60; ITGAL is in the range of about 2.16 to about 140; ITGB2 is in the range of about 6.5 to about 400; PSMB8 is in the range of about 3.0 to about 60 and TARP is in the range of about 0.0001 to about 300 as analyzed, for example, by qRT-PCR.

[0231] In embodiments, an increase of about 2-1000-fold in expression level of one or more genes in a biological sample of the subject is indicative of likelihood that subject will respond favorably to DPP inhibitor (e.g. Talabostat). The expression levels are relative to a subject who is non-responsive to therapy.

[0232] In embodiments, the expression of one or more genes is measured at the mRNA level. [0233] In embodiments, there is provided a treatment regimen for treating hematological cancer in a subject in need thereof, comprising administering to said subject, an effective amount of a DPP inhibitor on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration. In embodiments, said administration is followed by a rest period (no dose of DPP inhibitor is given) on days 4-7, 11-14, 18-21 and 25-28 in the 28-day treatment cycle.

[0234] In embodiments, the present disclosure provides a treatment regimen for treating hematological cancer in a subject in need thereof, the regimen comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration. In embodiments, said administration is followed by a rest period (no dose of Talabostat is given) on days 4-7, 11-14, 18-21 and 25-28 in the 28-day treatment cycle.

[0235] In embodiments, the present disclosure provides a method of treating hematological cancer in a subject in need thereof, the method comprising administering to the subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14, 18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration. In embodiments, said administration is followed by a rest period (no dose of Talabostat is given) on days 4-7, 11-14, 18-21 and 25- 28 in the 28-day treatment cycle.

[0236] In embodiments, there is provided a method of treating a subject with hematological cancer using a dipeptidyl peptidase (DPP) inhibitor, the method comprising a) measuring DNA copy number of DPP9 gene in the biological sample and b) administering to the subject an effective amount of the DPP inhibitor on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, if the DNA copy number of the DPP9 gene is equal to or higher than 3.

[0237] In embodiments, there is provided a method of treating a subject with a hematological cancer using a dipeptidyl peptidase (DPP) inhibitor, the method comprising a) measuring level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 relative to an HPRT1 gene and (b) administering to the subject an effective amount of the DPP inhibitor (e.g. Talabostat) on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, when the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30; AKT3 is in the range of about 0.02 to about 30; CARD9 is in the range of about 0.004 to about 40; CXCR4 is in the range of about 0.14 to about 150; EPC AM is in the range of about 0.00 to about 10; HLA-DMA is in the range of about 0.12 to about 10; HLA- DRA is in the range of about 0.58 to about 100; HLA-DRB3 is in the range of about 0.09 to about 30; IL17RA is in the range of about 0.2 to about 50; IL4R is in the range of about 0.03 to about 30; IL6R is in the range of about 1.18 to about 60; IRF8 is in the range of about 0.03 to about 60; ITGAL is in the range of about 2.16 to about 140; ITGB2 is in the range of about 6.5 to about 400; PSMB8 is in the range of about 3.0 to about 60 and TARP is in the range of about 0.0001 to about 300 as analyzed, for example, by qRT-PCR.

[0238] In embodiments, the DPP inhibitor is DPP2/DPP4/DPP8/DPP9/FAP inhibitor. In embodiments, the DPP2/DPP4/DPP8/DPP9/FAP inhibitor is Talabostat or a pharmaceutically acceptable salt thereof, preferably Talabostat mesylate.

[0239] In embodiments, there is provided a method of treating a subject having or suspected of having a haematological cancer, the method comprising: a) measuring DNA copy number of DPP9 gene in the biological sample, (b) if the DNA copy number of DPP9 gene between about 3 and about 50, administering to the subject an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration. [0240] In embodiments, there is provided a method of treating a subject having or suspected of having a haematological cancer, the method comprising: a) measuring DNA copy number of DPP9 gene in the biological sample; (b) if the DNA copy number of DPP9 gene is about 3 to about 13 administering to the subject an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0241] In embodiments, said administration is followed by a rest period (no dose of Talabostat is given) on days 4 -7, 11-14, 18-21 and 25-28 in the 28-day treatment cycle.

[0242] In embodiments, the present disclosure provides a method of enhancing immune function in a subject suffering from hematological cancer, the method comprising administering to the subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4- 7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0243] In embodiments, there is provided a method of enhancing an immune response in a subject suffering from myelodysplastic syndrome, the method comprising administering to said subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration

[0244] In embodiments, enhancing immune function is increase in T-cells, NK cells and monocytic/myeloid cells and suppression of Treg cells, wherein T-cells are CD45, CD3, CD4, and CD8, monocytic/myeloid cells are CD14, CD16, CD1 lb, HLA-DR.

[0245] In embodiments, enhancing immune function is increase in cytokines, wherein cytokines are G-CSF, GM-CSF, IFN-gamma, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-18, MIP-1 alpha, MLP-1 beta, MCP-1, TNF-alpha, TNF-beta, BDNF, Eotaxin-1, Factor VII, ICAM-1, IL-1 alpha, IL-1 beta, IL- Ira, IL-12p40, IL-12p70, IL-15, IL- 17, IL-23, MMP-3, MMP-9, SCF, VEGF.

[0246] In embodiments, the present disclosure provides a method of enhancing proinfl ammatory cytokine release (e.g. IL-18, IL-ip and IFN-y) in a subject afflicted with hematological cancer, the method comprising administering to said subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0247] In embodiments, the present disclosure provides a method of delaying progression of or preventing or delaying tumor recurrence, tumor growth or spread of tumor in a subject afflicted with hematological cancer (e.g. AML) comprising administering an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14, 18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0248] In embodiments, the hematological cancer is selected from a group consisting of leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN) and multiple myeloma.

[0249] In embodiments, the hematological cancer is acute myeloid leukemia. In embodiments, AML is refractory. In embodiments, AML is relapsed.

[0250] In embodiments, the hematological cancer is high — risk myelodysplastic syndrome (MDS). In embodiments, the myelodysplastic syndrome includes MDS with multilineage dysplasia (MDS-MLD), MDS with single lineage dysplasia (MDS-SLD), MDS with excess blasts (MDS-EB-1 and MDS-EB-2), MDS with ring sideroblasts (MDS-RS), MDS with isolated del(5q) and MDS, unclassifiable (MDS-U).

[0251] In embodiments, the hematological cancer is refractory MDS-EB-2 or relapsed MDS- EB-2.

[0252] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof may be administered as a twice daily dose in the regimen of this disclosure in one or, more multiple dosage units to achieve an effective total daily dose to treat a subject suffering from haematological cancer (e.g., AML or MDS-ES-2).

[0253] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 0.2 mg twice daily, about 0.3 mg twice daily, about 0.4 mg twice daily, about 0.6 mg twice daily or about 0.8 mg of Talabostat twice daily.

[0254] In embodiments, the present disclosure provides a treatment regimen for treating AML in a subject in need thereof, the regimen comprising administering to the subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14, 18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration, and wherein, Talabostat or a pharmaceutically acceptable salt thereof is administered to provide a total daily dose of Talabostat from about 0.4 mg to about 1.6 mg of Talabostat.

[0255] In embodiments, there is provided a method of treating a subject having or suspected of having acute myeloid leukemia (AML), the method comprising: a) obtaining a biological sample from the subject; b) measuring DNA copy number of DPP9 gene in the biological sample; wherein if the DNA copy number of DPP9 gene is about 3 to about 13, administering to the subject an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration

[0256] In embodiments, the DNA copy number of DPP9 gene is measured by RT-PCR, Multiplex ligation-dependent probe amplification (MLPA), Multiplex amplifiable probe hybridization (MAPH), Dynamic allele-specific hybridization (DASH), Comparative genomic hybridization (CGH), Oligonucleotides arrays, Genotype arrays or the like.

[0257] In embodiments, the assay comprises PCR amplifying a gene and determining the DNA copy number.

[0258] In embodiments, there is provided a method of treating a subject having or suspected of having acute myeloid leukemia (AML), the method comprising a) measuring level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL I 7RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 relative to an HPRT1 gene in a biological sample obtained from the subject and (b) administering to the subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, when the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30; AKT3 is in the range of about 0.02 to about 30; CARD9 is in the range of about 0.004 to about 40; CXCR4 is in the range of about 0.14 to about 150; EPCAM is in the range of about 0.00 to about 10; HLA-DMA is in the range of about 0.12 to about 10; HLA-DRA is in the range of about 0.58 to about 100; HLA-DRB3 is in the range of about 0.09 to about 30; IL17RA is in the range of about 0.2 to about 50; IL4R is in the range of about 0.03 to about 30; IL6R is in the range of about 1.18 to about 60; IRF8 is in the range of about 0.03 to about 60; ITGAL is in the range of about 2.16 to about 140; ITGB2 is in the range of about 6.5 to about 400; PSMB8 is in the range of about 3.0 to about 60 and TARP is in the range of about 0.0001 to about 300 as analyzed, for example, by qRT-PCR. [0259] In embodiments, the biological sample from the subject comprises nucleic acid molecules.

[0260] In embodiments, the total daily dose of Talabostat or a pharmaceutically acceptable salt thereof is about 0.4 mg, 0.6 mg, about 0.8 mg, about 1.2 mg, about 1.6 mg or about 2 mg of Talabostat.

[0261] In embodiments, said subject maintains a sustained response to progression of the cancer after cessation of treatment.

[0262] In embodiments, the present disclosure provides a treatment regimen for treating haematological cancer in a subject in need thereof, the regimen comprising administering to the subject about 0.2 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25- 28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0263] In embodiments, the present disclosure provides a treatment regimen for treating AML in a subject in need thereof, the regimen comprising administering to the subject about 0.2 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15- 17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0264] In embodiments, the present disclosure provides a treatment regimen for treating hematological cancer in a subject in need thereof, the regimen comprising administering to the subject about 0.3 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0265] In embodiments, the present disclosure provides a treatment regimen for treating AML in a subject in need thereof, the regimen comprising administering to the subject about 0.3 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15- 17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0266] In embodiments, the present disclosure provides a treatment regimen for treating hematological cancer in a subject in need thereof, the regimen comprising administering to the subject about 0.4 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0267] In embodiments, the present disclosure provides a treatment regimen for treating AML in a subject in need thereof, the regimen comprising administering to the subject about 0.4 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15- 17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0268] In embodiments, the present disclosure provides a treatment regimen for treating hematological cancer in a subject in need thereof, the regimen comprising administering to the subject about 0.6 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14, 18-21 and 25- 28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0269] In embodiments, the present disclosure provides a treatment regimen for treating AML in a subject in need thereof, the regimen comprising administering to the subject about 0.6 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15- 17 and 22-24 followed by a rest period on days 4-7, 11-14, 18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0270] In embodiments, the present disclosure provides a treatment regimen for treating hematological cancer in a subject in need thereof, the regimen comprising administering to the subject about 0.8 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0271] In embodiments, the present disclosure provides a treatment regimen for treating AML in a subject in need thereof, the regimen comprising administering to the subject about 0.8 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15- 17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0272] In embodiments, there is provided a method of treating hematological cancer in a subject in need thereof, the method comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration, and wherein Talabostat or a pharmaceutically acceptable salt thereof is administered to provide a total daily dose of Talabostat from about 0.4 mg to about 1.6 mg of Talabostat.

[0273] In embodiments, there is provided a method of treating acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration, and wherein Talabostat or a pharmaceutically acceptable salt thereof is administered to provide a total daily dose of Talabostat from about 0.4 mg to about 1.6 mg.

[0274] In embodiments, the present disclosure provides a method of treating hematological cancer in a subject in need thereof, the method comprising administering to the subject about 0.2 mg of Talabostat or a pharmaceutically acceptable salt thereof twice daily on days 1-3, 8- 10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0275] In embodiments, the present disclosure provides a method of treating acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to the subject about 0.2 mg of Talabostat or a pharmaceutically acceptable salt thereof twice daily on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0276] In embodiments, the present disclosure provides a method of treating hematological cancer in a subject in need thereof, the method comprising administering to the subject about 0.3 mg of Talabostat or a pharmaceutically acceptable salt thereof twice daily on days 1-3, 8- 10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0277] In embodiments, the present disclosure provides a method of treating acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to the subject about 0.3 mg of Talabostat or a pharmaceutically acceptable salt thereof twice daily on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0278] In embodiments, the present disclosure provides a method of treating hematological cancer in a subject in need thereof, the method comprising administering to the subject about 0.4 mg of Talabostat or a pharmaceutically acceptable salt thereof twice daily on days 1-3, 8- 10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14, 18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0279] In embodiments, the present disclosure provides a method of treating acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to the subject about 0.4 mg of Talabostat or a pharmaceutically acceptable salt thereof twice daily on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14, 18-21 and 25- 28 of each treatment cycle, wherein each cycle is of 28-day duration. [0280] In embodiments, the present disclosure provides a method of treating hematological cancer in a subject in need thereof, the method comprising administering to the subject about 0.6 mg of Talabostat or a pharmaceutically acceptable salt thereof twice daily on days 1-3, 8- 10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0281] In embodiments, the present disclosure provides a method of treating acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to the subject about 0.6 mg of Talabostat or a pharmaceutically acceptable salt thereof twice daily on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0282] In embodiments, the present disclosure provides a method of treating hematological cancer in a subject in need thereof, the method comprising administering to the subject about 0.8 mg of Talabostat or a pharmaceutically acceptable salt thereof twice daily on days 1-3, 8- 10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0283] In embodiments, the present disclosure provides a method of treating acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to the subject about 0.8 mg of Talabostat or a pharmaceutically acceptable salt thereof twice daily on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0284] In embodiments, AML is refractory or relapsed AML. In embodiments, the subject has AML that may be at an early stage or a late stage. In embodiments, AML is metastatic.

[0285] In embodiments, the treatment is administered for at least 12 weeks (e.g. three 4-week cycles), at least 14 weeks, at least 16 weeks or at least 24 weeks (e.g. six 4-week cycles).

[0286] In embodiments, the subject achieves a complete response within 2-4 weeks after treatment.

[0287] In embodiments, the present disclosure provides a method of enhancing immune function in a subject suffering from AML, the method comprising administering to said subj ect, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8- 10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0288] In embodiments, the present disclosure provides a method for reducing the toxicity of Talabostat or a pharmaceutically acceptable salt thereof with a lower effective dose of Talabostat, the method comprising administering Talabostat or a pharmaceutically acceptable salt thereof to a subject suffering from AML (e.g., relapsed/ refractory AML), according to the treatment regimen described herein.

[0289] In embodiments, the present disclosure provides a method for reducing the toxicity of Talabostat or a pharmaceutically acceptable salt thereof with a lower effective dose of Talabostat, the method comprising administering Talabostat or a pharmaceutically acceptable salt thereof to a subject suffering from MDS (e.g., MDS-EB-2), according to the treatment regimen described herein.

[0290] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is Talabostat mesylate.

[0291] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered twice daily.

[0292] In embodiments, Talabostat or a pharmaceutically acceptable salt is administered in divided doses.

[0293] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof may be administered orally at a dose of about 0.2 mg twice daily of Talabostat in divided doses. In embodiments, Talabostat or a pharmaceutically acceptable salt thereof may be administered orally at a dose of about 0.3 mg twice daily in divided doses.

[0294] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof may be administered orally at a dose of about 0.4 mg of Talabostat twice daily in divided doses.

[0295] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof may be administered orally at a dose of about 0.6 mg of Talabostat twice daily in divided doses.

[0296] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof may be administered orally at a dose of about 0.8 mg of Talabostat twice daily in divided doses.

[0297] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered orally in the morning and evening (e.g. in form of one or more tablets).

[0298] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof may be administered as a morning dose (e.g. at about 5 am, about 6 am, about 7 am, about 8 am, about 9 am, about 10 am, or about 11 am) and as an evening dose (e.g. at about 5 pm, about 6 pm, about 7 pm, about 8 pm, about 9 pm, about 10 pm, or about 11 pm).

[0299] In embodiments, the subject is administered Talabostat or a pharmaceutically acceptable salt thereof for one or more treatment cycles. For example, in embodiments, the subject is administered Talabostat or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 treatment cycles. [0300] In embodiments, there is provided a treatment regimen for treating high-risk myelodysplastic syndrome (MDS) in a subject in need thereof, the regimen comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4- 7, 11-14,18-21 and 25-28 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0301] In embodiments, MDS is metastatic. In embodiments, the subject has a MDS at early stage or at late stage. In embodiments, the myelodysplastic syndrome is high-risk MDS-EB-2. [0302] In embodiments, the present disclosure provides a method of treating MDS-EB-2 in a subject in need thereof, said method comprising administering to said subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof (e.g. Talabostat mesylate) on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles followed by rest on days 4-7, 11-14, 18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration. [0303] In embodiments, there is provided a method of treating a subject having or suspected of having myelodysplastic syndrome (MDS), the method comprising: a) obtaining a biological sample from the subject; b) measuring DNA copy number of DPP9 gene in the biological sample, wherein if the DNA copy number of DPP9 gene is about 3 to about 13, administering to the subject an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0304] In embodiments, there is provided a method of treating a subject having or suspected of having myelodysplastic syndrome, the method comprising a) measuring level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL I 7RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 relative to an HPRT1 gene in a biological sample obtained from the subject and (b) administering to the subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, when the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30; AKT3 is in the range of about 0.02 to about 30; CARD9 is in the range of about 0.004 to about 40; CXCR4 is in the range of about 0.14 to about 150; EPCAM is in the range of about 0.00 to about 10; HLA-DMA is in the range of about 0.12 to about 10; HLA-DRA is in the range of about 0.58 to about 100; HLA-DRB3 is in the range of about 0.09 to about 30; IL17RA is in the range of about 0.2 to about 50; IL4R is in the range of about 0.03 to about 30; IL6R is in the range of about 1.18 to about 60; IRF8 is in the range of about 0.03 to about 60; ITGAL is in the range of about 2.16 to about 140; ITGB2 is in the range of about 6.5 to about 400; PSMB8 is in the range of about 3.0 to about 60 and TARP is in the range of about 0.0001 to about 300 as analyzed, for example, by qRT-PCR.

