TREATING CANCER WITH A BROMODOMAIN AND EXTRA-TERMINAL (BET)

FAMILY INHIBITOR

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Application No.

62/869,103, filed July 1, 2019, U.S. Application No. 62/869,089, filed July 1, 2019, U.S.

Application No. 62/869,077, filed July 1, 2019, U.S. Application No. 62/869,059, filed July 1, 2019, U.S. Application No. 62/930,716, filed November 5, 2019, U.S. Application No.

62/930,724, filed November 5, 2019, U.S. Application No. 62/930,726, filed November 5, 2019, and U.S. Application No. 62/930,709, filed November 5, 2019, the entirety of each of which is hereby incorporated by reference.

TECHNICAL FIELD

[0002] The present disclosure relates to the treatment of cancer, using a BET inhibitor compound, optionally in combination with a hypomethylating agent.

BACKGROUND

[0003] Acute leukemias and relapsed/refractory mature B-cell non-Hodgkin lymphoma (NHL) represent a collection of diseases that typically have poor outcomes. The lack of significant new improvements in therapy for most acute leukemias and lymphomas highlights the unmet need in these diseases. BET bromodomain inhibition has emerged as a novel approach to the treatment of (acute myeloid leukemia) AML and other cancer types. Suppression of the BET family member BRD4 directly decreases expression of the MYC oncogene, implicating BRD4 inhibition as an effective small-molecule approach to suppress MYC expression in cancer cells.

[0004] The BET family of bromodomains (BRD2, BRD3, BRD4 and BRDT) binds to acetylated lysine residues on histones. The BET bromodomain family is part of the‘reader’ class of epigenetic proteins. In particular, BRD4 acts as an adaptor protein to recruit the positive transcription elongation factor b (P-TEFb) to promoter sites leading ultimately to transcription of genes relevant to oncology and other diseases, such as MYC. The mechanistic consequence of BET inhibition is downregulation of gene expression from BET super-enhancer driven genes, with the subsequent loss of proteins by proteolytic turnover. [0005] Compound A ((S)-(5-cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazo l-4-yl)- 3,4-dihydroquinolin-l(2H)-yl)(cyclopropyl)methanone) is one of many small molecule BET (Bromodomain and Extra-Terminal) family bromodomain inhibitor compounds disclosed in WO 2015/074064 (published May 21, 2015, the entirety of which is incorporated herein by reference) with significant structural differentiation from other more selective (+)-JQl based BET inhibitors. For example, the use of BET Inhibitor FT-1101 in human clinical trials is disclosed under clinical trial identifier NCT02543879 at the website clinicaltrials.gov.

SUMMARY

[0006] The present disclosure, among other things, provides certain technologies for treating cancer (e.g., acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and/or non- Hodgkin lymphoma (NHL)) and/or other BET-mediated diseases, disorders, or conditions in a subject. In some embodiments, the present disclosure provides methods of treating, stabilizing, or lessening the severity or progression of one or more diseases, disorders, or conditions (e.g., a cancer, e.g., AML/MDS and/or NHL) comprising administering a BET Inhibitor Compound, such as (S)-(5-cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol -4-yl)-3,4- dihydroquinolin-l(2H)-yl)(cyclopropyl)methanone (Compound A), or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the present disclosure encompasses the insight that particular dosing regimens of a BET Inhibitor Compound (e.g., Compound A, and compounds of Table 1) achieve one or more particular effects in a subject. In some embodiments, the present disclosure provides a method of administering a BET Inhibitor Compound (e.g., Compound A and compounds of Table 1) that achieves a particular plasma concentration, maintained over a certain time interval and/or for a particular fraction of time between doses. In some embodiments, the present disclosure provides a method of administering a BET Inhibitor Compound (e.g.,

Compound A and compounds of Table 1) that achieves a particular maximum concentration and/or area under the curve and/or half-life. In some embodiments, the present disclosure provides a method of administering a BET Inhibitor Compound (e.g., Compound A and compounds of Table 1) that achieves a particular time over a threshold (“TOT”) plasma concentration. The present disclosure encompasses the insight that maintaining particular exposure levels of BET Inhibitor Compounds (e.g., Compound A and compounds of Table 1) is effective at treating, stabilizing, or lessening the severity or progression of one or more diseases, disorders, or conditions (e.g., a cancer, e.g., AML/MDS and/or NHL). In some embodiments, methods described herein achieve a plasma concentration of a BET Inhibitor Compound (e.g., Compound A) within the subject, greater than about 100 nM for a particular fraction of time between doses (e.g., about 30-50% of time between doses). In some embodiments, the present disclosure also encompasses the recognition that such regimens can be used in combination with one or more known therapies, such as a hypomethylating agent (e.g., azacitidine).