[0305] In embodiments, said treatment is administered for at least 12 weeks (e.g. three 4-week cycles), or at least 24 weeks (e.g. six 4-week cycles). In embodiments, said treatment is administered for at least 14 weeks, or at least 16 weeks. In embodiments, the subject achieves a complete response within 2-4 weeks after treatment.

[0306] In embodiments, Talabostat mesylate is administered in one or more cycles to provide a total daily dose of Talabostat from about 0.4 mg to about 1.6 mg.

[0307] In embodiments, the present disclosure provides a method of treating MDS-EB-2 in a subject in need thereof, the method comprising administering to the subject about 0.2 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0308] In embodiments, the present disclosure provides a method of treating MDS-EB-2 in a subject in need thereof, the method comprising administering to the subject about 0.3 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0309] In embodiments, the present disclosure provides a method of treating MDS-EB-2 in a subject in need thereof, the method comprising administering to the subject about 0.4 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0310] In embodiments, the present disclosure provides a method of treating MDS-EB-2 in a subject in need thereof, the method comprising administering to the subject about 0.6 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration. [0311] In embodiments, the present disclosure provides a method of treating MDS-EB-2 in a subject in need thereof, the method comprising administering to the subject about 0.8 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 of each treatment cycle, wherein each cycle is of 28-day duration.

[0312] In embodiments, MDS-EB-2 is refractory or relapsed MDS-EB-2.

[0313] In embodiments, provided herein is a method of delaying progression of or preventing or delaying of recurrence, of MDS-EB-2 in a subject, the method comprising administering to the subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles followed by a rest period on days 4-7, 11-14, 18-21 and 25-28 of each treatment cycle, wherein , each cycle is of about 28 days duration.

[0314] In embodiments, the treatment regimen of the present disclosure produces an increased innate immune response, wherein the innate immune response may be increased by infiltration of innate immune cells, in particular T-cells and NK-cells. In embodiments, the present treatment regimen produces suppression of the Treg function.

[0315] In embodiments, the treatment regimen described herein results in a sustained response in the subject after cessation of the treatment.

[0316] In embodiments Talabostat or a pharmaceutically acceptable salt thereof is Talabostat mesylate.

[0317] In embodiments, the subject is a human. In embodiments, the subject is >18 years old. [0318] In embodiments, the subject has not been previously treated with a biotherapeutic or chemotherapeutic agent, i.e., is treatment naive. In embodiments, the subject has experienced little or no improvement after prior therapy with a biotherapeutic or chemotherapeutic agent. In embodiments, the subject has relapsed or progressed after treatment with previous therapies. In embodiments, the subject has failed to achieve a sustained response after prior therapy with a biotherapeutic or chemotherapeutic agent or like, i.e., is treatment- experienced.

[0319] In embodiments, the subject experienced intolerable toxicity from prior treatment therapies.

[0320] In embodiments, the subject has an ECOG performance score <2. In embodiments, the subject has an ECOG performance score of 1.

[0321] In embodiments, the subject has an ECOG performance score of 2.

[0322] In embodiments, treatment regimen or the methods according any of the embodiments, Talabostat or a pharmaceutically acceptable salt thereof is optionally administered in combination with one or more anti-cancer agent or therapy, wherein one or more anti-cancer agent or therapy is selected from a group comprising any cancer SOC, radiotherapy, chemotherapy or immunotherapy or the like.

[0323] In embodiments, one or more anti-cancer agents may be selected from hypomethylating agents (e.g. 5-Azacitidine, Decitabine, Guadecitabine ), BCL-2 inhibitors (e.g. Venetoclax, Navitoclax, Obatoclax, Subatoclax, Maritoclax, Gossypol, Apogossypol, TW-37, UMI-77, and BDA-366) or combinations thereof.

[0324] In embodiments, the subject achieves a stable disease response or better as per International Working Group (IWG) and European Leukemia Net (ELN) criteria for AML.

[0325] In embodiments, the subject achieves a partial response or better as per International Working Group (IWG) and European Leukemia Net (ELN) criteria for AML.

[0326] In embodiments, the subject achieves a complete response.

[0327] In embodiments, the subject achieves a complete response with incomplete count recovery (CRi) as per International Working Group (IWG) and European Leukemia Net (ELN) criteria for AML.

[0328] In embodiments, the subject achieves a morphologic leukemia-free state (MLFS) In embodiments, the subject achieves a hematologic improvement (HI).

COMBINATION TREATMENT REGIMEN

[0329] In embodiments, provided herein is a treatment regimen for treating cancer in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Decitabine , wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days and each treatment cycle is of about 28 days duration.

[0330] In embodiments, provided herein is a treatment regimen for treating hematological cancer in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Decitabine , wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22- 24 in one or more treatment cycles, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days and each treatment cycle is of about 28 days duration. [0331] In embodiments, provided herein is a treatment regimen for treating acute myeloid leukemia in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Decitabine , wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22- 24 in one or more treatment cycles, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days and each treatment cycle is of about 28 days duration

[0332] In embodiments, there is provided a treatment regimen for treating cancer in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the 28-day treatment cycle.

[0333] In embodiments, there is provided a treatment regimen for treating hematological cancer in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15- 17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the 28- day treatment cycle.

[0334] In embodiments, there is provided a treatment regimen for treating acute myeloid leukemia in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15- 17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the 28- day treatment cycle. [0335] In embodiments, there is provided a treatment regimen for treating acute myeloid leukemia in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15- 17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 15 mg/m ² as continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the 28-day treatment cycle.

[0336] In embodiments, Decitabine is administered orally. In embodiments, Decitabine is administered as oral tablet.

[0337] In embodiments, provided herein is a treatment regimen for treating myelodysplastic syndrome in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Decitabine , wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22- 24 in one or more treatment cycles, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days and each treatment cycle is of about 28 days duration.

[0338] In embodiments, there is provided a treatment regimen for treating myelodysplastic syndrome (e.g. MDS- EB-2) in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the 28-day treatment cycle.

[0339] In embodiments, there is provided a treatment regimen for treating myelodysplastic syndrome in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15- 17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 15 mg/m ² as continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the 28-day treatment cycle.

[0340] In embodiments, Decitabine is administered once daily in an amount of about 30 mg to about 100 mg. In embodiments, Decitabine is administered once daily in an amount of about 35 mg. In embodiments, Decitabine is administered once daily on days 1-5 of a 28-day cycle. [0341] In embodiments, there is provided a treatment regimen for treating cancer in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 75 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the 28-day treatment cycle. [0342] In embodiments, there is provided a treatment regimen for treating hematological cancer in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 75 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the 28-day treatment cycle

[0343] In embodiments, there is provided a treatment regimen for treating acute myeloid leukemia in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15- 17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 75 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the 28-day treatment cycle.

[0344] In embodiments, there is provided a treatment regimen for treating acute myeloid leukemia in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 100 mg/m ² daily for seven days, every four weeks and Venetoclax is administered once daily in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of in 28-day treatment cycle.

[0345] In embodiments, there is provided a treatment regimen for treating myelodysplastic syndrome in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15- 17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 75 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of in 28-day treatment cycle.

[0346] In embodiments, there is provided a treatment regimen for treating myelodysplastic syndrome in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 100 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond, in the 28-day treatment cycle.

[0347] In embodiments, Azacitidine is administered orally. In embodiments, Azacitidine is administered as oral tablet. In embodiments, Azacitidine is administered once daily in an amount of about 200 mg. In embodiments, Azacitidine is administered once daily in an amount of about 300 mg. In embodiments, Azacitidine is administered once daily on Days 1 through 14 of each 28-day cycle.

[0348] In embodiments, provided herein is a treatment regimen for treating cancer in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration. [0349] In embodiments, provided herein is a treatment regimen for treating hematological cancer in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22- 24 in one or more treatment cycles and each treatment cycle is of about 28 days duration.

[0350] In embodiments, provided herein is a treatment regimen for treating acute myeloid leukemia in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22- 24 in one or more treatment cycles and each treatment cycle is of about 28 days duration [0351] In embodiments, provided herein is a treatment regimen for treating myelodysplastic syndrome in a subject in need thereof, the regimen comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22- 24 in one or more treatment cycles and each treatment cycle is of about 28 days duration [0352] In embodiments, Venetoclax is administered orally. In embodiments, Venetoclax is administered as oral tablet. In embodiments, Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg on day 3 and beyond of each treatment cycle. In embodiments, Venetoclax is administered in an amount of about 400 mg orally once daily of each 28- day cycle in combination with Azacitidine or Decitabine.

METHODS FOR DETECTION OF COPY NUMBER

[0353] Methods of evaluating the copy number of a biomarker nucleic acid are well known to those of skill in the art. The presence or absence of chromosomal gain or loss can be evaluated simply by a determination of copy number of the regions or markers identified herein.

[0354] In embodiment, a biological sample is tested for the presence of copy number changes in genomic loci containing the genomic marker. A copy number of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or higher is predictive of likelihood of subject with hematological cancer or any solid tumor/cancer to be responsive to the treatment with dipeptidyl peptidase (DPP) inhibitors. [0355] Methods of evaluating the copy number of a biomarker locus include, but are not limited to, hybridization-based assays. qPCR and next gen sequencing.

[0356] In embodiments, the DNA copy number of DPP9 gene is measured by RT-PCR, Multiplex ligation-dependent probe amplification (MLPA), Multiplex amplifiable probe hybridization (MAPH), Dynamic allele-specific hybridization (DASH), Comparative genomic hybridization (CGH), Oligonucleotides arrays, Genotype arrays or the like.

[0357] DNA copy number of DPP9 gene could be used as a predictive biomarker for the selection of patients for the treatment with DPP inhibitors. In embodiments, the DPP inhibitor is Talabostat or a pharmaceutically acceptable salt thereof.

PHARMACEUTICAL FORMULATION:

[0358] In embodiments, the present disclosure provides for use in the treatment regimen herein a pharmaceutical formulation comprising an effective amount of Talabostat or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers or adjuvants. Any of the pharmaceutically acceptable carriers or adjuvants described herein, or known in the art, may be used.

[0359] In embodiments, the formulation comprising Talabostat or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or adjuvants are administered according to the treatment regimen disclosed herein to produce an anti-cancer effect in treating a subject suffering from hematological cancer (e.g., AML or MDS-EB-2) [0360] The pharmaceutical formulations of the present disclosure may be formulated in a variety of ways, including for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. In embodiments, the compositions may be formulated as the injectable or infusible solutions. The formulation is in a form suitable for oral, intravenous, intraarterial, intramuscular, subcutaneous, parenteral, transmucosal, transdermal, or topical administration. The formulation may be formulated as an immediate, controlled, extended or delayed release composition.

[0361]

[0362] In general, such formulations typically comprise a pharmaceutically acceptable carrier or adjuvant. As used herein, the term “pharmaceutically acceptable" means approved by a government regulatory agency or listed in the U.S. Pharmacopoeia or another generally recognized pharmacopoeia for use in animals, particularly in humans.

[0363] In embodiments, the formulation comprising Talabostat or a pharmaceutically acceptable salt thereof may be administered orally.

[0364] Pharmaceutical formulations of Talabostat or a pharmaceutically acceptable salt thereof for oral use herein may be administered, for example, in the form of tablets, capsules, powders, dispersible granules, sachets etc., or as aqueous solutions or suspensions, preferably tablets. Oral compositions generally include an inert carrier (for example, diluent) or an edible carrier. The formulations may be enclosed in a gelatin capsule or compressed into a tablet. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the formulation. The tablets, pills, capsules, granules, sachets, troches and the like can contain any of the following ingredients, or compounds of a similar nature; a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, primogel, or com starch; a lubricant such as magnesium stearate or stearates; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0365] In embodiments, an oral pharmaceutical formulation comprising Talabostat pharmaceutically acceptable salt thereof described herein may comprise one or more pharmaceutically acceptable carriers or adjuvants selected from the group comprising a bulking agent, buffer, surfactant, and pH modifier. The pharmaceutical formulation may be adjusted to give an appropriate pH.

[0366] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof is formulated as a tablet for oral administration according to the treatment regimen of this disclosure. The pharmaceutical tablet may be an immediate release or a modified release tablet. Tablet may be in the form of matrix or coated form.

[0367] In embodiments, the above-mentioned formulations or compositions can be manufactured by any of the processes known in the art.

[0368] An exemplary immediate release tablet comprises an effective amount of Talabostat or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers selected from diluents, binders, disintegrants, glidants, lubricants, pH modifying agents and combinations thereof.

[0369] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof may be formulated as a modified release matrix tablet. An exemplary extended-release tablet comprises an effective amount of Talabostat or a pharmaceutically acceptable salt thereof and pharmaceutically-acceptable carrier or adjuvant are selected from the diluents, binders, modified release material, glidants, lubricants, colorants and combinations thereof. Alternatively, a modified release tablet comprises immediate release core and coating wherein said coating comprises modified release material and other pharmaceutical excipients. [0370] In embodiments, the amount of Talabostat in a unit dose is about 0.2 mg per tablet, 0.4 mg per tablet, about 0.6 mg per tablet, about 0.8 mg per tablet, about 1.0 mg per tablet, about 1.2 mg per tablet, about 1.4 mg per tablet, and about 1.6 mg per tablet.

[0371] Various methods can be used for manufacturing tablets of Talabostat or a pharmaceutically acceptable salt thereof for use in the treatment regimen of this disclosure. One process includes dissolving Talabostat in a suitable solvent (with or without binder) and this solution is distributed uniformly over filler particles (which may contain other materials) to form agglomerated parti cles/granules. Wet granulation, coating or spraying processes can also be used. Granules may be appropriately sized or may be further processed by a dry granulation/slugging/roller compaction method followed by a milling step to achieve suitable granules of specific particle size distribution. The sized granules may be further blended with other components and/or and then lubricated in a suitable blender and compressed into tablets of specific dimensions using appropriate tooling. Coating of the tablets, where appropriate, may be performed using conventional methods and standard equipment.

[0372] In embodiments, Talabostat or a pharmaceutically acceptable salt thereof can also be entrapped in microcapsules. Such microcapsules are prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatinmicrocapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions as described in Remington: The Science and Practice of Pharmacy, 22. sup. nd Edition, 2012, Pharmaceutical Press, London.

[0373] In embodiments, pharmaceutical formulations include liposomes. Methods to produce liposomes are known to those of skill in the art. For example, some liposomes can be generated by reverse phase evaporation with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes can be extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0374] In embodiments, sustained-release preparations comprising active drug (e.g. Talabostat) described herein can be produced. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing a drug conjugate, where the matrices are in the form of shaped articles (e.g., films or microcapsules). Examples of sustained-release matrices include polyesters, hydrogels such as poly(2- hydroxyethyl-methacrylate) or poly(vinyl alcohol), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid- glycolic acid copolymers such as the LUPRON DEPOT. TM. (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

OUTCOME:

[0375] Subjects suffering from hematological cancers administered DPP inhibitor or a pharmaceutically acceptable salt thereof according to the treatment regimen disclosed herein preferably experience improvement in transfusion frequency, peripheral blast reduction or symptom improvement of hematological cancer. In embodiments, improvement may be measured by a reduction in the quantity and/or size of measurable tumor lesions.

[0376] In embodiments, the DPP inhibitor is a DPP2/DPP4/DPP8/DPP9/FAP inhibitor.

[0377] In embodiments, the DPP inhibitor is Talabostat or a pharmaceutically acceptable salt thereof (e g. Talabostat mesylate).

[0378] In embodiments, the hematological cancer is selected from leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN) and multiple myeloma.

[0379] In embodiments, the haematological cancer is acute myeloid leukemia.

[0380] Subjects suffering from AML (e.g., relapsed/refractory AML) administered Talabostat or a pharmaceutically acceptable salt thereof according to the treatment regimen disclosed herein preferably experience improvement in transfusion frequency, peripheral blast reduction or symptom improvement of AML. In embodiments, improvement may be measured by a reduction in the quantity and/or size of measurable tumor lesions.

[0381] In embodiment, lesions can be measured using X-rays or CT or MRI scans.

[0382] In embodiment, improvement may be measured by an inhibition of tumor growth in AML.

[0383] In embodiment, extension of progression free survival and/or overall survival may be provided to a subject suffering from AML (e g., relapsed/refractory AML).

[0384] In embodiments, the anti-cancer response is cytotoxic effect in AML, a clinical response, a decrease in AML specific biomarkers, an increase in T-cells, NK cells and monocytic/myeloid cells and increase in anti-cancer cytokines or a combination thereof.

[0385] In embodiments, the initiating, sustaining or enhancing an anti-cancer immune response is for the treatment of AML. In embodiments, the anti-tumor response is reduction in metastasis, delay in metastasis or prevention of metastasis. [0386] In embodiments, the anti-cancer response is inducing tumor cell death, AML regression, preventing or delaying AML recurrence or AML elimination.

[0387] In embodiments, subjects suffering from AML (e.g., relapsed/refractory AML) administered Talabostat or a pharmaceutically acceptable salt thereof according to the treatment regimen disclosed herein may exhibit a complete remission (CR), complete response with incomplete count recovery (CRi), partial response (PR), morphologic leukemia-free state (MLFS) and hematologic improvement (HI).

[0388] In embodiment, subjects suffering from AML (e.g., relapsed/refractory AML) administered Talabostat or a pharmaceutically acceptable salt thereof according to the treatment regimen disclosed herein exhibit hematologic improvement.

[0389] In embodiment, subjects suffering from AML (e.g., relapsed/refractory AML) administered Talabostat or a pharmaceutically acceptable salt thereof according to the treatment regimen disclosed herein exhibit morphologic leukemia-free state (MLFS)..

[0390] In embodiments, subjects suffering from AML (e.g., relapsed/refractory AML) administered Talabostat or a pharmaceutically acceptable salt thereof according to the treatment regimen disclosed herein may experience reduced or inhibited AML growth.

[0391] In embodiments, one or more of the following may occur in subjects suffering from AML (e.g. relapsed/refractory AML) when administered with Talabostat or a pharmaceutically acceptable salt thereof according to the treatment regimen disclosed herein: the number of cancer cells may be reduced, retarded, slowed, or stopped AML growth; recurrence of AML may be prevented or delayed; one or more of the symptoms associated with AML may be alleviated.

[0392] Subjects suffering from MDS (e.g., MDS EB-2) administered Talabostat or a pharmaceutically acceptable salt thereof according to the treatment regimen disclosed herein preferably experience improvement in transfusion frequency, peripheral blast reduction or symptom improvement of MDS. In embodiments, improvement may be measured by a reduction in the quantity and/or size of measurable tumor lesions.

[0393] In embodiment, extension of progression free survival and/or overall survival may be provided to a subject suffering from MDS.

[0394] In embodiments, the anti-cancer response is cytotoxic effect in MDS, a clinical response, a decrease in MDS specific biomarkers, an increase in T-cells, NK cells and monocytic/myeloid cells and increase in anti-cancer cytokines or a combination thereof. [0395] In embodiments, the initiating, sustaining or enhancing an anti-cancer immune response is for the treatment of MDS. In embodiments, the anti-tumor response is reduction in metastasis, delay in metastasis or prevention of metastasis.

[0396] In embodiments, the anti-cancer response is inducing tumor cell death, MDS regression, preventing or delaying MDS recurrence or MDS elimination.

[0397] In embodiments, subjects suffering from MDS administered Talabostat or a pharmaceutically acceptable salt thereof according to the treatment regimen disclosed herein may exhibit a complete remission (CR), complete response with incomplete count recovery (CRi), partial response (PR), morphologic leukemia-free state (MLFS) and hematologic improvement (HI).

[0398] In embodiment, subjects suffering from MDS administered Talabostat or a pharmaceutically acceptable salt thereof according to the treatment regimen disclosed herein exhibit hematologic improvement.

[0399] In embodiment, subjects suffering from MDS administered Talabostat or a pharmaceutically acceptable salt thereof according to the treatment regimen disclosed herein exhibit morphologic leukemia-free state (MLFS).

[0400] In embodiments, subjects suffering from MDS administered Talabostat or a pharmaceutically acceptable salt thereof according to the treatment regimen disclosed herein may experience reduced or inhibited MDS growth.

[0401] In embodiments, one or more of the following may occur in subjects suffering from MDS (e.g. MDS EB-2) when administered with Talabostat or a pharmaceutically acceptable salt thereof according to the treatment regimen disclosed herein: the number of cancer cells may be reduced;, retarded, slowed, or stopped MDS growth; recurrence of MDS may be prevented or delayed; one or more of the symptoms associated with MDS may be alleviated.

[0402] In embodiments, the treatment regimen of the present disclosure may result in the CD8+ T cells in the subject having enhanced priming, activation, proliferation and/or cytolytic activity after administration of Talabostat or a pharmaceutically acceptable salt thereof.

[0403] In embodiments, the number of T-cells (CD45, CD3, CD4, and CD8), NK-cells (CD56), and monocytic/myeloid cells (CD14, CD16, CDl lb, HLA-DR) is elevated after administration of Talabostat or a pharmaceutically acceptable salt thereof.

[0404] In embodiments, the cancer has increased levels of NK cells (CD56) in the presence of Talabostat or a pharmaceutically acceptable salt thereof when used according to the treatment regimen described herein. [0405] In embodiments, the number of CD4+ and/or CD8+ T cells is elevated after administration of Talabostat or a pharmaceutically acceptable salt thereof.

[0406] In embodiments, the activated CD4+ and/or CD8+ T cells is characterized by y-IFN+ producing CD4+ and/or CD8+ T cells and/or enhanced cytolytic activity relative to prior to the administration of Talabostat or a pharmaceutically acceptable salt thereof.

[0407] In embodiments, T cells exhibit increased release of cytokines selected from the group consisting of G-CSF, GM-CSF, IFN-gamma, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-18, MIP-1 alpha, MIP-1 beta, MCP-1, TNF-alpha, TNF-beta, BDNF, Eotaxin-1, Factor VII, ICAM-1, IL-1 alpha, IL-1 beta, IL- Ira, IL-12p40, IL-12p70, IL-15, IL- 17, IL-23, MMP-3, MMP-9, SCF and VEGF.

[0408] In embodiments, the CD4+ and/or CD8+ T cells exhibit increased release of cytokines selected from the group consisting of G-CSF, MCP-1, Eotaxin, IFN-g, TNF-a and interleukins (IL-5, IL-6, IL-Ib, IL-12p70, IL 18).

[0409] In embodiments, the CD4+ and/or CD8+ T cell is an effector memory T cell. In embodiments, the CD4+ and/or CD8+ effector memory T cell is characterized by IFN+ producing CD4+ and/or CD8+ T cells and/or enhanced cytolytic activity.

[0410] In embodiments, the serum levels of cytokine IL-18 and/or chemokine GM- CSF, G- CSF in the subject are increased in the presence of Talabostat or a pharmaceutically acceptable salt thereof.

[0411] In embodiments, subjects suffering from AML have elevated levels of T-cell infiltration when Talabostat or a pharmaceutically acceptable salt thereof is administered according to the treatment regimen described herein.

[0412] In embodiments, subjects suffering from AML have suppressed/decreased levels of T- regulatory cells (Treg cells) in the presence of Talabostat or a pharmaceutically acceptable salt thereof when used according to the treatment regimen described herein.

[0413] In embodiments, subjects suffering from MDS have elevated levels of T-cell infiltration when Talabostat or a pharmaceutically acceptable salt thereof is administered according to the treatment regimen described herein.

[0414] In embodiments, subjects suffering from MDS have suppressed/decreased levels of T- regulatory cells (Treg cells) in the presence of Talabostat or a pharmaceutically acceptable salt thereof when used according to the treatment regimen described herein.

[0415] The treatment regimen or the methods described herein may result in an inhibition of tumor size more than about 10%, more than about 20%, more than about 21%, more than about 22%, more than about 23%, more than about 24%, more than about 25%, more than about 26%, more than about 27%, more than about 28%, more than about 29%, more than about 30%, more than about 31%, more than about 32%, more than about 33%, more than about 34%, more than about 35%, more than about 36%, more than about 37%, more than about 38%, more than about 39%, more than about 40%, more than about 41%, more than about 42%, more than about 43%, more than about 44%, more than about 45%, more than about 46%, more than about 47%, more than about 48%, more than about 49%, more than about 50%, more than about 51%, more than about 52%, more than about 53%, more than about 54%, more than about 55%, more than about 56%, more than about 57%, more than about 58%, more than about 59%, more than about 60%, more than about 61%, more than about 62%, more than about 63%, more than about 64%, more than about 65%, more than 66%, more than 67%, more than about 68%, more than about 69%, more than about 70%, more than about 71%, more than about 72%, more than about 73%, more than about 74%, more than about 75%, more than about 76%, more than about 77%, more than about 78%, more than about 79%, more than about 80%, more than about 81%, more than about 82%, more than about 83%, more than about 84%, more than about 85%, more than about 86%, more than about 87%, more than about 88%, more than about 89%, more than about 90%, more than about 91%, more than about 92%, more than about 93%, more than about 94%, more than about 95%, more than about 96%, more than about 97%, more than about 98%, more than about 99% up to about

100%.

[0416] In embodiments, the treatment regimen or the methods described herein can result in an increase (e.g., a 1% to 400%, 1% to 380%, 1% to 360%, 1% to 340%, 1% to 320%, 1% to 300%, 1% to 280%, 1% to 260%, 1% to 240%, 1% to 220%, 1% to 200%, 1% to 180%, 1% to 160%, 1% to 140%, 1% to 120%, 1% to 100%, 1% to 95%, 1% to 90%, 1% to 85%, 1% to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 400%, 5% to 380%, 5% to 360%, 5% to 340%, 5% to 320%, 5% to 300%, 5% to 280%, 5% to 260%, 5% to 240%, 5% to 220%, 5% to 200%, 5% to 180%, 5% to 160%, 5% to 140%, 5% to 120%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 10%, 10% to 400%, 10% to 380%, 10% to 360%, 10% to 340%, 10% to 320%, 10% to 300%, 10% to 280%, 10% to 260%, 10% to 240%, 10% to 220%, 10% to 200%, 10% to 180%, 10% to 160%, 10% to 140%, 10% to 120%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 20% to 400%, 20% to 380%, 20% to 360%, 20% to 340%, 20% to 320%, 20% to 300%, 20% to 280%, 20% to 260%, 20% to 240%, 20% to 220%, 20% to 200%, 20% 180%, 20% to 160%, 20% to 140%, 20% to 120%, 20% to 100%, 20% to 90%, 20% to 80%,% to 70%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 400%, 30% to0%, 30% to 360%, 30% to 340%, 30% to 320%, 30% to 300%, 30% to 280%, 30% to 260%,% to 240%, 30% to 220%, 30% to 200%, 30% to 180%, 30% to 160%, 30% to 140%, 30% 120%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%,% to 40%, 40% to 400%, 40% to 380%, 40% to 360%, 40% to 340%, 40% to 320%, 40% 300%, 40% to 280%, 40% to 260%, 40% to 240%, 40% to 220%, 40% to 200%, 40% to0%, 40% to 160%, 40% to 140%, 40% to 120%, 40% to 100%, 40% to 90%, 40% to 80%,% to 70%, 40% to 60%, 40% to 50%, 50% to 400%, 50% to 380%, 50% to 360%, 50% to0%, 50% to 320%, 50% to 300%, 50% to 280%, 50% to 260%, 50% to 240%, 50% to 220%,% to 200%, 50% to 180%, 50% to 160%, 50% to 140%, 50% to 140%, 50% to 120%, 50% 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 400%, 60% to 380%,% to 360%, 60% to 340%, 60% to 320%, 60% to 300%, 60% to 280%, 60% to 260%, 60% 240%, 60% to 220%, 60% to 200%, 60% to 180%, 60% to 160%, 60% to 140%, 60% to0%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 400%, 70% to 380%,% to 360%, 70% to 340%, 70% to 320%, 70% to 300%, 70% to 280%, 70% to 260%, 70% 240%, 70% to 220%, 70% to 200%, 70% to 180%, 70% to 160%, 70% to 140%, 70% to0%, to 100%, 70% to 90%, 70% to 80%, 80% to 400%, 80% to 380%, 80% to 360%, 80% 340%, 80% to 320%, 80% to 300%, 80% to 280%, 80% to 260%, 80% to 240%, 80% to0%, 80% to 200%, 80% to 180%, 80% to 160%, 80% to 140%, 80% to 120%, 80% to 100%,% to 90%, 90% to 400%, 90% to 380%, 90% to 360%, 90% to 340%, 90% to 320%, 90% 300%, 90% to 280%, 90% to 260%, 90% to 240%, 90% to 220%, 90% to 200%, 90% to0%, 90% to 160%, 90% to 140%, 90% to 120%, 90% to 100%, 100% to 400%, 100% to0%, 100% to 360%, 100% to 340%, 100% to 320%, 100% to 300%, 100% to 280%, 100% 260%, 100% to 240%, 100% to 220%, 100% to 200%, 100% to 180%, 100% to 160%, 100% 140%, 100% to 120%, 120% to 400%, 120% to 380%, 120% to 360%, 120% to 340%, 120% 320%, 120% to 300%, 120% to 280%, 120% to 260%, 120% to 240%, 120% to 220%, 120% 200%, 120% to 180%, 120% to 160%, 120% to 140%, 140% to 400%, 140% to 380%, 140% 360%, 140% to 340%, 140% to 320%, 140% to 300%, 140% to 280%, 140% to 260%, 140% 240%, 140% to 220%, 140% to 200%, 140% to 180%, 140% to 160%, 160% to 400%, 160% 380%, 160% to 360%, 160% to 340%, 160% to 320%, 160% to 300%, 160% to 280%, 160% 260%, 160% to 240%, 160% to 220%, 160% to 200%, 160% to 180%, 180% to 400%, 180% 380%, 180% to 360%, 180% to 340%, 180% to 320%, 180% to 300%, 180% to 280%, 180% 260%, 180% to 240%, 180% to 220%, 180% to 200%, 200% to 400%, 200% to 380%, 200% to 360%, 200% to 340%, 200% to 320%, 200% to 300%, 200% to 280%, 200% to 260%, 200% to 240%, 200% to 220%, 220% to 400%, 220% to 380%, 220% to 360%, 220% to 340%, 220% to 320%, 220% to 300%, 220% to 280%, 220% to 260%, 220% to 240%, 240% to 400%, 240% to 380%, 240% to 360%, 240% to 340%, 240% to 320%, 240% to 300%, 240% to 280%, 240% to 260%, 260% to 400%, 260% to 380%, 260% to 360%, 260% to 340%, 260% to 320%, 260% to 300%, 260% to 280%, 280% to 400%, 280% to 380%, 280% to 360%, 280% to 340%, 280% to 320%, 280% to 300%, 300% to 400%, 300% to 380%, 300% to 360%, 300% to 340%, or 300% to 320%) in the time of survival of the patient (e.g., as compared to a patient having a similar cancer and administered a different treatment or not receiving a treatment).

[0417] The response evaluation is performed as per AML response criteria.

KITS:

[0418] In embodiments, provided herein are kits useful for determining the likelihood of a subject with hematological cancer to be responsive to the treatment with DPP inhibitor.

[0419] In embodiments, a kit for detecting whether a subject having a hematological cancer is sensitive to the treatment with a DPP inhibitor, wherein the kit comprises means/reagents for quantifying DNA copy number of DPP9 gene in a sample of the subject.

[0420] In embodiments, a kit for detecting whether a subject having a hematological cancer is sensitive to the treatment with a DPP inhibitor, wherein the kit comprises means/reagents for measuring target gene and genes involved in immune pathways expression levels in a biological sample of the subject relative to an HPRT1 gene.

[0421] Examples of reagents to facilitate detection of at least one biomarker in a biological sample can include internal standards and solvents (e.g., chloroform/methanol) capable of extracting biomarkers from a biological sample, which are also compatible with mass spectroscopy.

[0422] Such kits can additionally or optionally include a biological sample collection means, such as a syringe, scalpel, swab, tweezers, or the like.

[0423] In embodiments, the kits provided herein employ means for detecting the expression of a biomarker by qPCR, microarray, or next gen sequencing.

[0424] In embodiments, the kit includes a formulation comprising Talabostat or pharmaceutically acceptable salt thereof with or without instructions for use.

[0425] In embodiments, the kit comprises a package insert comprising instructions for using Talabostat or pharmaceutically acceptable salt thereof to treat or delay progression of hematological cancer (e.g. AML/MDS-EB-2) in a subject or to enhance immune function of a subject having cancer.

[0426] In embodiments, the kit comprises a container that includes, but is not limited to bottles, vials (e.g., dual chamber vials), syringes (such as single or dual chamber syringes) and test tubes.

[0427] The container may be formed from a variety of materials such as glass or plastic.

[0428] In embodiments, the kit may comprise a label (e.g., on or associated with the container) or a package insert. The label or the package insert may indicate that the compound contained therein may be useful or intended for treating or delaying progression of hematological cancer (e.g. AML/MDS-EB-2) in a subject or for enhancing immune function of a subject.

SPECIFIC EMBODIMENTS:

[0429] Embodiment 1. A treatment regimen for treating cancer in a subject in need thereof, comprising administering to said subject, an effective amount of dipeptidyl peptidase (DPP) inhibitor on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration

[0430] Embodiment 2. A method of treating a subject having or suspected of having a cancer, the method comprising: a) measuring DNA copy number of DPP9 gene in a biological sample obtained from the subject,

(b) if the DNA copy number of DPP9 gene is between about 3 and about 50, administering to the subject an effective amount of the DPP inhibitor on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0431] Embodiment 3. A method of enhancing immune function in a subject suffering from hematological cancer, the method comprising administering to said subject, an effective amount of a DPP inhibitor on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0432] Embodiment 4. A method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor, the method comprising a) measuring level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP, or PSMB8 in a biological sample obtained from the subject; and b) administering to the subject an effective amount of the DPP inhibitor on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, if the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30; AKT3 is in the range of about 0.02 to about 30; CARD9 is in the range of about 0.004 to about 40; CXCR4 is in the range of about 0.14 to about 150; EPCAM is in the range of about 0.00 to about 10; HLA-DMA is in the range of about 0.12 to about 10; HLA-DRA is in the range of about 0.58 to about 100; HLA-DRB3 is in the range of about 0.09 to about 30; IL17RA is in the range of about 0.2 to about 50; IL4R is in the range of about 0.03 to about 30; IL6R is in the range of about 1.18 to about 60; IRF8 is in the range of about 0.03 to about 60; ITGAL is in the range of about 2.16 to about 140; ITGB2 is in the range of about 6.5 to about 400; PSMB8 is in the range of about 3.0 to about 60, or TARP is in the range of about 0.0001 to about 300.