[0008] In some embodiments, the present disclosure provides novel intermittent dosing schedules for (S)-(5-cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol -4-yl)-3,4- dihydroquinolin-l(2H)-yl)(cyclopropyl)methanone (Compound A) useful for the treatment of a disease, disorder, or condition (e.g., cancer).

(Compound A)

[0009] Various BET inhibitor compounds are being evaluated in human clinical trials (e.g., Table 1 below). The characteristics of some BET inhibitors include high oral bioavailability and solubility and a long observed human blood half-life (e.g. 2-2.5 days), supporting intermittent administration (e.g., weekly (QW), biweekly (Q2W) or monthly (QM)) of a BET Inhibitor Compound, or a pharmaceutically acceptable salt thereof, to treat certain forms of cancer. In certain embodiments, methods of administering a BET Inhibitor Compound achieve target exposure over an (approximate) 100 nM threshold for about 30-50% of the time between doses (time over threshold, or“TOT”). Said TOT was found to provide tumor regressions, which is believed to correlate with -80% MYC suppression and regression in AML and lymphoma models. In some embodiments, methods of treatment do not include administration of a BET Inhibitor Compound on consecutive days or too frequently for prolonged periods of time (e.g., >7d) without intermittent dosing.

[0010] For example, Compound A has been evaluated in human clinical trials (e.g.,

Examples 4-6 below). The characteristics of Compound A, including high oral bioavailability, solubility, and a long observed human blood half-life (e.g. 2-2.5 days), support intermittent administration (e.g., QW, Q2W or QM) of Compound A to treat certain forms of cancer.

Preferred methods of administering Compound A achieve target exposure over an (approximate) 100 nM threshold for about 30-50% of the time between doses ( TOT). Said TOT was found to provide tumor regressions, which is believed to correlate with -80% MYC suppression and regression in AML and lymphoma models. For example, as described herein, 400 mg QOW yields TOT of 2 to 4 days (15%-28% of dosing period), while 400 mg QW may yield target TOT of 30 -50% of dosing period. Preferably, methods of treatment do not include administration of Compound A on consecutive days or too frequently for prolonged periods of time (e.g., >7d) without intermittent dosing.

[0011] The intermittent administration of therapeutically effective amounts of a BET

Inhibitor at the intervals provided herein (e.g., once per week, or less frequently at higher doses) is useful for the treatment of certain diseases, disorders, or conditions (e.g., cancer, including AML/MDS and/or NHL). The intermittent administration of therapeutically effective amounts of a Compound A, or a pharmaceutically acceptable salt thereof, at the intervals provided herein (e.g., once per week, or less frequently at higher doses) is useful for the treatment of certain diseases, disorders, or conditions (e.g., cancer, including AML/MDS and/or NHL). For example, Compound A can be administered in a total dose of about 300 mg - 600 mg (e.g., 300 mg or 600 mg) once every week or once every other week, depending on the patient being treated, and whether Compound A is administered as a single agent (SA) or in combination with other therapeutic agents (e.g. azacitidine), as disclosed herein. In some embodiments, Compound A can be administered in a total dose of about 300 mg - 400 mg (e.g., 300 mg or 400 mg) once every week or once every other week, depending on the patient being treated. In some embodiments, patients diagnosed with AML/MDS can be treated by administering a total of 400 mg of Compound A every other week (QOW), or by administering a total of 300 mg of

Compound A every week (QW). In some embodiments, Compound A can be administered in a total dose of about 400 mg once every other week. For example, patients diagnosed with acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) can be treated by administering a total of 400 mg of Compound A every other week (QOW), or by administering a total of 300 mg of Compound A every week (QW). In some embodiments, patients diagnosed with AML/MDS can be treated by administering a total of 400 mg of Compound A every other week (QOW). In some embodiments, patients diagnosed with NHL can be treated with 400 mg of Compound A QOW.

[0012] The administration of Compound A under conditions effective to inhibit the BET bromodomain can have antitumor activity in tumors that depend on BET-driven transcription programs. The present disclosure encompasses the recognition that the efficacy of a BET family bromodomain inhibitor can be driven by short half-life genes and proteins, the loss of which drive an anti-tumor response. Thus, without being bound by theory, a defined drug exposure followed by a holiday can result in the downregulation of target genes, while longer lived maintenance genes responsible for driving toxicity may be less affected. This discovery was supported by the preclinical data for Compound A and the subsequent administration of

Compound A in human clinical trials.