[0433] Embodiment 5. The treatment regimen according to embodiment 1 or the method according to any of embodiments 2 to 4, wherein the cancer is a hematological cancer selected from a group consisting of leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms

(MPN) and multiple myeloma.

[0434] Embodiment 6. The treatment regimen or the method according to embodiment 5, wherein the hematological cancer is acute myeloid leukemia.

[0435] Embodiment 7. The treatment regimen or the method according to embodiment 6, wherein the acute myeloid leukemia is refractory AML or relapsed AML.

[0436] Embodiment 8. The treatment regimen or the method according to embodiment 5, wherein the hematological cancer is myelodysplastic syndrome (MDS).

[0437] Embodiment 9. The treatment regimen or the method according to embodiment 8, wherein myelodysplastic syndrome includes MDS with multilineage dysplasia (MDS-MLD), MDS with single lineage dysplasia (MDS-SLD), MDS with excess blasts (MDS-EB-1 and MDS-EB-2), MDS with ring sideroblasts (MDS-RS), MDS with isolated del(5q) and MDS, and unclassifiable (MDS-U).

[0438] Embodiment 10. The treatment regimen or the method according to embodiment 8 or 9, wherein myelodysplastic syndrome is MDS-EB-2. [0439] Embodiment 11. The treatment regimen according to embodiment 1 or the method according to any of embodiments 2 to 4, wherein after cessation of treatment said subject maintains a sustained response to progression of the cancer.

[0440] Embodiment 12. The treatment regimen according to embodiment 1 or the method according to any of embodiments 2 to 4, wherein the DPP inhibitor is a DPP2/DPP4/DPP8/DPP9/FAP inhibitor.

[0441] Embodiment 13. The treatment regimen or the method according to embodiment 12, wherein the DPP2/DPP4/DPP8/DPP9/FAP inhibitor is Talabostat or a pharmaceutically acceptable salt thereof.

[0442] Embodiment 14. The treatment regimen or the method according to embodiment 13, wherein Talabostat or a pharmaceutically acceptable salt thereof is Talabostat mesylate.

[0443] Embodiment 15. The method according to embodiment 2, wherein the DNA copy number of DPP9 gene is about 3 to 13.

[0444] Embodiment 16. The treatment regimen or the method according to embodiment 13, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered orally in the morning and evening.

[0445] Embodiment 17. The treatment regimen or the method according to embodiment 16, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered orally as one or more tablets.

[0446] Embodiment 18. The treatment regimen according to embodiment 1 or the method according to any of embodiments 2 to 4, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of from about 0.4 mg to about 2.0 mg of Talabostat.

[0447] Embodiment 19. The treatment regimen or the method according to embodiment 18, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of from about 0.6 mg to about 1.6 mg of Talabostat.

[0448] Embodiment 20. The treatment regimen according to embodiment 1 or the method according to any of embodiments 2 to 4, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.2 mg of Talabostat twice daily.

[0449] Embodiment 21. The treatment regimen according to embodiment 1 or the method according to any of embodiments 2 to 4, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg of Talabostat twice daily. [0450] Embodiment 22. The treatment regimen according to embodiment 1 or the method according to any of embodiments 2 to 4, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.4 mg of Talabostat twice daily.

[0451] Embodiment 23. The treatment regimen according to embodiment 1 or the method according to any of embodiments 2 to 4, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.6 mg of Talabostat twice daily.

[0452] Embodiment 24. The treatment regimen according to embodiment 1 or the method according to any of embodiments 2 to 4, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.8 mg twice daily

[0453] Embodiment 25. The treatment regimen according to embodiment 1 or the method according to any of embodiments 2 to 4, wherein Talabostat or a pharmaceutically acceptable salt thereof is Talabostat mesylate.

[0454] Embodiment 26. The treatment regimen according to embodiment 1 or the method according to any of embodiments 2 to 4, wherein the administration is followed by a rest period on days 4 to 7, 11 to 14, 18 to 21 and 25 to 28 in a 4-week treatment cycle.

[0455] Embodiment 27. The treatment regimen for treating myelodysplastic syndrome in a subject in need thereof according to embodiment 26, wherein the regimen comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4- 7, 11-14,18-21 and 25-28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration.

[0456] Embodiment 28. The treatment regimen or the method according to any of the preceding embodiments, wherein the assay selected from quantitative polymerase chain reaction (qPCR) and next gen sequencing assay is performed to measure DNA copy number and level of expression of genes.

[0457] Embodiment 29. The treatment regimen or the method according to any of the preceding embodiments, wherein the subject is not previously treated with any chemotherapy. [0458] Embodiment 30. The treatment regimen or the method according to any of the preceding embodiments, wherein the subject has relapsed after treatment with previous chemotherapy.

[0459] Embodiment 31. The treatment regimen or the method according to any of the preceding claims, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered optionally in combination with one or more additional anticancer agents. [0460] Embodiment 32. The treatment regimen or the method according to any of the preceding embodiments, wherein one or more additional anticancer agents are selected from the group comprising hypomethylating agents, BCL-2 inhibitors or combinations thereof [0461] Embodiment 33. A method of treating acute myeloid leukemia in a subject, the method comprising administering to said subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax.

[0462] Embodiment 34. The method according to embodiment 33, wherein the Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days.

[0463] Embodiment 35. The method according to embodiment 33, wherein the Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days starting on day 1.

[0464] Embodiment 36. The method according to embodiment 33, wherein Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2, and about 400 mg once daily on day 3 and beyond of the treatment cycle.

[0465] Embodiment 37. A method of treating acute myeloid leukemia in a subject, the method comprising administering to said subject an effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 75 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the treatment cycle.

[0466] Embodiment 38. A method of treating myelodysplastic syndrome in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 20 mg/m ² as continuous intravenous infusion over 1 hour daily for 5 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the treatment cycle.

[0467] Embodiment 39. A method of treating myelodysplastic syndrome in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 75 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the treatment cycle.

[0468] Embodiment 40. The treatment regimen or the method according to any of the preceding embodiments, wherein the subject achieves a stable disease response or better as per International Working Group (IWG) and European Leukemia Net (ELN) criteria for AML.

[0469] Embodiment 41. The treatment regimen or the method according to any of the preceding embodiments, wherein the subject achieves a partial response or better as per International Working Group (IWG) and European Leukemia Net (ELN) criteria for AML.

[0470] Embodiment 42. The treatment regimen or the method according to any of the preceding embodiments, wherein the subject achieves a complete response or complete response with incomplete count recovery (CRi) as per International Working Group (IWG) and European Leukemia Net (ELN) criteria for AML.

[0471] Embodiment 43. The treatment regimen or the method according to any of the preceding embodiments, wherein the subject achieves a morphologic leukemia-free state (MLFS) or hematologic improvement (HI)

[0472] Embodiment 44. A method of treating a subject having or suspected of having a cancer, the method comprising: a) measuring DNA copy number of DPP9 gene in the biological sample;

(b) if the DNA copy number of DPP9 gene is about 3 to about 13, administering to the subject an effective amount of the DPP inhibitor on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0473] Embodiment 45. A method of treating a subject with a cancer using a dipeptidyl peptidase (DPP) inhibitor, the method comprising: a) measuring level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, 1L17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 relative to an HPRT1 gene and;

(b) administering to the subject an effective amount of the DPP inhibitor (e.g. Talabostat) on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, when the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30; AKT3 is in the range of about 0.02 to about 30; CARD9 is in the range of about 0.004 to about 40; CXCR4 is in the range of about 0.14 to about 150; EPC AM is in the range of about 0.00 to about 10; HLA-DMA is in the range of about 0.12 to about 10; HLA-DRA is in the range of about 0.58 to about 100; HLA-DRB3 is in the range of about 0.09 to about 30; IL17RA is in the range of about 0.2 to about 50; IL4R is in the range of about 0.03 to about 30; IL6R is in the range of about 1.18 to about 60; IRF8 is in the range of about 0.03 to about 60; ITGAL is in the range of about 2.16 to about 140; ITGB2 is in the range of about 6.5 to about 400; PSMB8 is in the range of about 3.0 to about 60 and TARP is in the range of about 0.0001 to about 300 as analyzed, for example, by qRT-PCR

[0474] Embodiment 45. The method of embodiment 44, wherein an increase of about 2-1000- fold in expression level of one or more genes in a biological sample of the subject is indicative of likelihood that subject will respond favorably to DPP inhibitor.

[0475] Embodiment 46 The method of embodiment 44 or 45, wherein the expression levels are relative to a subject who is non-responsive to therapy.

[0476] Embodiment 47. The method of embodiments 44 to 46, wherein the expression of one or more genes is measured at the mRNA level.

[0477] Embodiment 48. The method according to embodiment 44, wherein administration is followed by a rest period (no dose of DPP inhibitor is given) on days 4-7, 11-14, 18-21 and 25- 28 in the 28-day treatment cycle.

[0478] Embodiment 49. A treatment regimen for treating haematological cancer in a subj ect in need thereof, comprising administering to said subject, an effective amount of a DPP inhibitor on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0479] Embodiment 50. A treatment regimen for treating haematological cancer in a subject in need thereof, the regimen comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0480] Embodiment 51. A method for treating haematological cancer in a subject in need thereof, the method comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14, 18-21 and 25-28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration. [0481] Embodiment 52. A method of treating a subject with haematological cancer using a dipeptidyl peptidase (DPP) inhibitor, the method comprising: a) performing assay to measure DNA copy number of DPP9 gene in the biological sample and b) administering to the subject an effective amount of the DPP inhibitor on days 1- 3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, if the DNA copy number of the DPP9 gene is equal to or higher than 3.

[0482] Embodiment 53. A method of treating a subject with a haematological cancer using a dipeptidyl peptidase (DPP) inhibitor, the method comprising: a) performing assay to. measure level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA- DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 relative to an HPRT1 gene and (b ) administering to the subject an effective amount of the DPP inhibitor (e.g. Talabostat) on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, when the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30; AKT3 is in the range of about 0.02 to about 30; CARD9 is in the range of about 0.004 to about 40; CXCR4 is in the range of about 0.14 to about 150; EPCAM is in the range of about 0.00 to about 10; HLA-DMA is in the range of about 0.12 to about 10; HLA-DRA is in the range of about 0.58 to about 100; HLA-DRB3 is in the range of about 0.09 to about 30; IL17RA is in the range of about 0.2 to about 50; IL4R is in the range of about 0.03 to about 30; IL6R is in the range of about 1.18 to about 60; IRF8 is in the range of about 0.03 to about 60; ITGAL is in the range of about 2.16 to about 140; ITGB2 is in the range of about 6.5 to about 400; PSMB8 is in the range of about 3.0 to about 60 and TARP is in the range of about 0.0001 to about 300 as analyzed, for example, by qRT- PCR

[0483] Embodiment 54. The treatment regimen according to embodiments 49-50 or the method according to any of embodiments 51- 53, wherein said administration is followed by a rest period (no dose of Talabostat is given) on days 4-7, 11-14, 18-21 and 25-28 in the 28-day treatment cycle. [0484] Embodiment 55. The treatment regimen according to embodiments 49-50 or the method according to any of embodiments 51-53, wherein the DPP inhibitor is DPP2/DPP4/DPP8/DPP9/FAP inhibitor.

[0485] Embodiment 56. The treatment regimen or the method according to embodiment 55, wherein the DPP2/DPP4/DPP8/DPP9/FAP inhibitor is Talabostat or a pharmaceutically acceptable salt thereof, preferably Talabostat mesylate.

[0486] Embodiment 57. A method of treating a subject having or suspected of having a haematological cancer, the method comprising: a) performing assay to measure DNA copy number of DPP9 gene in the biological sample wherein if the DNA copy number of DPP9 gene between about 3 and about 50, such value is indicative of likelihood that subject will respond favorably to Talabostat or a pharmaceutically acceptable salt thereof; b) administering to the subject an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0487] Embodiment 58. A method of treating a subject having or suspected of having a haematological cancer, the method comprising: a) performing assay to measure DNA copy number of DPP9 gene in the biological sample wherein if the DNA copy number of DPP9 gene is about 3 to about 13, such value is indicative of likelihood that subject will respond favorably to Talabostat or a pharmaceutically acceptable salt thereof; b) administering to the subject an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0488] Embodiment 59. The method according to embodiment 57 or 58, wherein said administration is followed by a rest period (no dose of Talabostat is given) on days 4 -7, 11- 14, 18-21 and 25-28 in the 28-day treatment cycle.

[0489] Embodiment 60. A method of enhancing immune function in a subject suffering from haematological cancer, the method comprising administering to the subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration.

[0490] Embodiment 61. A method of enhancing immune function in a subject suffering from hematological cancer, the method comprising administering to the subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14,18-21 and 25-28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration.

[0491] Embodiment 62. The treatment regimen or the method according to any of embodiments 49 to 61, wherein the hematological cancer is selected from a group consisting of leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN) and multiple myeloma.

[0492] Embodiment 63. The treatment regimen or the method according to any of embodiments 49 to 61, wherein the hematological cancer is acute myeloid leukemia.

[0493] Embodiment 64. The treatment regimen or the method according to embodiment 63, wherein the acute myeloid leukemia is refractory AML or relapsed AML.

[0494] Embodiment 65. The treatment regimen or the method according to embodiment 63 wherein the hematological cancer is myelodysplastic syndrome (MDS).

[0495] Embodiment 66. The treatment regimen or the method according to embodiment 65, wherein myelodysplastic syndrome includes MDS with multilineage dysplasia (MDS-MLD), MDS with single lineage dysplasia (MDS-SLD), MDS with excess blasts (MDS-EB-1 and MDS-EB-2), MDS with ring sideroblasts (MDS-RS), MDS with isolated del(5q) and MDS, unclassifiable (MDS-U).

[0496] Embodiment 67. The treatment regimen or the method according to embodiment 65 or 66, wherein myelodysplastic syndrome is MDS-EB-2

[0497] Embodiment 68. The treatment regimen or the method according to any of embodiments 44 to 67, wherein after cessation of treatment the subject maintains a sustained response to progression of the cancer.

[0498] Embodiment 69. The treatment regimen or the method according to any of embodiments 44 to 67, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered orally in the morning and evening.

[0499] Embodiment 70. The treatment regimen or the method according to any of embodimentss 44 to 67, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered orally as one or more tablets.

[0500] Embodiment 71. The treatment regimen or the method according to any of embodiments 44 to 67, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of from about 0.4 mg to about 1.6 mg of Talabostat. [0501] Embodiment 72. The treatment regimen or the method according to any of embodiments44 to 67, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of from about 0.6 mg to about 1.6 mg of Talabostat.

[0502] Embodiment 73. The treatment regimen or the method according to any of embodiments 44 to 67, wherein Talabostat or a pharmaceutically acceptable salt thereof is Talabostat mesylate.

[0503] Embodiment 74. The treatment regimen or the method according to any of embodiments 44 to 67, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.2 mg of Talabostat twice daily.

[0504] Embodiment 75. The treatment regimen or the method according to any of embodiments 44 to 67, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg of Talabostat twice daily.

[0505] Embodiment 76. The treatment regimen or the method according to any of embodiments 44 to 67, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.4 mg of Talabostat twice daily.

[0506] Embodiment 77. The treatment regimen or the method according to any of embodiments 44 to 67, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.6 mg of Talabostat twice daily.

[0507] Embodiment 78. The treatment regimen or the method according to any of embodiments 44 to 67, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.8 mg of Talabostat twice daily.

[0508] Embodiment 79. A method of enhancing proinflammatory cytokine release (e g. IL-18, IL-ip and IFN-y) in a subject afflicted with hematological cancer, the method comprising administering to said subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration

[0509] Embodiment 80. A treatment regimen for treating AML in a subject in need thereof, the regimen comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14, 18-21 and 25-28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration.

[0510] Embodiment 81. A method of treating AML in a subject in need thereof, the method comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 followed by a rest period on days 4-7, 11-14, 18-21 and 25-28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration.

[0511] Embodiment 82. A method of enhancing immune function in a subject suffering from AML, the method comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration.

[0512] Embodiment 83. The treatment regimen according to embodiment 80 or the method according to embodiments 81 or 82, wherein after cessation of treatment the subject maintains a sustained response to progression of AML.

[0513] Embodiment 84. The treatment regimen according to embodiment 80 or the method according to embodiments 81 or 82, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered orally.

[0514] Embodiment 85. The treatment regimen according to embodiment 80 or the method according to embodiments 81 or 82, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered orally as one or more tablets.

[0515] Embodiment 86. The treatment regimen according to embodiment 80 or the method according to embodiments 81 or 82, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of from about 0.4 mg to about 1.6 mg of Talabostat. [0516] Embodiment 87. The treatment regimen according to embodiment80 or the method according to embodiments 81 or 82, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of from about 0.6 mg to about 1.6 mg of Talabostat. [0517] Embodiment 88. The treatment regimen according to embodiment 80 or the method according to embodiment 81 or 82, wherein Talabostat or a pharmaceutically acceptable salt thereof is Talabostat mesylate.