[0013] Compound A is an equipotent inhibitor of all BET family bromodomains (Kd < 20 nM), as judged by a panel of biochemical binding assays. In cellular models, Compound A has sub-micromolar anti-proliferative activity across broad panels of both hematological and solid tumor-derived cell lines. In the MV-4-11 acute myeloid leukemia cell line, downregulation of the demonstrated BET target oncogene MYC by Compound A closely correlates to its potency on cellular proliferation, suggesting that the anti-proliferative effect is associated with the suppression of Myc protein levels. Following a single oral dose of 55 mg/kg Compound A in mice bearing the MV-4-11 xenograft, MYC mRNA levels were suppressed by 80-90% by 4 hours post dose, and sustained suppression of >70% was observed through at least 12 hours post dose. The maximum suppression of Myc protein (-80%) was associated with unbound plasma levels of Compound A at 1 to 2 fold above the cellular GEo. Oral dosing of Compound A in vivo led to significant tumor growth inhibition, including tumor regressions, as a single agent.

[0014] The present disclosure also provides a novel combination therapy for the treatment of cancer, comprising administration of a BET Inhibitor Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) and a hypomethylating agent, such as azacitidine. In some embodiments, the BET Inhibitor Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) is administered about 24 hours after the hypomethylating agent. The present disclosure is based in part on the discovery of a synergistic effect of pretreatment of multiple cell lines with azacitidine prior to treatment with Compound A (Example 7).

Accordingly, in some embodiments, the methods of treatment include a step of administering a therapeutically effective amount of Compound A or pharmaceutically acceptable salt thereof (e.g., 150 mg - 400 mg) about 24 hours after the administration of azacitidine.

[0015] In some embodiments, Compound A is administered to the patient in need thereof using an intermittent dosing schedule (e.g., once every other week), including at least one administration of Compound A about 24 hours after administration of a hypomethylating agent (e.g., azacitidine).

[0016] In some embodiments, intermittent administration of therapeutically effective amounts of Compound A at the intervals provided herein is useful for the treatment of certain cancer patients, including adult patients diagnosed with acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) or NHL. In combination with a hypomethylating agent (e.g., azacitidine), Compound A can be dosed below the maximum tolerated dose (MTD), starting at about 50% of the MTD, and optionally increased in successive doses up to the MTD, if tolerated.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure l is a chemical synthesis of Compound A.

[0018] Figure 2 is a graph showing results from a mouse xenograft study described in

Example 4.

[0019] Figure 3 A is a graph showing the day 1, dose normalized (Cmax/dose in

ng/mL/(mg)) ratio measured in patients receiving 80-400 mg of Compound A.

[0020] Figure 3B is a graph showing the ratio of measured AUC values in a human clinical trial.

[0021] Figure 3C is a graph showing the plasma concentrations for the administration of 400 mg of Compound A in a human clinical trial.

[0022] Figure 3D is a graph showing the plasma concentrations for the administration of 260 mg of Compound A in a human clinical trial.

[0023] Figure 4 is a summary of Compound A dose escalation, as described in Example 6.

[0024] Figure 5 displays time on treatment for patients receiving certain dosing schedules of

Compound A. SD = stable disease. CRi = complete remission with incomplete hematologic recovery.

[0025] Figure 6 is a plot of mean concentration of Compound A (ng/mL) at various time points after first oral dose. [0026] Figure 7A is a box-and-whisker plot of CCR1 modulation at 4 hrs post-dose for various doses (80-600 mg) of Compound A. The whiskers in Figure 7A represent maximum and minimum values, the box encompasses the middle two quartiles, and the line in the middle of the box plots the median.

[0027] Figure 7B is a box-and-whisker plot of HEXIM1 modulation at 4 hrs post-dose for various doses (80-600 mg) of Compound A. The whiskers in Figure 7B represent maximum and minimum values, the box encompasses the middle two quartiles, and the line in the middle of the box plots the median.

[0028] Figure 8A is a plot of mean concentration of Compound A (ng/mL) at various time points after a single 300 mg oral dose of Compound A.

[0029] Figure 8B is a plot of HEXIM1 expression (relative quantification (RQ)) over time after a single 300 mg oral dose of Compound A.

[0030] Figure 8C is a plot of CCR1 expression (relative quantification (RQ)) over time after a single 300 mg oral dose of Compound A.

[0031] Figure 9 is a plate map of a combination experiment for analyzing synergy between Compound A and azacitidine.

DEFINITIONS

[0032] The term“about”, when used herein in reference to a value, refers to a value that is similar, in context to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by“about” in that context. For example, in some embodiments, the term“about” may encompass a range of values that within (i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0033] As used herein, the term“administering” or“administration” typically refers to administration of a composition to a subject to achieve delivery of an active agent to a site of interest (e.g., a target site which may, in some embodiments, be a site of disease or damage, and/or a site of responsive processes, cells, tissues, etc.) As will be understood by those skilled in the art, reading the present disclosure, in some embodiments, one or more particular routes of administration may be feasible and/or useful in the practice of the present disclosure. For example, in some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent ( e.g ., a plurality of doses separated in time) and/or periodic (e.g., individual doses separated by a common period of time) dosing.

[0034] The term“pharmaceutically acceptable salt,” as used herein, refers to a form of a relevant compound as a salt appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and/or lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in ./. Pharmaceutical Sciences, 66: 1-19 (1977).

[0035] As used herein, the term“subject” refers an organism, typically a mammal (e.g., a human). In some embodiments, a subject is suffering from a relevant disease, disorder or condition. In some embodiments, a human subject is an adult, adolescent, or pediatric subject.

In some embodiments, a subject is at risk of (e.g., susceptible to), e.g, at elevated risk of relative to an appropriate control individual or population thereof, a disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, a subject is an individual to whom diagnosis and/or therapy and/or prophylaxis is and/or has been administered. The terms“subject” and“patient” are used interchangeably herein.

[0036] As used herein, the term“treat” (also“treatment” or“treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition.

DETATLF/D DESCRIPTION

[0037] The present disclosure, among other things, provides certain technologies for treating cancer (e.g., acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and/or non- Hodgkin lymphoma (NHL)) and/or other BET-mediated diseases, disorders, or conditions in a subject. In particular, the present disclosure encompasses the insight that certain dosing regimens of BET Inhibitor Compounds (e.g., Compound A), administered to achieve one or more particular effects (e.g., a particular exposure level for a particular duration and/or a particular area under the curve and/or a particular half-life), achieve unexpectedly beneficial results related to treatment of certain diseases, disorders, or conditions.

[0038] For example, AML/MDS and NHL are serious, life threatening diseases, and have a high rate of relapse driven by genetic mutations and deregulated epigenetic control. Treatment options are limited, especially in cases where the disease has recurred. Recently, researchers have discovered the use of BET bromodomain inhibition for treatment of certain diseases, disorders, and conditions, including AML/MDS and NHL. Certain preclinical and clinical studies highlight the relevance of targeting the bromodomain and extra-terminal (BET) family as an efficient strategy of target transcription irrespective of the presence of epigenetic mutations. The BET family of proteins are important epigenetic regulators involved in promoting gene expression of critical oncogenes by keeping an abnormal chromatin state in various hematologic malignancies, including MM, acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), and mantle cell lymphoma (MCL). Among the oncogenes known to be regulated by BET proteins in these diseases, MYC is probably the most relevant, as it is overexpressed in about 60%-70% of all cancers. See Reyes-Garau, el al ., Cancers (Basel), 11(1483): 1-19 (2019). Suppression of the BET family member BRD4 directly decreases expression of the MYC oncogene, implicating BRD4 inhibition as an effective small-molecule approach to suppress MYC expression in cancer cells. [0039] In some embodiments, the present disclosure provides methods of treating, stabilizing, or lessening the severity or progression of one or more diseases, disorders, or conditions (e.g., a cancer, e.g., AML/MDS and/or NHL) comprising administering a BET Inhibitor Compound, such as (S)-(5-cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol -4- yl)-3,4-dihydroquinolin-l(2H)-yl)(cyclopropyl)methanone (Compound A), or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the present disclosure encompasses the insight that particular dosing regimens of a BET Inhibitor Compound (e.g., Compound A, and compounds of Table 1) achieve one or more particular effects in a subject. In some embodiments, the present disclosure provides a method of administering a BET Inhibitor Compound (e.g., Compound A and compounds of Table 1) that achieves a particular plasma concentration, maintained over a certain time interval and/or for a particular fraction of time between doses. In some embodiments, the present disclosure provides a method of administering a BET Inhibitor Compound (e.g.,

Compound A and compounds of Table 1) that achieves a particular maximum concentration and/or area under the curve and/or half-life. In some embodiments, the present disclosure provides a method of administering a BET Inhibitor Compound (e.g., Compound A and compounds of Table 1) that achieves a particular time over a threshold plasma concentration (“TOT”). The present disclosure encompasses the insight that maintaining particular exposure levels of BET Inhibitor Compounds (e.g., Compound A and compounds of Table 1) is effective at treating, stabilizing, or lessening the severity or progression of one or more diseases, disorders, or conditions (e.g., a cancer, e.g., AML/MDS and/or NHL). In some embodiments, methods described herein achieve a concentration of a BET Inhibitor Compound (e.g., Compound A) within the subject, greater than about 100 nM for a particular fraction of time between doses (e.g., about 30-50% of time between doses). In some embodiments, the present disclosure also encompasses the recognition that such regimens can be used in combination with one or more known therapies, such as a hypomethylating agent (e.g., azacitidine).

BET Inhibitor Compounds

[0041] Exemplary BET Inhibitor Compounds, e.g., for use in methods provided herein, are shown in Table 1 below.

Table 1

[0042] One example of a BET Inhibitor Compound is (S)-(5-cyclobutoxy-2-methyl-6-(l- (piperidin-4-yl)-lH-pyrazol-4-yl)-3,4-dihydroquinolin-l(2H)- yl)(cyclopropyl)methanone (Compound A), which can be provided in a pharmaceutically acceptable salt form. In some embodiments, Compound A is provided in the form of a succinate salt. Compound A is an orally bioavailable compound that demonstrates potent and equivalent biochemical activity against all BET family members. BET inhibition by Compound A is associated with modulation of expression of oncogenes, such as MYC.