[0518] Embodiment 89. A method of treating AML (e.g. refractory or relapsed AML) in a subject in need thereof, said method comprising administering to said subject about 0.2 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 followed by a rest period on days 4 to 7, 11 to 14, 18 to 21 and 25 to 28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration [0519] Embodiment 90. A method of treating AML (e.g. refractory or relapsed AML) in a subject in need thereof, said method comprising administering to said subject about 0.3 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 followed by a rest period on days 4 to 7, 11 to 14, 18 to 21 and 25 to 28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration. [0520] Embodiment 91. A method of treating AML (e.g. refractory or relapsed AML) in a subject in need thereof, said method comprising administering to said subject about 0.4 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 followed by a rest period on days 4 to 7, 11 to 14, 18 to 21 and 25 to 28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration [0521] Embodiment 92. A method of treating AML (e g. refractory or relapsed AML) in a subject in need thereof, said method comprising administering to said subject about 0.6 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 followed by a rest period on days 4 to 7, 11 to 14,18 to 21 and 25 to 28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration. [0522] Embodiment 93. A method of treating AML (e.g. refractory or relapsed AML) in a subject in need thereof, said method comprising administering to said subject about 0.8 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 followed by a rest period on days 4 to 7, 11 to 14,18 to 21 and 25 to 28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration. [0523] Embodiment 94. A method of treating a subject having or suspected of having acute myeloid leukemia (AML), the method comprising: a) obtaining a biological sample from the subject; b) measuring DNA copy number of DPP9 gene in the biological sample wherein if the DNA copy number of DPP9 gene is about 3 to about 13, administering to the subject an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0524] Embodiment 95. The method according to embodiment 94, wherein the DNA copy number of DPP9 gene is measured by RT-PCR, Multiplex ligation-dependent probe amplification (MLP A), Multiplex amplifiable probe hybridization (MAPH), Dynamic allelespecific hybridization (DASH), Comparative genomic hybridization (CGH), Oligonucleotides arrays, Genotype arrays or the like.

[0525] Embodiment 96. The method according to embodiment 94 or 95, wherein the assay comprises PCR amplifying a gene and determining the DNA copy number.

[0526] Embodiment 97. A method of treating a subject having or suspected of having acute myeloid leukemia (AML), the method comprising a) measuring level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA-DRB3, IL I 7RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 relative to an HPRT1 gene and (b) administering to the subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, when the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30; AKT3 is in the range of about 0.02 to about 30; CARD9 is in the range of about 0.004 to about 40; CXCR4 is in the range of about 0.14 to about 150; EPC AM is in the range of about 0.00 to about 10; HLA-DMA is in the range of about 0.12 to about 10; HLA-DRA is in the range of about 0.58 to about 100; HLA-DRB3 is in the range of about 0.09 to about 30; IL17RA is in the range of about 0.2 to about 50; IL4R is in the range of about 0.03 to about 30; IL6R is in the range of about 1.18 to about 60; IRF8 is in the range of about 0.03 to about 60; ITGAL is in the range of about 2.16 to about 140; ITGB2 is in the range of about 6.5 to about 400; PSMB8 is in the range of about 3.0 to about 60 and TARP is in the range of about 0.0001 to about 300 as analyzed, for example, by qRT-PCR.

[0527] Embodiment 98. A method of treating MDS-EB-2 in a subject in need thereof, said method comprising administering to said subject about 0.2 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof (e.g. Talabostat mesylate) on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 followed by a rest period on days 4 to 7, 11 to 14 18 to 21 and 25 to 28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration.

[0528] Embodiment 99. A method of treating MDS-EB-2 in a subject in need thereof, said method comprising administering to said subject about 0.3 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof (e.g. Talabostat mesylate) on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 followed by a rest period on days 4 to 7, 11 to 14,18 to 21 and 25 to 28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration.

[0529] Embodiment 100. A method of treating MDS-EB-2 in a subject in need thereof, said method comprising administering to said subject about 0.4 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof (e.g. Talabostat mesylate) on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 followed by a rest period on days 4 to 7, 11 to 14,18 to 21 and 25 to 28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration.

[0530] Embodiment 101. A method of treating MDS-EB-2 in a subject in need thereof, said method comprising administering to said subject about 0.6 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof (e.g. Talabostat mesylate) on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 followed by a rest period on days 4 to 7, 11 to 14 18 to 21 and 25 to 28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration.

[0531] Embodiment 102. A treatment regimen for treating MDS-EB-2 in a subject in need thereof, said method comprising administering to said subject 0.8 mg twice daily of Talabostat or a pharmaceutically acceptable salt thereof (e.g. Talabostat mesylate) on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 followed by a rest period on days 4 to 7, 11 to 14,18 to 21 and 25 to 28 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration. [0532] Embodiment 103. A treatment regimen for treating MDS-EB-2 in a subject in need thereof, said method comprising administering to said subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof (e.g. Talabostat mesylate) on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration and wherein total daily dose of Talabostat from about 0.4 mg to about 1.6 mg of Talabostat per day.

[0533] Embodiment 104. The treatment regimen according to embodiment 103, wherein administration is followed by a rest period on days 4 to 7, 11 to 14 ,18 to 21 and 25 to 28 in each 28-days cycle.

[0534] Embodiment 105. The treatment regimen according to embodiments 102 to 104 or the method according to embodiments 97-101, wherein the MDS-EB-2 is refractory MDS-EB-2 or relapsed MDS-EB-2.

[0535] Embodiment 106. treatment regimen according to embodiments 102 to 104 and methods according to any of the embodiments 97 to 101, wherein Talabostat mesylate is administered orally.

[0536] Embodiment 107. The treatment regimen according to embodiments 102 to 104 or the methods according to any embodiments 97 to 101, wherein Talabostat mesylate is administered orally as one or more tablets.

[0537] Embodiment 108. The treatment regimen according to embodiments 102 to 104 or the methods according to any embodiments 97 to 101, wherein Talabostat mesylate is administered in the morning and evening.

[0538] Embodiment 109. A method of enhancing an innate immune response in a subject suffering from AML, the method comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof, wherein the enhanced innate immune response is associated with increase in immune cells, and wherein Talabostat is administered on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration [0539] Embodiment 110: The method according to embodiment 109, wherein the immune cells are T-cells (CD45, CD3, CD4, and CD8), NEC cells and monocytic/myeloid cells (CD14, CD16, CD1 lb, HLA-DR) or any combination thereof.

[0540] Embodiment 111: A method of enhancing an innate immune response in a subject suffering from AML, the method comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof, wherein the enhanced innate immune response is associated with cytokines response and Talabostat is administered on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration

[0541] Embodiment 112. The method of embodiment according to embodiment 111, wherein the cytokines are G-CSF, GM-CSF, IFN-gamma, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL- 10, IL-18, MIP-1 alpha, MIP-1 beta, MCP-1, TNF-alpha, TNF-beta, BDNF, Eotaxin-1, Factor VII, ICAM-1, IL-1 alpha, IL-1 beta, IL-lra, IL-12p40, IL-12p70, IL-15, IL-17, IL-23, MMP- 3, MMP-9, SCF, VEGF or any combination thereof

[0542] Embodiment 113: A method of enhancing an innate immune response in a subject suffering from AML, the method comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof, wherein the enhanced innate immune response is associated with suppression of T-regulatory cells and Talabostat is administered on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration period.

[0543] Embodiment 114: The method according to embodiment 111 or 113, wherein the AML is refractory AML or relapsed AML.

[0544] Embodiment 115. The method according to embodiment 113, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered orally.

[0545] Embodiment 116. The method according to embodiment 115, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered orally in one or more tablets.

[0546] Embodiment 117. The method according to embodiment 113 or 114, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of from about 0.4 mg to about 1.6 mg of Talabostat.

[0547] Embodiment 118. The method according to embodiment 113 or 114, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of from about 0.6 mg to about 1.6 mg of Talabostat.

[0548] Embodiment 119. The method according to embodiment 113 or 114, wherein Talabostat or a pharmaceutically acceptable salt thereof is Talabostat mesylate. [0549] Embodiment 120: A method for delaying progression or preventing or delaying AML recurrence, in a subject suffering from AML the method comprising administering to said subject, an effective amount of Talabostat or a pharmaceutically acceptable salt thereof, wherein Talabostat is administered on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration.

[0550] Embodiment 121. The treatment regimen or the methods according any of the preceding embodiments, wherein Talabostat or a pharmaceutically acceptable salt thereof is optionally administered in combination with one or more anti -cancer agent or therapy.

[0551] Embodiment 122. The treatment regimen or the methods according to embodiment 121, wherein one or more anti-cancer agent or therapy is selected form a group comprising any cancer SOC, radiotherapy, chemotherapy or immunotherapy.

[0552] Embodiment 123. The treatment regimen or the methods according to embodiment 122, wherein one of the additional anticancer agents is a hypomethylating agent.

[0553] Embodiment 124. The treatment regimen or the methods according to embodiment 122, wherein one of the additional anticancer agents is a BCL-2 inhibitor.

[0554] Embodiment 125. The treatment regimen or the methods according to embodiment 122, wherein one or more of the additional anticancer agents is a combination of hypomethylating agent and BCL-2 inhibitor.

[0555] Embodiment 126. The treatment regimen or the methods according to embodiment 123, wherein the hypomethylating agent is Decitabine.

[0556] Embodiment 127. The treatment regimen or the methods according to embodiment 123, wherein the hypomethylating agent is Azacitidine.

[0557] Embodiment 128. The treatment regimen or the methods according to embodiment 124, wherein the BCL-2 inhibitor is Venetoclax.

[0558] Embodiment 129. A method for reducing the toxicity of Talabostat or a pharmaceutically acceptable salt thereof with a lower effective dose of Talabostat, the method comprising administering to a subject suffering from AML (e g., relapsed/ refractory AML), Talabostat or a pharmaceutically acceptable salt thereof to said subject on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration.

[0559] Embodiment 130. A method for reducing the toxicity of Talabostat or a pharmaceutically acceptable salt thereof with a lower effective dose of Talabostat, the method comprising administering to a subject suffering from MDS-EB-2 (e.g., relapsed/ refractory MDS-EB-2), Talabostat or a pharmaceutically acceptable salt thereof to said subject on days 1 to 3, 8 to 10, 15 to 17 and 22 to 24 in one or more treatment cycles and wherein each treatment cycle is of about 28 days duration.

[0560] Embodiment 131. The treatment regimen or the methods according any of the preceding embodiments, wherein the treatment is administered for at least 12 weeks (e.g. three 4-week cycles), at least 14 weeks, at least 16 weeks or at least 24 weeks (e.g. six 4-week cycles).

[0561] Embodiment 132. The treatment regimen or the methods according any of the preceding embodiments, wherein the subject achieves a complete response within 2-4 weeks after treatment.

[0562] Embodiment 133. A method of treating a subject having or suspected of having myelodysplastic syndrome (MDS), the method comprising: a) obtaining a biological sample from the subject; b) measuring DNA copy number of DPP9 gene in the biological sample wherein if the DNA copy number of DPP9 gene is about 3 to about 13, administering to the subject an effective amount of the Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration.

[0563] Embodiment 134. A method of treating a subject having or suspected of having myelodysplastic syndrome, the method comprising a) performing assay to. measure level of expression of one or more of the target genes and genes involved in immune pathways selected from the group consisting of DPP9, DPP8, caspase 1, CARD8, CARD9, PYCARD, AKT3, CXCR4, HLA-DMA, HLA-DRA, HLA- DRB3, IL17RA, IL4R, IL6R, IRF8, ITGAL, ITGB2, TARP and PSMB8 relative to an HPRT1 gene and (b) administering to the subject an effective amount of Talabostat or a pharmaceutically acceptable salt thereof on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles, wherein each treatment cycle is of about 28 days duration, when the mRNA expression level of genes DPP9 in the range of about 0.7 to about 30, DPP8 in the range of about 0.4 to about 10; caspase 1 in the range of about 0.1 to about 60; CARD8 in the range of about 1.7 to about 100; PYCARD is in the range of about 0.5 to about 30; AKT3 is in the range of about 0.02 to about 30; CARD9 is in the range of about 0.004 to about 40; CXCR4 is in the range of about 0.14 to about 150; EPCAM is in the range of about 0.00 to about 10; HLA- DMA is in the range of about 0.12 to about 10; HLA-DRA is in the range of about 0.58 to about 100; HLA-DRB3 is in the range of about 0.09 to about 30; IL17RA is in the range of about 0.2 to about 50; IL4R is in the range of about 0.03 to about 30; IL6R is in the range of about 1.18 to about 60; IRF8 is in the range of about 0.03 to about 60; ITGAL is in the range of about 2.16 to about 140; ITGB2 is in the range of about 6.5 to about 400; PSMB8 is in the range of about 3.0 to about 60 and TARP is in the range of about 0.0001 to about 300 as analyzed, for example, by qRT-PCR.

[0564] Embodiment 135. The method of embodiment 133 or 134, wherein the myelodysplastic syndrome is high-risk MDS-EB-2.

[0565] Embodiment 136. The treatment regimen or the methods according any of the preceding embodiments, wherein the subject achieves a stable disease response or better as per International Working Group (IWG) and European Leukemia Net (ELN) criteria for AML.

[0566] Embodiment 137. The treatment regimen or the methods according any of the preceding embodiments, wherein the subject achieves a partial response or better as per International Working Group (IWG) and European Leukemia Net (ELN) criteria for AML.

[0567] Embodiment 138. The treatment regimen or the methods according any of the preceding embodiments, wherein the subject achieves a complete response or complete response with incomplete count recovery (CRi) as per International Working Group (IWG) and European Leukemia Net (ELN) criteria for AML

[0568] Embodiment 139. The treatment regimen or the methods according any of the preceding embodiments, wherein the subject achieves a morphologic leukemia-free state (MLFS)

[0569] Embodiment 140. The treatment regimen or the methods according any of the preceding embodiments, wherein the subject achieves a hematologic improvement (HI).

[0570] Embodiment 141. The treatment regimen or the methods according any of the preceding embodiments, wherein the treatment is administered for at least 12 weeks (e.g. three 4-week cycles), or at least 24 weeks (e.g. six 4-week cycles).

[0571] Embodiment 142. The treatment regimen or the methods according any of the preceding embodiments, wherein the treatment is administered for at least 14 weeks, or at least 16 weeks. [0572] Embodiment 143. The treatment regimen or the methods according any of the preceding embodiments, wherein the subject achieves a complete response within 2-4 weeks after treatment.

[0573] Embodiment 144. The treatment regimen or the methods according any of the preceding embodiments, wherein Talabostat is administered as long as a clinical benefit is observed or until there is a complete remission (CR) or unmanageable toxicity.

[0574] Embodiment 145. The treatment regimen or the methods according any of the preceding embodiments, wherein the subject has not been previously treated with a biotherapeutic or chemotherapeutic agent, i.e., is treatment- naive. [0575] Embodiment 146. The treatment regimen or the methods according any of the preceding embodiments, wherein the subject has experienced little or no improvement after prior therapy with a biotherapeutic or chemotherapeutic agent.

[0576] Embodiment 147. The treatment regimen or the methods according any of the preceding embodiments, wherein the subject has relapsed or progressed after treatment with previous therapies.

[0577] Embodiment 148. The treatment regimen or the methods according any of the preceding embodiments, wherein the subject has failed to achieve a sustained response after prior therapy with a biotherapeutic or chemotherapeutic agent or like, i.e., is treatment- experienced.

[0578] Embodiment 149. The treatment regimen or the methods according any of the preceding embodiments, wherein the human subject is 18 years or older.

[0579] Embodiment 150. The treatment regimen or the methods according any of the preceding embodiments, wherein the subject has an ECOG performance score <2.

[0580] Embodiment 151. The treatment regimen or the methods according any of the preceding embodiments, wherein the subject has an ECOG performance of 1.

[0581] Embodiment 152. A method of treating hematological cancer in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 20 mg/m2 as continuous intravenous infusion over 1 hour daily for 5 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the 28-day treatment cycle..

[0582] Embodiment 153. A method of treating hematological cancer in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 15 mg/m ² as continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the treatment cycle.

[0583] Embodiment 154. A method of treating acute myeloid leukemia in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 15 mg/m2 as continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days and Venetoclax is administered in an amount of about 100 mg on day 1 , about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the treatment cycle.

[0584] Embodiment 155. A method of treating hematological cancer in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 75 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the treatment cycle .

[0585] Embodiment 156. A method of treating hematological cancer in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 100 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the treatment cycle.

[0586] Embodiment 157. A method of treating acute myeloid leukemia in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 100 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the treatment cycle.

[0587] Embodiment 158. A method of treating myelodysplastic syndrome in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Decitabine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Decitabine is administered at a dose of 15 mg/m ² as continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the treatment cycle.

[0588] Embodiment 159. A method of treating myelodysplastic syndrome in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof, Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 75 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the treatment cycle.

[0589] Embodiment 160. A method of treating myelodysplastic syndrome in a subject in need thereof, the method comprising administering to said subject a combination comprising effective amounts of Talabostat or a pharmaceutically acceptable salt thereof and Azacitidine and Venetoclax, wherein Talabostat is administered on days 1-3, 8-10, 15-17 and 22-24 in one or more treatment cycles and each treatment cycle is of about 28 days duration, Azacitidine is administered subcutaneously at a dose of 100 mg/m ² daily for seven days, every four weeks and Venetoclax is administered in an amount of about 100 mg on day 1, about 200 mg on day 2 and about 400 mg once daily on day 3 and beyond of the treatment cycle.