[0043] Compound A demonstrates sub-micromolar growth inhibitory effects on a variety of hematological and solid tumor cell lines. When these cellular effects were investigated in in vivo mouse xenograft models, such as MV-4-11, significant anti -tumor activity, including regressions, were observed on a variety of schedules and at tolerated dose levels. The anti-tumor activity observed in these studies coincided with downregulation of MYC. In a MV-4-11 human acute myeloid leukemia tumor xenograft model in mice, treatment with Compound A at 15 mg/kg QD and 55 mg/kg Q3D resulted in: (1) significantly decreased tumor volumes relative to vehicle, (2) suppressed MYC gene expression in tumors, and (3) maintained high Compound A exposure levels in plasma for 24 hr post treatment. In addition, treatment of a mLY6043 Myc driven murine lymphoma model with Compound A at 35 mg/kg Q3D resulted in significant tumor growth inhibition and at 55 mg/kg Q3D resulted in tumor regression.

[0044] BET inhibition by Compound A resulted in down-regulation of MYC gene and protein expression and displayed sub-micromolar growth inhibitory effects on a wide variety of hematological and solid tumor cell lines in vitro, including FLT3 mutated leukemia cell lines. Treatment of mice bearing human tumor xenografts in vivo with Compound A resulted in significant anti-tumor activity including tumor regression in the FLT-3 mutated MV-4-11 leukemia model on a variety of dosing schedules and at tolerated doses. The in vivo anti-tumor activity was associated with down-regulation of MYC gene expression in tumors.

[0045] In some embodiments, Compound A is provided and/or utilized in accordance with the present disclosure as a pharmaceutically acceptable salt. As already noted herein, pharmaceutically acceptable salts are well known in the art. In some embodiments, Compound A is provided and/or utilized as a succinate salt.

[0046] In some embodiments, Compound A is provided and/or utilized in accordance with the present disclosure in a solid form. In some embodiments, Compound A is provided and/or utilized in accordance with the present disclosure in an amorphous solid form, in a crystalline solid form, or in a mixture thereof. The use of any and all such forms are contemplated by the present disclosure.

[0047] Certain salts and solid forms of Compound A are described in WO 2020/006329, published on February 1, 2020, the entire contents of which are hereby incorporated by reference.

[0048] In some embodiments, Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 4.4, 6.8, 9.1, 15.3, and 38.8. In some embodiments, Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8. In some embodiments, Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8, corresponding to d-spacing (angstroms ± 0.2) of 20.1, 13.0, 9.7, 6.8, 5.8, 5.5, 4.5, 2.5, and 2.3 (respectively). In some embodiments, Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) having three or more characteristic diffractions at angles (2 theta ± 0.2) of 4.4, 6.8, 9.1, 15.3, and 38.8. In some embodiments, Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) having three or more characteristic diffractions at angles (2 theta ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8. In some embodiments, Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) having three or more characteristic diffractions at angles (2 theta ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8, corresponding to d-spacing (angstroms ± 0.2) of 20.1, 13.0, 9.7, 6.8, 5.8, 5.5, 4.5, 2.5, and 2.3 (respectively). In some embodiments, Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) as described in Example 1.

[0049] It will be understood that, throughout this disclosure, reference to an amount (e.g., in mg) of Compound A means the amount of Compound A in free base form. Accordingly, Compound A may be provided and/or utilized as, e.g., a salt form of Compound A such that the amount of the salt (or other form) is an amount that corresponds to the“free base equivalent” of Compound A. For example,“300 mg Compound A” means, e.g., approx. 300 mg of Compound A Free Base, 381.8 mg of Compound A Monosuccinate, etc.

Provided Methods

1. Dosing Regimens

[0050] Provided herein are methods of treating a patient suffering from a disease, disorder or condition (e.g., a cancer), comprising administering Compound A (e.g., by administering a composition that comprises and/or delivers Compound A as described herein) to the patient. In some embodiments, provided methods comprise administering Compound A or a

pharmaceutically acceptable salt thereof to a patient in need thereof, according to a regimen established to achieve one or more particular effects (e.g., a particular maximum concentration and/or a particular area under the curve and/or a particular half-life and/or a particular target exposure, e.g., for a particular fraction of time between doses) in a relevant population of patients. In some such embodiments, a relevant population of patients is or comprises patients with relapsed/refractory (R/R) AML/MDS, or non-Hodgkin lymphoma (NHL).

[0051] In some embodiments, a particular effect is or comprises a particular mean maximum concentration (Cmax). In some embodiments, a particular effect is or comprises a mean Cmax of greater than about 200 ng/mL, greater than about 300 ng/mL, greater than about 600 ng/mL, greater than about 900 ng/mL, greater than about 1000 ng/mL, or greater than about 1400 ng/mL. In some embodiments, a particular effect is or comprises a mean Cmax of from about 200 ng/mL to about 1400 ng/mL, about 300 ng/mL to about 1400 ng/mL, about 600 ng/mL to about 1400 ng/mL, about 900 ng/mL to about 1400 ng/mL, about 600 ng/mL to about 1000 ng/mL or about 900 ng/mL to about 1000 ng/mL.

[0052] In some embodiments, a particular effect is or comprises a particular mean plasma concentration maintained over a particular period of time. In some embodiments, a particular effect is or comprises a particular mean plasma concentration maintained for about 3 days, about 7 days, about 14 days, or about 28 days. In some embodiments, a particular effect is or comprises a mean plasma concentration of greater than about 50 ng/mL, greater than about 75 ng/mL, greater than about 100 ng/mL, greater than about 150 ng/mL, greater than about 200 ng/mL, or greater than about 250 ng/mL maintained for about 3 days, about 7 days, about 14 days, or about 28 days.

[0053] In some embodiments, a particular effect is or comprises a particular mean Cmax and a particular mean plasma concentration maintained over a particular period of time. In some embodiments, a particular effect is or comprises a mean Cmax of greater than about 200 ng/mL, greater than about 300 ng/mL, greater than about 600 ng/mL, greater than about 900 ng/mL, greater than about 1000 ng/mL, or greater than about 1400 ng/mL; and a mean plasma concentration of greater than about 50 ng/mL, greater than about 75 ng/mL, greater than about 100 ng/mL, greater than about 150 ng/mL, greater than about 200 ng/mL, or greater than about 250 ng/mL maintained for about 3 days, about 7 days, about 14 days, or about 28 days.

[0054] In some embodiments, a particular effect is or comprises a particular mean area under the curve over 168 hours or one week (AUC ₍ oi ₆₈₎ ). In some embodiments, a particular effect is or comprises a mean AU 0168) of greater than about 8000 ng*hr/mL, greater than about 11000 ng*hr/mL, greater than about 16000 ng*hr/mL, greater than about 26000 ng*hr/mL, greater than about 52000 ng*hr/mL, greater than about 55000, or greater than about 93000 ng*hr/mL. In some embodiments, a particular effect is or comprises a mean AUC(oi68) of from about 8000 ng*hr/mL to about 93000 ng*hr/mL, from about 11000 ng*hr/mL to about 93000 ng*hr/mL, from about 16000 ng*hr/mL to about 93000 ng*hr/mL, from about 26000 ng*hr/mL to about 93000 ng*hr/mL, from about 52000 ng*hr/mL to about 93000 ng*hr/mL, from about 55000 ng*hr/mL to about 93000 ng*hr/mL, from about 11000 ng*hr/mL to about 55000 ng*hr/mL, from about 16000 ng*hr/mL to about 55000 ng*hr/mL, from about 26000 ng*hr/mL to about 55000 ng*hr/mL, or from about 52000 ng*hr/mL to about 55000 ng*hr/mL.

[0055] In some embodiments, a particular effect is or comprises a particular half-life (ti/2).

In some embodiments, a particular effect is or comprises a ti/2 of greater than about 40 hours, greater than about 50 hours, or greater than about 55 hours. In some embodiments, a particular effect is or comprises a ti/2 of from about 40 hours to about 60 hours, from about 50 hours to about 60 hours, or from about 55 hours to about 60 hours.

[0056] In some embodiments, a particular effect is or comprises a target plasma

concentration over about 100 nM, e.g., for about 30% to about 50% of time between doses.

[0057] Methods of treating a patient diagnosed with cancer that depends on a BET-driven transcription program are provided herein. In some embodiments, methods of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program are provided herein. In some embodiments, a method comprises administering to the patient in need thereof a therapeutically effective dose of a BET Inhibitor Compound every week in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.

[0058] BET Inhibitor Compounds can be administered to a patient in need thereof in an amount to achieve target exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. In some embodiments, a BET Inhibitor Compound is administered to a patient in need thereof once a week (QW) in an amount sufficient to achieve target exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. In some embodiments, a BET Inhibitor

Compound is administered to a patient in need thereof once every other week (QOW) in an amount sufficient to achieve target exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. [0059] In some embodiments, provided methods comprise administering Compound A or a pharmaceutically acceptable salt thereof as a single agent (SA) therapy. In some embodiments, provided methods comprise administering Compound A or a pharmaceutically acceptable salt thereof as part of a combination therapy (e.g., as described herein).