EXAMPLES:

[0590] Example 1. A Phase 1 Study of Talabostat mesylate in Relapsed/Refractory Acute Myeloid Leukemia or Relapsed/Refractory Myelodysplastic Syndrome with Excess Blasts - 2. [0591] Primary Objectives

[0592] 1. To determine the MTD or recommended Phase 2 dose (RP2D) of Talabostat as a single agent on days 1-3, 8-10, 15-17 and 22-24 in a 4-week cycle schedule.

[0593] To evaluate the safety of Talabostat in an AML population given as a cycle of days 1- 3, 8-10, 15-17 and 22-24 in a 4-week cycle.

[0403] Secondary Objectives 1. The secondary objectives of the study include:

2. To estimate response rates — complete remission (CR), complete response with incomplete count recovery (CRi), partial response (PR), morphologic leukemia-free state (MLFS) and hematologic improvement (HI) of Talabostat as a single agent

3. To estimate the median overall survival (OS) of Talabostat as a single agent

4. To estimate the median duration of response (DOR) of Talabostat as a single agent

5. To assess pharmacokinetics of Talabostat regimen as a single agent on days 1-3, 8-10, 15-17 and 22-24 in a 4-week cycle schedule

[0404] Exploratory objectives

1. To assess the pharmacodynamic profile of Talabostat with the single agent by measuring relevant effects on cytokines predicted to be modulated by Talabostat.

2. To explore the relationship between baseline and on-treatment circulating tumor neoantigens and T-cell repertoire and clinical outcomes (Central Laboratory)

3. To explore the relationship between baseline tumor messenger ribonucleic acid (mRNA) immune profiling panel and clinical outcomes.

4. To measure the inhibitory effect of Talabostat on FAP and DPP 4/8/9 in marrow samples both pre- and post-treatment with Talabostat as a single agent

5. To evaluate potential biomarkers such as Copy Number Variants (CNV) and mRNA of DPP9, DPP8, DPP4, FAP, Caspase-1, Pro-caspase- 1, NLRP1, and CARD8.

[0405] PARTICIPANT SELECTION

ELIGIBILITY CRITERIA

1. Age 18 and older

2. Subjects with evidence of AML that meet at least one of the following criteria:

Relapsed AML: as evidence by >5% myeloblasts in the bone marrow, or reappearance of blasts in the peripheral blood

Refractory AML: <2 prior induction regimens (example: patients who receive 7 + 3 followed by

5 + 2 would count as one induction regimen)

OR

Subjects with WHO defined myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) as defined by blast count between 10% -19% in the bone marrow or peripheral blood blasts 5%- 19% or Auer rods noted and refractory or relapsed after at least 4 cycles of a hypomethylating agent (Azacitidine, Decitabine, or oral Decitabine /cedazuridine)

3. ECOG performance status <2 (Karnofsky >60%)

4. Participants must have adequate organ and marrow function as defined below:

• Estimated Creatinine Clearance >30 mL/min by Cockroft-Gault calculation

• Total Bilirubin <1.5 x ULN*

• ALT and AST <3x ULN*

• EF >35%

*unless considered due to leukemic organ involvement NOTE: Subjects with Gilbert’s Syndrome may have a total bilirubin >1.5 x ULN per discussion with overall study PI.

5. WBC <25,000 / pL on day of 1 of cycle 1; cytoreduction is permitted with hydroxyurea which is allowed throughout cycle 1 until cycle 2 days 1

6. Human immunodeficiency virus (HlV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

7. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

8. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

9. Participants with treated central nervous system (CNS) disease are eligible if follow-up brain imaging after CNS-directed therapy shows no evidence of progression

10. Male subjects must agree to refrain from unprotected sex and sperm donation from initial drug administration until 1 year after the last dose of study drug.

11. Females of childbearing potential (i.e. not postmenopausal for at least 1 year or not surgically sterile) must have negative results by a serum pregnancy test performed within 7 days of day 1. Females must agree to refrain from unprotected sex/adequate contraception via barrier method from initial drug administration until 1 year after the last dose of study drug. [0001] Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

1. Subjects who have known Acute Promyelocytic Leukemia.

2. Subjects with active CNS involvement with AML.

3. Participants who have had chemotherapy, other investigational therapy, immunotherapy, or radiotherapy within 2 weeks or 5 half-lives from prior therapy, whichever is longer, prior to the first dose of study medication. Hydroxyurea is allowed with no required washout, and hydroxyurea may be administered for the first cycle of the protocol for patients who have proliferative disease (WBC <25K) with a maximum allowed dose of 6 g per day.

4. Participants who have received oral tyrosine kinase inhibitors (TKIs) within two weeks or 5 half-lives (whichever is longer) of the first dose of study medication.

5. Subjects who are <100 days from allogeneic bone marrow transplant.

6. Subjects who have active graft-versus host disease are not eligible. Patients should be off calcineurin inhibitors for at least 28 days (4 weeks) prior to start of study treatment day#l.

7. Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxi cities >Grade 1) with the exception of alopecia.

8. Participants who are receiving any other investigational agents.

9. Concomitant medications: It is strongly encouraged that patients who are on strong inducers or inhibitors of CYP3A4 be changed to a comparable drug if possible.

Patients are not permitted to be on a gliptin (sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin).

10. Patients with a history of orthostatic hypotension with a baseline SBP <100, or history of uncontrolled hypertension.

11. Subject has cardiovascular disability status of NYHA class >2

12. No concurrent active malignancies are allowed on study for >2 years prior to treatment start with the exception of currently treated basal cell or squamous cell carcinoma of the skin, carcinoma in-situ of the cervix or breast, or low-grade prostate cancer.

13. Patients with known active hepatitis B virus (HBV) infection should be excluded because of potential effects on immune function and/or drug interactions. However, if a patient has HBV history with an undetectable HBV load by polymerase chain reaction (PCR), no liver-related complications, and is on definitive HBV therapy, then he/she would be eligible for study.

14. Patients with known active hepatitis C virus (HCV) infection. Patients with a history of HCV infection who received definitive therapy and has an undetectable viral load by PCR would be eligible.

15. Participants with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Any other prior or ongoing condition, in the opinion of the investigator, that could adversely affect the safety of the patient or impair the assessment of study results. As patients with AML and MDS are prone to infections, if patients are actively being treated with appropriate antibiotics or antifungal therapy with clinical evidence of infection control, then they will be considered eligible for study.

16. Participants with psychiatric illness/social situations that would limit compliance with study requirements.

17. Pregnant women are excluded from this study because Talabostat have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued.

[0594] TREATMENT PLAN

[0595] Treatment regimen

[0596] This is a phase 1 trial that is utilize dose escalation in a standard 3 + 3 format. The study is evaluate the safety and tolerability of Talabostat on days 1-3, 8-10, 15-17 and 22-24 of a 28-day cycle for patients with relapsed/refractory AML or relapsed/refractory MDS-EB-2 (refer table 1). No investigational or commercial agents or therapies other than those described below are administered with the intent to treat the patient’s malignancy, except for hydroxyurea.

[0597] Table 1

Total daily dose does not exceed 1.6 mg (0.8 mg BID)

[0598] Patients are observed for DLT during Cycle 1. Three patients are treated initially with Talabostat 0.3 mg PO BID on days 1-3, 8-10, 15-17 and 22-24 or each 28-day cycle:

[0599] If >1 of the 3 original patients has a DLT in Cycle 1, after a discussion between BioXcel and the investigator, either 3 patients (if 1 patient experiences a DLT) are added at the Talabostat 0.3 mg PO BID dose level or the dose level will be decreased to 0.2 mg daily.

[0600] If there are no DLTs in Cycle 1, the dose of Talabostat is escalated to 0.4 mg in the next cohort of 3 patients. For this next Talabostat 0.4 mg BID cohort:

If less than one-third of the patients experience a DLT, consideration is be given to dose escalation to 0.6 mg Talabostat

If one-third of the patients experience a DLT, an additional 3 patients are treated at this dose level. If less than or equal to one of 6 patients then has a DLT, then we expands to the 0.6 mg dose level.

If more than or equal to one-third of the 6 patients treated experience a DLT, a discussion is held between the investigators and BioXcel as to how to proceed

The same rules as above will apply when moving from the 0.6 mg dose level to the 0.8 mg dose level.

[0601] In the event that 0 of 3 patients in a dose level experience a DLT, the dose level may still be expanded to 6 evaluable patients based on observed toxicity at the current dose level at the discretion of the Sponsor-Investigator I to capture patient safety prior to expanding.

[0602] Treatment -Talabostat mesylate

[0603] Talabostat will be given orally with first dose of each cycle given in the clinic, and patients will then take doses at home BID. They will also receive the morning dose on day 3, 8, 15 and 22 of cycle 1 in the clinic and C2D1.

[0604] Procedures:

[0605] Cycle 1 Labs is obtained Days 1, 3, 8, 15, 22 and any additional time at the discretion of the treating physician. [0606] Cycle 2 labs is obtained on Days 1, 8, 15, 22 and any additional time at the discretion of the treating physician.

[0607] Subsequent cycles will have labs on Day 1 of each cycle and any additional time at the discretion of the treating physician.

[0608] Bone marrow biopsy (including aspirate, core, flow cytometry, flow for MRD, cytogenetics and rapid heme panel) is performed at Cycle 1 Day 22.

[0609] Bone marrow biopsy (including aspirate, core, flow cytometry, and flow for MRD will be sent on subsequent bone marrow biopsies) is performed at the end of Cycles 2, 4, and 6. After Cycle 6, bone marrow biopsies are obtained every 3 cycles. A repeat marrow is performed at any time when there is suspicion of relapse if a response is attained, or at the discretion of the treating physician.

[0610] STUDY CALENDAR

[0611] Baseline screening evaluations are to be performed within 14 days of protocol therapy, including the mandatory pre-treatment bone marrow aspirate research sample, except as specifically noted. In the event that the participant’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. [0612] Assessments must be performed prior to administration of any study agent, unless otherwise specified in the protocol.

[0613] The DLT window is after the first 28-day cycle, however, if the bone marrow biopsy on day 22 demonstrates a morphologic leukemia free state (MLFS), the DLT window for cytopenias will be 35 days. At the end of Cycle 2, patients with evidence of disease progression are removed from study unless there is evidence of treatment tolerability and clinical benefit (i.e., improvement in transfusion frequency, peripheral blast reduction or symptom improvement). Patients with evidence of disease progression may be allowed to stay on study if deriving clinical benefit with approval from the Sponsor Investigator.

[0614] Pre-Treatment Criteria

[0615] Cycle 1, Day 1

[0616] Since these patients carry the diagnosis of AML there are no hematologic criteria to initiate therapy (Cycle 1, Day 1). Patients need to meet the eligibility criteria that has been established in the Inclusion and Exclusion criteria. For all patients, the WBC must be less than 25,000/pL on the first day of therapy. Hydroxyurea is permitted throughout the first cycle of treatment.

[0617] Subsequent Cycles [0618] In order to initiate subsequent cycles:

[0619] If the patient has persistent disease (demonstrated by Day 21 marrow showing persistent disease, peripheral blasts, or persistent leukemia cutis or any other extramedullary disease), there are no hematologic requirements to start Cycles 2-4. Patient who started treatment as AML but have de-escalated to MDS due to treatment in Cycle 1 have no hematologic requirements to start Cycles 2-4.

[0620] In the absence of disease (based on bone marrow or peripheral blood standards as above), patients must have an absolute neutrophil count of >500 x 10 ⁹ /L and platelet count of >50,000 x 10 ⁹ /L to proceed, otherwise administration of treatment will be delayed.

[0621] If patients have developed nonhematological toxicities during the previous cycle, these need to resole to no more than Grade 1 prior to the start of subsequent cycles.

[0622] Agent Administration

[0623] Talabostat

[0624] Administration: Talabostat mesylate is an oral medication. All pills should be taken at the same time with approximately 240 mL of water and not on an empty stomach. Tablets must be swallowed whole and must not be broken, chewed or crushed. The dose should be administered at approximately the same time each day. If vomiting occurs >10 minutes after dosing of Talabostat, no further attempts at dosing that particular Talabostat dose should take place; dosing should resume with the next dose. This should be documented. The next dose should be taken at the usual time.

[0625] Unit: Tablets

[0626] Route: Oral

[0627] Dose levels include 0.2 mg BID (dose level -1, if necessary), 0.3 mg BID, 0.4 mg BID, 0.6 mg BID, and 0.8 mg BID of Talabostat.

[0628] Supportive care measures: To minimize risk of hypotension, patients should be advised to maintain adequate hydration while taking Talabostat treatment, such as drinking at least 2 liters of fluids per day, including fluids with electrolytes. Factors such as strenuous exercise, heat, humidity, fever, gastrointestinal disturbance may increase hydration needs.

[0629] It is decided by the individual investigating physician if the patient is to be admitted for Cycle 1 of therapy. It is advised that if the uric acid is >10, patients should receive rasburicase 6 mg IV x 1. All other patients should be initiated on allopurinol 300 mg daily or renal dose equivalent. If a patient develops any clinically significant laboratory changes suggestive of TLS within the first 24 hours after either the first dose or during dose escalation, Venetoclax dose escalation should be withheld until resolution. Dosing and TLS monitoring/prophylaxis/management schemas that have been safely administered to date from Phase 1/2 AML studies will be used in this study.

[0630] Any overdose or incorrect administration of study drug is noted on the Study Drug. Administration eCRF. Adverse events associated with an overdose or incorrect administration of study drug is recorded on the AE eCRF.

[0631] Criteria for Taking a Participant Off Protocol Therapy

[0632] Duration of therapy depends on individual response, evidence of disease progression and tolerance. In the absence of treatment delays due to AE(s), treatment is continued for up to 12 cycles or until one of the following criteria applies: a. Disease progression (as defined by ELN 2017 criteria for AML) b. Intercurrent illness that prevents further administration of treatment c. Unacceptable AE(s) d. Participant demonstrates an inability or unwillingness to comply with the oral medication regimen and/or documentation requirements e. Participant decides to withdraw from the protocol therapy f. General or specific changes in the participant's condition render the participant unacceptable for further treatment in the judgment of the treating investigator g. For AML patients: If study subject has not achieved at least a Morphologic Leukemia Free State (MLFS) by 4 cycles of therapy, they will be removed from protocol. h. For MDS-EB-2 patients: If subjects have not received at least a hematologic improvement by the completion of 4 cycles, they will be removed from study.

[0633] Participants will be removed from the protocol therapy when any of these criteria apply. The reason for removal from protocol therapy, and the date the participant was removed, must be documented in the case report form (CRF). Alternative care options will be discussed with the participant.

[0634] When a participant is removed from protocol therapy and/or is off of the study, the participant’s status must be updated in OnCore in accordance with REGIST-OP-1.

[0635] Duration of Follow Up

[0636] Participants are followed for up to 52 weeks after removal from protocol therapy or until death, whichever occurs first. Participants removed from protocol therapy for unacceptable AE(s) will be followed until resolution or stabilization of the AE.

[0637] Criteria for Taking a Participant Off Study

[0638] Participants are removed from study when any of the following criteria apply: i. Lost to follow-up ii. Withdrawal of consent for data submission iii Death

[0639] The reason for taking a participant off study, and the date the participant is removed, must be documented in the CRF. In addition, the study team ensure that the participant’s status is updated in OnCore in accordance with REGIST-OP-1.

[0640] BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES

[0641] Laboratory Correlative Studies

[0642] Correlative laboratory studies will be performed to assess pharmacokinetics, cytokine response, and T-cell inflammatory response after treatment with Talabostat to the leukemia cells. Prior to obtaining the samples, each tube is labelled with the patient study number, date collected, site of collection (peripheral blood v. marrow). Each category will be addressed below:

[0643] Correlative Study 1 : Pharmacokinetics in AML patients

[0644] Collection of Pharmacokinetic specimens

[0645] PK samples from peripheral blood are collected at the following times as in below table 2:

Table 2.

[0646] In the event a step-up dosing strategy is implemented, then collect samples as indicated for Cycle 1, Day 1 for the first dose at the new level when possible.

[0647] Handling of Specimens

[0648] Detailed instructions for collecting, processing, storing and shipping samples are provided in a separate laboratory manual.

[0649] Correlative study 2: Cytokine response to Talabostat

[0650] Collection of samples for cytokines studies:

[0651] Peripheral blood samples will be collected in a 8.5 mL EDTA vacutainer tube at the following timepoints:

Cycle 1 Day 1: pre-dose, 4 hours (±30 minutes), 8 hours (±30 minutes) Cycle 1 Day 3: pre-dose, 4 hours (±30 minutes), 8 hours (±30 minutes)

Cycle 1 Day 8: pre-dose

Cycle 1 Day 15: pre-dose.

Cycle 2 day 1: pre-dose.

[0652] Samples are sent to Myriad Labs for the following cytokines: G-CSF, GM-CSF, IFN- Y,IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-18, MIP-1 a, MIP-1 0, MCP-1, TNF- a,TNF-0, BDNF, Eotaxin-1, Factor VII, ICAM-1,IL-1 oc, IL-1 0, IL-lra, IL-12p40, IL-12p70, IL-15, IL-17, IL-23, MMP-3, MMP-9, SCF, and VEGF

[0653] Correlative study 3: T-cell morphology and subsets in marrow studies.