[0060] In some embodiments, provided methods comprise administering Compound A or a pharmaceutically acceptable salt thereof once a week (QW). In some embodiments, provided methods comprise administering Compound A or a pharmaceutically acceptable salt thereof once every other week (QOW). In some embodiments, provided methods comprise administering Compound A or a pharmaceutically acceptable salt thereof once a month (QM).

[0061] In some embodiments, provided methods comprise administering Compound A or a pharmaceutically acceptable salt thereof in a dose of about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, or about 800 mg.

[0062] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof in a total dose of about 300 mg-400 mg of Compound A every week (QW).

[0063] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof in a total dose of about 300 mg-400 mg of Compound A every other week (Q2W or QOW).

[0064] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof in a total dose of about 300 mg-600 mg of Compound A once per month (QM or Q4W).

[0065] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof in a total dose of about 400 mg of Compound A every other week (Q2W or QOW).

[0066] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per week (QW) in an amount of 200 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per week (QW) in an amount of 300 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per week (QW) in an amount of 400 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per week (QW) in an amount of 600 mg.

[0067] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once every other week (QOW) in an amount of 200 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is

administered to a patient in need thereof once every other week (QOW) in an amount of 300 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is

administered to a patient in need thereof once every other week (QOW) in an amount of 400 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is

administered to a patient in need thereof every other week (QOW) in an amount of 500 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof every other week (QOW) in an amount of 600 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once every other week (QOW) in an amount of 800 mg.

[0068] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per month (QM) or once every four weeks (Q4W) in an amount of 300 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per month (QM) or once every four weeks (Q4W) in an amount of 400 mg. In some embodiments, Compound A or a

pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per month (QM) or once every four weeks (Q4W) in an amount of 600 mg.

[0069] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is preferably administered to a patient in need thereof as a single agent (SA) every other week. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered at a total dose of about 400 mg of Compound A every other week (QOW), preferably once per day.

2. Diseases, Disorders, and Conditions

[0070] In some embodiments, provided methods are useful for treating cancer (e.g.,

AML/MDS or NHL). In some embodiments, provided methods are useful for treating cancer (e.g., AML/MDS or NHL) that is relapsed or refractory to standard therapies. In some embodiments, provided methods are useful for treating AML/MDS. In some embodiments, provided methods are useful for treating relapsed or refractory AML (e.g., with intermediate or unfavorable risk cytogenetics and/or lacking FLT3 ITD or TKD alterations). In some embodiments, provided methods are useful for treating FLT3-mutated AML. In some embodiments, provided methods are useful for treating NHL.

[0071] In some methods, Compound A or a pharmaceutically acceptable salt thereof is administered for the treatment of patients with relapsed or refractory AML with intermediate or unfavorable risk cytogenetics and lacking FLT3 ITD or TKD alterations. In some methods, Compound A or a pharmaceutically acceptable salt thereof is administered for the treatment of patients with AML harboring FLT3(ITD) or FLT3(TKD) alterations that is relapsed or refractory to standard therapies.

[0072] Based in part on this, preclinical methods of treatment of patients diagnosed with FLT3 mutated AML comprise the administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof as a single agent (SA) in some embodiments. In some embodiments, preclinical methods of treatment of patients diagnosed with FLT3 mutated AML comprise the administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof in combination with other therapeutic agents. Methods of treatment are illustrated in the Examples for the treatment of patients diagnosed with AML/MDS or NHL. For example, patients diagnosed with AML, NHL, and AML/MDS can be treated with therapeutically effective amounts of Compound A as a single agent. Other patients diagnosed with AML, NHL, and AML/MDS can be treated with therapeutically effective amounts of Compound A or a pharmaceutically acceptable salt thereof in combination with azacitidine.

3. Combination Therapy

[0073] The present disclosure also provides methods of administering combination therapy comprising a BET Inhibitor Compound (e.g., Compound A) and a hypomethylating agent (e.g., azacitidine). In some embodiments, the present disclosure provides insight that intermittent dosing regimens for BET Inhibitor Compounds, e.g., those described herein, may also be useful in combination with a hypomethylating agent (e.g., azacitidine). In some embodiments, provided methods comprise administering Compound A (e.g., according to a dosing regimen described herein) to a patient who is receiving or has received a hypomethylating agent (e.g., azacitidine). Additionally, the present disclosure encompasses the recognition that combination therapy (e.g., with azacitidine) may require that timing of intermittent dosing regimens for BET Inhibitor Compounds (e.g., Compound A) be adjusted (e.g., in dose, frequency, and/or timing in relation to dosing of another therapy) in order to provide one or more desirable outcomes. In some embodiments, provided combination therapies comprise a first lower dose of BET Inhibitor Compound (e.g., Compound A) followed by one or more higher doses, e.g., separated by a particular time period.