[0654] A bone marrow biopsy is performed at screening and to assess for response to treatment at Cycle 1 Day 22 (± 1 day) (See Table 3). Flow cytometry is additionally assessed for T-cell markers and also the core is stained for T-cell immunohistochemistry (CD3, CD4, CD8, CD25, CD56, CD57). Table 3; Cohort A, Study Events

a Doses on Cycle 1 Days 1, 3, 8, 15, 22 and Cycle 2 day 1 are given in clinic. b Vital signs, including sitting and standing blood pressure, prior to administration of Talabostat mesylate

C The patient will take a BP reading at least twice a day (if the blood pressure is not done that day in clinic), once in the morning and once in the late afternoon/evening, prior to Talabostat mesylate dosing. d Blood pressures will be reviewed during the clinic visits during cycle 1. e Differential per institutional standards f Including: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total protein, albumin, calcium, phosphorus, uric acid, total bilirubin, ALT (SGPT), AST (SGOT), alkaline phosphatase, LDH; Screening and day 1 of each cycle to include lactic acid; pre-study (screening) also includes creatine phosphokinase (CPK) g Urine or serum pregnancy test performed within 14 days of Day 1 for women of childbearing potential h Performed within 30 days of first protocol treatment i AE monitoring to continue for 30 days following last treatment j To be performed after consent, within 14 days prior to start of first cycle of study treatment for prestudy marrow to include aspirate for mandatory correlative studies. Further performed on Cycle 1 Day 22, end of Cycle 2, 4 and 6 and then every 3 cycles until relapse. Bone marrow biopsy window is ±2 days. To be sent for aspirate, core, and MRD flow or other studies as clinically indicated k PK sampling, to be collected Cycle 1 Day 1, 3, 8, 15, Day 22, and Cycle 2 Day 1. If laboratory staffing would preclude PK draws on a specified day (e.g., the weekend), then it is acceptable to change a PK day(s) to a different day that Talabostat mesylate is given (please discuss with PI if questions).

1 Samples to be collected Cycle 1 Day 1, 3, 8, 15, Day 22 (optional), and Cycle 2 Day 1.

[0656] STATISTICAL CONSIDERATIONS

[0657] This is a multi-center open-label phase 1 dose escalation study of Talabostat as a single agent using a 3 + 3 design followed by Talabostat in combination with hypomethylating agent and Venetoclax with an expansion cohort. The primary objective is to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of Talabostat. DLTs will be evaluated in cycle 1.

[0658] Study Design/Endpoints

[0659] For this phase 1 dose escalation trial patients enters in cohorts of three and receive single agent Talabostat on days 1-3, 8-10, 15-17 and 22-24 of a 28 day cycle. As this is a new dosing schema that varies from the previous solid tumor trials, we utilizes a 3 + 3 design that evaluates 4 different dose levels (0.3 mg bid, 0.4 mg bid, 0.6 mg bid, and 0.8 mg bid of Talabostat) and a dose level (-1) at 0.2 mg bid in case of initial toxicity.

[0660] Dose level 1 is the starting dose. At a given dose level, if in the first three patients none have experienced DLT in cycle 1 (28 days) the dose is escalated. However, if 2 out of the first 3 patients experience DLT in the first 3 patients, then the dose is de-escalated to a lower daily dose of Talabostat. If one out of the first three patients has a DLT at the current dose level, then a new set of three patients is treated at that dose level. If there is no DLT in the new set of three patients, then the dose is escalated. If one or more of these three additional patients experience a DLT, then patient entry at that dose level is stopped, and the MTD has been exceed and the dose will be deescalated.

[0661] The table below (Table 4) gives the operating characteristics of this design for the probability of dose escalation based on the true but unknown rate of DLT at a given dose level. For example, if the true but unknown rate of DLT is 20%, the probability of escalation is 0.71, but 0.31 if the true but unknown rate of DLT is 40%.

Table 4. Probability of Dose Escalation

[0662] Overall survival is estimated using the method of Kaplan and Meier calculated from the date of the first dose to death or last known follow-up. Progression-free survival will be estimated from the date of first dose to the date of first progression or death from any cause and is censored at the last response assessment date. For patients who have a response, the time to CR/CRi will be estimated from the date of first dose to the date of CR/CRi and reported with 90% confidence intervals. The response duration is also estimated and calculated from the date of first response to the date of to the date of progression or death and is estimated using the method of Kaplan and Meier and subjects without progression or death is censored at the last response assessment date. [0663] Sample Size, Accrual Rate and Study Duration

[0664] The Phase 1 portion of this study follows a 3 + 3 dose escalation, to evaluate safety, and toxicity. Up to 24 patients enroll in the trial. We estimate 1 year of accrual (approximately 1-2 patients enrolled per month) to reach this target number of subjects. The DFCI Leukemia Program alone sees over 200 new AML patients per year, many of which are eligible for this trial at some point in their disease process. Potential patient numbers are similar at the outside sites. The study duration is estimated to be approximately 2 years, with up to one additional year for survival monitoring.

[0665] Reporting and Exclusions

[0666] Evaluation of Toxicity [0667] All participants who receive at least one dose of study treatments are evaluable for toxicity. Participants who are alive and remain in the study until 28 days after the first treatment day are considered evaluable for dose- limiting toxicity. Non-evaluable participants in the dose escalation stage will be replaced

[0668] Evaluation of Efficacy Endpoints

[0669] All analyses are intent-to-treat.

[0670] Example 2: A Phase 1 Study of Talabostat mesylate in Combination with hypomethylating agents (Decitabine or Azacitidine) and Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome and in Treatment Naive Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome ineligible for standard induction chemotherapy.

[0671] Primary Objectives

[0672] The primary objectives of the study are:

1. To evaluate the safety of Talabostat mesylate in an AML or high-risk MDS population given as a cycle of days 1-3, 8-10, 15-17 and 22-24 in a 4-week cycle

2. To evaluate the safety of Talabostat mesylate in combination with hypomethylating agent (HMA) + Venetoclax given as 4-week cycles.

[0673] Secondary Objectives

[0674] The secondary objectives of the study include:

1. To determine the MTD or recommended Phase 2 dose (RP2D) of Talabostat mesylate as a single agent on days 1-3, 8-10, 15-17 and 22-24 in a 4-week cycle schedule.

2. To estimate response rates — complete remission (CR), complete response with incomplete count recovery (CRi), partial response (PR), morphologic leukemia-free state (MLFS) and hematologic improvement (HI) of Talabostat mesylate as a single agent and in combination with HMA + Venetoclax.

3. To estimate the median overall survival (OS) of Talabostat mesylate as a single agent and in combination with HMA + Venetoclax.

4. To estimate the median duration of response (DOR) of Talabostat mesylate as a single agent and in combination with HMA + Venetoclax. 5. To assess pharmacokinetics of Talabostat mesylate regimen as a single agent day 1-3, 8-10, 15-17 and 22-24 in a 4-week cycle schedule and in combination with HMA+ Venetoclax.

[0675] Exploratory objectives

1. To assess the pharmacodynamic profile of Talabostat mesylate with the single agent regimen and in combination with HMA + Venetoclax by measuring relevant effects on cytokines predicted to be modulated by Talabostat mesylate

2. To explore the relationship between baseline and on-treatment circulating tumor neoantigens and T-cell repertoire and clinical outcomes (Central Laboratory)

3. To explore the relationship between baseline tumor messenger ribonucleic acid (mRNA) immune profiling panel and clinical outcomes.

4. To measure the inhibitory effect of Talabostat mesylate on FAP and DPP 4/8/9 in marrow samples both pre- and post-treatment with Talabostat mesylate as a single agent and in combination with HMA + Venetoclax.

5. To evaluate potential biomarkers such as Copy Number Variants (CNV) and mRNA of DPP9, DPP8, DPP4, FAP, Caspase- 1, Pro-caspase- 1 , NLRP1, and CARD8.

[0676] PARTICIPANT SELECTION

[0677] Eligibility criteria

1. Age 18 and older

2. Subjects with evidence of AML that meet at least one of the following criteria:

Treatment Naive AML patient who is considered ineligible for standard induction chemotherapy

Relapsed AML: as evidence by >5% myeloblasts in the bone marrow, or reappearance of blasts in the peripheral blood

Refractory AML: <2 prior induction regimens (example: patients who receive 7 + 3 followed by 5 + 2 would count as one induction regimen) ECOG performance status <2 (Karnofsky >60%). Life expectancy greater than 3 months. Participants must have adequate organ and marrow function as defined below:

Creatinine Clearance >30 mL/min (by Cockcroft-Gault) or Creatinine <1.5x ULN

Total Bilirubin <1.5 x ULN*

ALT and AST <3x ULN*

EF >35%

* unless considered due to leukemic organ involvement

NOTE: Subjects with Gilbert’s Syndrome may have a total bilirubin >1,5 x ULN per discussion with overall study PI. [Cohort B] WBC <25,000 / pL on day of 1 of cycle 1; cytoreduction is permitted with hydroxyurea which is allowed throughout cycle 1 until cycle 2 days 1. Human immunodeficiency virus (FHV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Participants with treated central nervous system (CNS) disease are eligible if follow-up brain imaging after CNS-directed therapy shows no evidence of progression Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Male subjects must agree to refrain from unprotected sex and sperm donation from initial drug administration until 90 days after the last dose of study drug. Females of childbearing potential (i.e not postmenopausal for at least 1 year or not surgically sterile) must have negative results by a serum pregnancy test performed within 7 days of day 1.

14. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria Subjects who have known Acute Promyelocytic Leukemia. Subjects with active CNS involvement with AML. Participants who have had chemotherapy or radiotherapy within 2 weeks or 5 half-lives from initiation of therapy. Subjects who are <100 days from allogeneic bone marrow transplant. Subjects who have active graft- versus host disease requiring immunosuppression >10 mg prednisone daily. Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxi cities >Grade 1) with the exception of alopecia. Participants who are receiving any other investigational agents. Use of either Decitabine, azacitibine, or Venetoclax within 4 months of starting treatment, or history of allergic reaction of any of these compounds. Concomitant medications: It is strongly encouraged that patients who are on strong inducers or inhibitors of CYP3A4 be changed to a comparable drug if possible. Patients are not permitted to be on a gliptin (sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin). Patients with a history of orthostatic hypotension with a baseline SBP <100, or history of uncontrolled hypertension. Subject has cardiovascular disability status of NYHA class >2 No concurrent active malignancies are allowed on study for >2 years prior to treatment start with the exception of currently treated basal cell or squamous cell carcinoma of the skin, carcinoma in-situ of the cervix or breast, or low-grade prostate cancer. Patients with known active hepatitis B virus (HBV) infection should be excluded because of potential effects on immune function and/or drug interactions. However, if a patient has HBV history with an undetectable HBV load by polymerase chain reaction (PCR), no liver- related complications, and is on definitive HBV therapy, then he/she would be eligible for study. Patients with known active hepatitis C virus (HCV) infection. Patients with a history of HCV infection who received definitive therapy and has an undetectable viral load by PCR would be eligible.

15. Participants with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Any other prior or ongoing condition, in the opinion of the investigator, that could adversely affect the safety of the patient or impair the assessment of study results. As patients with AML and MDS are prone to infections, if patients are actively being treated with appropriate antibiotics or antifungal therapy with clinical evidence of infection control, then they will be considered eligible for study.

16. Participants with psychiatric illness/social situations that would limit compliance with study requirements.

17. Pregnant women are excluded from this study because Azacitidine, Decitabine , Venetoclax, and Talabostat all have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued.

[0678] TREATMENT PLAN

[0679] Treatment regimen

[0680] This is a phase 1 trial that will utilize dose escalation in a standard 3 + 3 format. There are two cohorts in this study. The first cohort (cohort A) will evaluate the safety and tolerability of Talabostat mesylate on days 1-3, 8-10, 15-17 and 22-24 of a 28-day cycle for patients with relapsed/refractory AML (Table 5). No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the patient’s malignancy, except for hydroxyurea.

Table 5.

* Additional dosing schedules, eg. modified pulse dosing (days 1-3, 8-10, 15-17 of 28 days cycle) or step-up dosing may also be evaluated during the Dose Escalation Stage. Total daily dose will not exceed 1.6 mg (0.8 mg BID)

[0681] Lead-in Stage (Cohort A):

[0682] Patients will be observed for DLT during Cycle 1 . Three patients will be treated initially with Talabostat mesylate 0.3 mg PO BID on days 1-3, 8-10, 15-17 and 22-24 or each 28-day cycle: [0683] If >1 of the 3 original patients has a DLT in Cycle 1, after a discussion between BioXcel and the investigator, either 3 patients (if 1 patient experiences a DLT) will be added at the Talabostat mesylate 0.3 mg PO BID dose level, the dose level will be decreased to 0.2 mg daily or a modified pulse dosing (days 1-3, 8-10, 15-17 of 28 days cycle) or step-up/dose priming strategy may be incorporated based on the time to onset and nature of the DLT(s).

[0684] If there are no DLTs in Cycle 1, the dose of Talabostat mesylate will be escalated to 0.6 mg in the next cohort of 3 patients. For this next Talabostat mesylate 0.6 mg BID cohort:

If less than one-third of the patients experience a DLT, consideration will be given to dose escalation to 0.8 mg Talabostat mesylate

If one-third of the patients experience a DLT, an additional 3 patients will be treated at this dose level. If less than or equal to one of 6 patients then has a DLT, then we will expand to the 0.8 mg dose level.

If more than or equal to one-third of the 6 patients treated experience a DLT, a discussion will be held between the investigators and BioXcel as to how to proceed [0685] Following dose escalation to Talabostat mesylate 0.8 mg PO BID in 3 patients:

[0686] If there are no DLTs, Cohort B (the combination study) will be initiated at dose -1 of the determined lead-in dose (if no DLT noted in the 0.8 mg dose level the dose level of 0.6 mg BID will be chosen).

[0687] In the event that 0 of 3 patients in a dose level experience a DLT, the dose level may still be expanded to 6 evaluable patients based on observed toxicity at the current dose level at the discretion of the overall PI to capture patient safety prior to expanding.

[0688] Treatment of Lead-in Stage (Cohort A) [0689] Talabostat mesylate will be given orally with first dose of each cycle given in the clinic, and patients will then take doses at home BID. They will also receive the morning dose on day 3, 8, 15 and 22 of cycle 1 in the clinic.

[0690] Procedures:

[0691] Cycle 1 Labs will be obtained Days 1 , 3, 8, 15, 22 and any additional time at the discretion of the treating physician.

[0692] Cycle 2 labs will be obtained on Days 1, 8, 15, 22 and any additional time at the discretion of the treating physician.

[0693] Subsequent cycles will have labs on Day 1 of each cycle and any additional time at the discretion of the treating physician.

[0694] Bone marrow biopsy (including aspirate, core, flow cytometry, flow for MRD, cytogenetics and rapid heme panel) will be performed at Cycle 1 Day 22.

[0695] Bone marrow biopsy (including aspirate, core, flow cytometry, and flow for MRD will be sent on subsequent bone marrow biopsies) will be performed at the end of Cycles 2, 4, and 6. After Cycle 6, bone marrow biopsies will be obtained every 3 cycles. A repeat marrow will be performed at any time when there is suspicion of relapse if a response is attained, or at the discretion of the treating physician.

[0696] The DLT window will be after the first 28-day cycle, however, if the bone marrow biopsy on day 24 demonstrates a morphologic leukemia free state (MLFS), the DLT window for cytopenias will be 42 days. At the end of Cycle 2, patients with evidence of disease progression will be removed from study unless there is evidence of treatment tolerability and clinical benefit (i.e., improvement in transfusion frequency, peripheral blast reduction or symptom improvement). Patients with evidence of disease progression may be allowed to stay on study if deriving clinical benefit with approval from the overall PI.

[0697] Combination Phase (Cohort B)

[0698] The combination study will combine the standard of care hypomethylatmg agent (Decitabine or Azacitidine) and Venetoclax with Talabostat mesylate (Table 6). This will be initiated at one dose level below the determined maximum tolerated dose from Cohort A. For example, if the maximum tolerated dose from the Cohort A study is 0.8 mg, then the dose level of 0.6 mg BID will be chosen as the initial dose of Cohort B. Table 6. a Venetoclax will be dose escalated per label at 100 mg day 1, 200 mg day 2, then 400 mg daily. b Azacitidine 75 mg/m ² days 1-7 can be substituted for Decitabme at the discretion of the treating physician.

[0699] Patients will be observed for DLT during Cycle 1 . Three patients will be treated initially with Talabostat mesylate (at one dose level below the single agent dose determined in Cohort A. Talabostat mesylate (dose escalation will proceed as follows:

[0700] If >1 of the 3 original patients has a DLT in Cycle 1, after a discussion between BioXcel and the investigator, either 3 patients (if 1 patient experiences a DLT) will be added at the current dose level, the dose level will be decreased one level or a modified pulse dosing strategy or step- up/dose priming strategy may be incorporated based on the time to onset and nature of the DLT(s). [0701] If there are no DLTs in Cycle 1, the dose of Talabostat mesylate will be escalated to the next level in the next cohort of 3 patients. i. If less than one-third of the patients experience a DLT, consideration will be given to dose escalation of Talabostat mesylate ii. If one-third of the patients experience a DLT, an additional 3 patients will be treated at this dose level. If less than or equal to one of 6 patients then has a DLT, then we will expand to the next mg dose level. iii. If more than or equal to one-third of the 6 patients treated experience a DLT, a discussion will be held between the investigators and BioXcel as to how to proceed [0702] To ensure that safety profile at the MID or RP2D is acceptable, an additional 10 patients will be enrolled at the final expansion dose in Cohort B.

[0703] Treatment of Combination arm (Cohort B)

[0704] Talabostat mesylate will be given orally with first dose of each cycle in the clinic, and patients will then take doses at home BID. They will also receive the morning dose of Cycle 1 Days 3, 8, and 15 in the clinic.

[0705] Patients will receive all doses of the hypomethylating agent (Decitabine Days 1-5 or Azacitidine Days 1-7) in clinic.

[0706] Procedures:

Cycle 1 Labs will be obtained Days 1, 3, 8, 15, 22 and any additional time at the discretion of the treating physician.

Cycle 2 labs will be obtained on Days 1, 8, 15, 22 and any additional time at the discretion of the treating physician.

Subsequent cycles will have labs on Day 1 of each cycle and any additional time at the discretion of the treating physician.

Bone marrow biopsy (including aspirate, core, flow cytometry, flow for MRD, cytogenetics and rapid heme panel) will be performed at Cycle 1 Day 22.

Bone marrow biopsy (including aspirate, core, flow cytometry, and flow for MRD will be sent on subsequent bone marrow biopsies) will be performed at the end of Cycles 2, 4, and 6. After Cycle 6, bone marrow biopsies will be obtained every 3 cycles. A repeat marrow will be performed at any time when there is suspicion of relapse if a response is attained.

[0707] The DLT window will be after the first 28-day cycle, however, if the bone marrow biopsy on day 24 demonstrates a morphologic leukemia free state (MLFS), the DLT window for cytopenias will be 42 days. At the end of Cycle 2, patients with evidence of disease progression will be removed from study unless there is evidence of treatment good tolerability and clinical benefit (i.e. improvement in transfusion frequency, peripheral blast reduction or symptom improvement. Patients with evidence of disease progression may be allowed to stay on study if deriving clinical benefit with approval from the overall PI.

[0708] Pre-Treatment Criteria

[0709] Cycle 1, Day 1 [0710] Since these patients carry the diagnosis of AML there are no hematologic criteria to initiate therapy (Cycle 1, Day 1). Patients need to meet the eligibility criteria that has been established in the Inclusion and Exclusion criteria. For patients in the combination arm (Cohort B), the WBC must be less than 25,000/pL on the first day of therapy. Hydroxyurea is permitted throughout the first cycle of treatment in both Cohort A and B.

[0711] Subsequent Cycles

[0712] In order to initiate subsequent cycles:

[0713] If the patient has persistent disease (demonstrated by Day 21 marrow showing persistent disease, peripheral blasts, or persistent leukemia cutis or any other extramedullary disease), there are no hematologic requirements to start Cycles 2-4. Patient who started treatment as AML but have de-escalated to MDS due to treatment in Cycle 1 have no hematologic requirements to start Cycles 2-4.

[0714] In the absence of disease (based on bone marrow or peripheral blood standards as above), patients must have an absolute neutrophil count of >500 x 109/L and platelet count of >50,000 x 109/L to proceed, otherwise administration of treatment will be delayed.

[0715] Agent Administration

[0716] Talabostat mesylate

[0717] Administration: Talabostat mesylate is an oral medication. All pills should be taken at the same time with approximately 240 mL of water and not on an empty stomach. Tablets must be swallowed whole and must not be broken, chewed or crushed. The dose should be administered at approximately the same time each day. If vomiting occurs >10 minutes after dosing of Talabostat mesylate, no further attempts at dosing that particular Talabostat mesylate dose should take place; dosing should resume with the next dose. This should be documented. The next dose should be taken at the usual time.

[0718] Unit: Tablets

[0719] Route: Oral

[0720] Dose levels include 0.2 mg BID (dose level -1, if necessary), 0.3 mg BID, 0.6 mg BID, and 0.8 mg BID of Talabostat.

[0721] Supportive care measures: To minimize risk of hypotension, patients should be advised to maintain adequate hydration while taking Talabostat mesylate treatment, such as drinking at least 2 liters of fluids per day, including fluids with electrolytes. Factors such as strenuous exercise, heat, humidity, fever, gastrointestinal disturbance may increase hydration needs. Administration of at least 500 mL of intravenous (IV) fluids can be considered in conjunction with other infusions (e.g. Decitabine Days 1-5 of each cycle) or as needed, at investigator’s discretion.

[0722] Criteria for Taking a Participant Off Protocol Therapy

[0723] Duration of therapy will depend on individual response, evidence of disease progression and tolerance. In the absence of treatment delays due to AE(s), treatment may continue for up to 12 cycles or until one of the following criteria applies: a. Disease progression (as defined by ELN 2017 criteria for AML and by IWG criteria for MDS) b. Intercurrent illness that prevents further administration of treatment c. Unacceptable AE(s) d. Participant demonstrates an inability or unwillingness to comply with the oral medication regimen and/or documentation requirements e. Participant decides to withdraw from the protocol therapy f. General or specific changes in the participant's condition render the participant unacceptable for further treatment in the judgment of the treating investigator

[0724] Participants will be removed from the protocol therapy when any of these criteria apply. The reason for removal from protocol therapy, and the date the participant was removed, must be documented in the case report form (CRF). Alternative care options will be discussed with the participant.

[0725] When a participant is removed from protocol therapy and/or is off of the study, the participant’s status must be updated in OnCore in accordance with REGIST-OP-1.

[0726] Duration of Follow Up

[0727] Participants will be followed for up to 52 weeks after removal from protocol therapy or until death, whichever occurs first. Participants removed from protocol therapy for unacceptable AE(s) will be followed until resolution or stabilization of the AE.

[0728] Criteria for Taking a Participant Off Study

[0729] Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death [0730] The reason for taking a participant off study, and the date the participant was removed, must be documented in the CRF. In addition, the study team will ensure the participant’s status is updated in OnCore in accordance with REGIST-OP-1.

[0731] Laboratory Correlative Studies

[0732] Correlative laboratory studies will be performed to assess pharmacokinetics, cytokine response, and T-cell inflammatory response after treatment with Talabostat mesylate to the leukemia cells. Prior to obtaining the samples, each tube will be labelled with the patient study number, date collected, site of collection (peripheral blood v. marrow). Each category will be addressed below:

[0733] Correlative Study 1 : Pharmacokinetics in AML patients

[0734] Collection of Pharmacokinetic specimens

[0735] PK samples from peripheral blood will be collected at the following times: Cycle 1 Day 1 : pre-dose, 2 hours (± 30 min), 4 hours (±30 minutes), 8 hours (±30 minutes) Cycle 1 Day 3: pre-dose, 2 hours (± 30 min), 8 hours (±30 minutes)

Cycle 1 Day 8: pre-dose and 2 hours (± 30 min) if possible.

Cycle 1 Day 15: pre-dose and 2 hours (± 30 min) if possible.

Cycle 1 Day 22: pre-dose and 2 hours (± 30 mm) if possible.

Cycle 2 Day 1 : pre-dose.

[0736] In the event a step-up dosing strategy is implemented, then collect samples as indicated for Cycle 1, Day 1 for the first dose at the new level when possible.

[0737] Handling of Specimens

[0738] Detailed instructions for collecting, processing, storing and shipping samples are provided in a separate laboratory manual.

[0739] Correlative study 2: Cytokine response to Talabostat

[0740] Collection of samples for cytokines studies: a. Peripheral blood samples will be collected in a 8.5 mL EDTA vacutainer tube at the following timepoints:

Cycle 1 Day 1 : pre-dose, 4 hours (±30 minutes), 8 hours (±30 minutes) Cycle 1 Day 3: pre-dose, 4 hours (±30 minutes), 8 hours (±30 minutes) Cycle 1 Day 8: pre-dose

Cycle 1 Day 15: pre-dose.

Cycle 2 day 1 : pre-dose.

[0741] Samples will be sent to Myriad Labs for the following cytokines: G-CSF, GM-CSF, IFN- Y,IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-18, MIP-1 a, MIP-1 0, MCP-1, TNF-oc,TNF- 0, BDNF, Eotaxin-1, Factor VII, ICAM-1,IL-1 a, IL-1 0, IL-lra, IL-12p40, IL-12p70, IL-15, IL- 17, IL-23, MMP-3, MMP-9, SCF, and VEGF

[0742] Handling of Specimens

[0743] Detailed instructions for collecting, processing, storing and shipping samples are provided in a separate laboratory manual.

[0744] Correlative study 3: T-cell morphology and subsets in marrow studies.

[0745] A bone marrow biopsy will be performed at screening and to assess for response to treatment at Cycle 1 Day 22 (± 1 day). Flow cytometry will be additionally assessed for T-cell markers and also the core will be stained for T-cell immunohistochemistry (CD3, CD4, CD8, CD25, CD56, CD57).

[0746] STUDY CALENDAR

[0747] Baseline screening evaluations are to be performed within 14 days of protocol therapy, including the mandatory pre-treatment bone marrow aspirate research sample, except as specifically noted (Table 7 and Table 8). In the event that the participant’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy.

[0748] Assessments must be performed prior to administration of any study agent, unless otherwise specified in the protocol.

[0749] Table 7 : Cohort A, Study Events a Doses on Cycle 1 Days 1, 3, 8, 15, 22 and Cycle 2 day 1 are given in clinic. bVital signs, including siting and standing blood pressure, prior to administration of Talabostat c Daily during the Talabostat dosing days of Cycle 1, and during the first week following any intra-patient dose escalation (should step-up/priming dosing be used), the patient will perform at home blood pressure monitoring at least twice daily, once in the morning and once in the late aftemoon/evening, prior to Talabostat dosing. The patient will record blood pressure measurements on a log and will be asked to bring the log with them to every clinic visit during Cycle 1 and during the first cycle that their dose is escalated. The patient will be instructed that if their blood pressure is below 100 mmHg systolic or 50 mmHg diastolic, they must call their physician for further instruction. (CALL FROM CLINIC FOR THE FIRST WEEK CHECKING BP NUMBERS) dDuring the first cycle of treatment, on Talabostat treatment days + plus 1 (days 1-4, 8-11, 15-18 and 22- 25) when the patient is not otherwise seen in the clinic, the study team will maintain regular daily contact with the patient to remind them of oral hydration guidelines, review any side effects, and review the at- home blood pressure measurements

^e Differential per institutional standards

Including: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total protein, albumin, calcium, phosphorus, uric acid, total bilirubin, ALT (SGPT), AST (SGOT), alkaline phosphatase, LDH; Screening and day 1 of each cycle to include lactic acid; pre-study (screening) also includes creatine phosphokinase (CPK) ^g Urine or serum pregnancy test performed within 14 days of Day 1 for women of childbearing potential ^h Performed within 30 days of first protocol treatment

AE monitoring to continue for 30 days following last treatment

To be performed after consent, within 14 days prior to start of first cycle of study treatment for prestudy marrow to include aspirate for mandatory correlative studies. Further performed on Cycle IDay 22, end of Cycle 2, 4 and 6 and then every 3 cycles until relapse. Bone marrow biopsy window is ±2 days. ^k PK sampling, to be collected Cycle 1 Day 1, 3, 8, 15, Day 22, and Cycle 2 Day 1. If laboratory staffing would preclude PK draws on a specified day (e.g., the weekend), then it is acceptable to change a PK day(s) to a different day that Talabostat is given

'correlative sampling for cytokines. Samples to be collected Cycle 1 Day 1, 3, 8, 15, Day 22 (optional), and Cycle 2 Day 1.

[0750] Table 8: Cohort B, Study Events a Doses on Cycle 1 Days 1, 3, 8, 15, 22 and Cycle 2 day 1 are given in clinic. bVital signs, including sitting and standing blood pressure, prior to administration of Talabostat. c Daily during the Talabostat dosing days of Cycle 1, and during the first week following any intra-patient dose escalation (should step-up/priming dosing be used), the patient will perform at home blood pressure monitoring at least twice daily, once in the morning and once in the late aftemoon/evening, prior to Talabostat dosing. The patient will record blood pressure measurements on a log and will be asked to bring the log with them to every clinic visit during Cycle 1 and during the first cycle that their dose is escalated. The patient will be instructed that if their blood pressure is below 100 mmHg systolic or 50 mmHg diastolic, they must call their physician for further instruction. dDuring the first cycle of treatment, on Talabostat treatment days + plus 1 (days 1-4, 8-11, 15-18 and 22- 25) when the patient is not otherwise seen in the clinic, the study team will maintain regular daily contact with the patient to remind them of oral hydration guidelines, review any side effects, and review the at- home blood pressure measurements. eDifferential per institutional standards including: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total protein, albumin, calcium, phosphorus, uric acid, total bilirubin, ALT (SGPT), AST (SGOT), alkaline phosphatase, LDH; Screening and day 1 of each cycle to include serum lactate; pre-study (screening) also includes creatine phosphokinase (CPK)

⁸ Urine or serum pregnancy test performed within 14 days of Day 1 for women of childbearing potential hPerformed within 30 days of first protocol treatment

‘AE monitoring to continue for 30 days following last treatment

'To be performed after consent, within 14 days prior to start of first cycle of study treatment for prestudy marrow to include aspirate for mandatory correlative studies. Further performed on Cycle 1 Day 22, end of Cycle 2, 4 and 6 and then every 3 cycles until relapse. Bone marrow biopsy window is ±2 days. kPK sampling, to be collected Cycle 1 Day 1, 3, 8, 15, Day 22, and Cycle 2 Day 1. If laboratory staffing would preclude PK draws on a specified day (e g., the weekend), then it is acceptable to change a PK day(s) to a different day that Talabostat is given

¹ correlative sampling for cytokines. Samples to be collected Cycle 1 Day 1, 3, 8, 15, Day 22 (optional), and Cycle 2 Day 1. [0751] STATISTICAL CONSIDERATIONS

[0752] This is a multi-center open-label phase 1 dose escalation study of Talabostat mesylate as a single agent using a 3 + 3 design followed by Talabostat in combination with hypomethylating agent and Venetoclax with an expansion cohort. The primary objective is to determine the maximum tolerated dose (mtd) or recommended phase 2 dose (RP2D) of Talabostat in combination with hypomethylating agents with AMLor high-risk MDS. DLTs will be evaluated in cycle 1.

[0753] Study Design/Endpoints

[0754] For the Phase 1 dose escalation cohort A portion of the trial patients will enter in cohorts of three and receive single agent Talabostat on Days 1-3, 8-10, 15-17 and 22-24 of a 28 day Cycle. As this is a new dosing schema that varies from the previous solid tumor trials, we will be utilizing a 3 + 3 design that will evaluate 3 different dose levels (0.3 mg BID, 0.6 mg BID, and 0.8 mg BID) and a dose level (-1) in case of initial toxicity.

[0755] Dose level 1 will be the starting dose. At a given dose level, if in the first three patients none have experienced DLT in cycle 1 (28 days) the dose will be escalated. However, if 2 out of the first 3 patients experience DLT in the first 3 patients, then the dose will be de-escalated to a lower daily dose of Talabostat. If one out of the first three patients has a DLT at the current dose level, then a new set of three patients will be treated at that dose level. If there is no DLT in the new set of three patients, then the dose can be escalated. If one or more of these three additional patients experience a DLT, then patient entry at that dose level is stopped, and the MTD has been exceed and the dose will be de-escalated.

[0756] Following the dose escalation portion in cohort A, the investigators will determine the expansion dose of cohort B, starting one dose level lower (-1) than the RP2D. This phase will then have a safety run-in to sure that the RP2D dose is safe with the addition of hypomethylating agents and Venetoclax. The table below (table 9) gives the operating characteristics of this design for the probability of dose escalation based on the true but unknown rate of DLT at a given dose level. For example, if the true but unknown rate of DLT is 20%, the probability of escalation is 0.71, but 0.31 if the true but unknown rate of DLT is 40%.

[0757] Table 9. Probability of Dose Escalation

[0758] To ensure that toxicity at the MTD or RP2D is acceptable, we will enroll an additional 10 patients at the expansion dose in Cohort B.

[0759] Overall survival will be estimated using the method of Kaplan and Meier calculated from the date of the first dose to death or last known follow-up. Progression-free survival will be estimated from the date of first dose to the date of first progression or death from any cause and will be censored at the last response assessment date. For patients who have a response, the time to CR/CRi will be estimated from the date of first dose to the date of CR/CRi and reported with 90% confidence intervals. The response duration will also be estimated and will be calculated from the date of first response to the date of to the date of progression or death and will be estimated using the method of Kaplan and Meier and subjects without progression or death will be censored at the last response assessment date.

[0760] Sample Size, Accrual Rate and Study Duration

[0761] The Phase 1 portion of this study will follow a 3 + 3 dose escalation with an expansion group in Cohorts A and B, as described above, to evaluate safety, toxicity and to determine the Phase 2 dose of Talabostat in combination with hypomethylating agent plus Venetoclax (Cohort B). Up to 18 patients may enroll in the dose escalation portion cohort A and 6 patients in cohort B for a total of potentially 24 patients in the Phase 1 dose escalation and a further 10 patients in the expansion cohort. Accrual is open to males and females of all races and ethnic groups. We estimate 1-2 years of accrual (approximately 1-2 patients enrolled per month) to reach this target number of subjects. The DFCI Leukemia Program alone sees over 200 new AML patients per year, many of which will be eligible for this trial at some point in their disease process. Potential patient numbers are similar at the outside sites. The study duration is estimated to be approximately 2-3 years, with up to one additional year for survival monitoring. [0762] Reporting and Exclusions

[0763] Evaluation of Toxicity [0764] All participants who receive at least one dose of study treatments are evaluable for toxicity. Participants who are alive and remain in the study until 28 days after the first treatment day are considered evaluable for dose-limiting toxicity. Non-evaluable participants in the dose escalation stage will be replaced.

[0765] Evaluation of Efficacy Endpoints [0766] All analyses are intent-to-treat.