[0074] As used herein,“combination therapy” or“in combination with” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all“doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments,“administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0075] Currently, azacitidine is recommended for patients suffering from AML that are unable to tolerate intensive salvage therapy. This guidance is based on studies showing azacitidine at a dose of 75 mg/m ² can induce Complete Remission (CR) rates of 16% to 21% and median survival times of 6 to 9 months in older patients with relap sed/refractory AML.

[0076] The AML panel of the National Comprehensive Cancer Care Network treatment guidelines also recommend azacitidine as lower intensity therapy for patients aged >60 years, and who are not candidates for intensive induction therapy, citing a study in patients with high risk myelodysplastic syndrome (MDS) and AML in which a significant survival benefit was found with 5-azacitidine compared with conventional care regimens, with a median overall survival (OS) of 24.5 versus 16 months and 2-year OS rates of 50% and 16%, respectively CP= 001). [0077] Azacitidine (Vidaza®) is labeled for an indication for adult patients who are not eligible for haematopoietic stem cell transplantation (HSCT) with:

• intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the

International Prognostic Scoring System (IPSS)

• chronic myelomonocytic leukemia (CMML) with 10-29 % marrow blasts without

myeloproliferative disorder

• acute myeloid leukemia (AML) with 20-30 % blasts and multi -lineage dysplasia,

according to World Health Organization (WHO) classification,

• AML with >30% marrow blasts according to the WHO classification.

[0078] The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m ² of body surface area, injected subcutaneously, daily for 7 days, followed by a rest period of 21 days (28-day treatment cycle).

It is recommended that patients be treated for a minimum of 6 cycles. Treatment should be continued as long as the patient continues to benefit or until disease progression. There remains a need for therapies for the treatment of certain forms of cancer, including AML, and NHL.

[0079] In some provided methods, Compound A or a pharmaceutically acceptable salt thereof can be administered with azacitidine to treat certain forms of cancer. Compound A displayed synergistic growth inhibitory activity in combination with azacitidine in leukemia cell lines. The hypomethylating agent (HMA) azacitidine is approved for the treatment of subtypes of MDS and is a recommended treatment option in AML patients who are not candidates for or who have failed intensive cytotoxic induction/consolidation regimens. Resistance to azacitidine therapy in AML has been shown to be mediated by BET proteins. Compound A in combination with azacitidine is synergistic in vitro in human leukemia cell lines; the greatest synergy was observed when cells were pre-treated with azacitidine for 24 h followed by Compound A.

Upregulation of PD-L1/PD-L2 after HMA treatment in both AML and MDS patients has been reported, indicating a diminished response to azacitidine therapy via immunotolerance may play a role in HMA treatment failures in AML/MDS. BET inhibitors have been shown to reduce PD- L1 expression of tumor cells, thus providing additional rationale for the combination of

Compound A and azacitidine in AML/MDS patients. In some methods, Compound A or a pharmaceutically acceptable salt thereof is administered in combination with azacitidine for the treatment of patients with relapsed or refractory AML, or previously untreated AML unfit for intensive therapy.

[0080] In some embodiments, provided combination therapies are useful for treating cancer (e.g., AML/MDS or NHL). In some embodiments, provided combination therapies are useful for treating cancer (e.g., AML/MDS or NHL) that is relapsed or refractory to standard therapies. In some embodiments, provided combination therapies are useful for treating AML/MDS. In some embodiments, provided combination therapies are useful for treating relapsed or refractory AML (e.g., with intermediate or unfavorable risk cytogenetics and/or lacking FLT3 ITD or TKD alterations). In some embodiments, provided combination therapies are useful for treating FLT3- mutated AML. In some embodiments, provided combination therapies are useful for treating NHL.

[0081] In some methods, Compound A or a pharmaceutically acceptable salt thereof is administered for the treatment of patients with relapsed or refractory AML with intermediate or unfavorable risk cytogenetics and lacking FTL3 ITD or TKD alterations. In some methods, Compound A or a pharmaceutically acceptable salt thereof is administered for the treatment of patients with AML harboring FLT3(ITD) or FLT3(TKD) alterations that is relapsed or refractory to standard therapies.

[0082] Accordingly, in some embodiments, methods of treatment of patients diagnosed with FLT3 mutated AML comprise the administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof in combination with azacitidine. Methods of treatment are illustrated in the Examples, for the treatment of patients diagnosed with AML/MDS or NHL. For example, patients diagnosed with AML, NHL, and AML/MDS can be treated with therapeutically effective amounts of Compound A or a pharmaceutically acceptable salt thereof in combination with azacitidine. In some embodiments, at least one dose of

Compound A or a pharmaceutically acceptable salt thereof is administered at least about 24 hours after azacitidine.

[0083] In some embodiments, provided combination therapies comprise administering a hypomethylating agent (e.g., azacitidine) according to its labeled dosing regimen.

[0084] In some embodiments, provided combination therapies comprise administering Compound A or a pharmaceutically acceptable salt thereof once a week (QW). In some embodiments, provided combination therapies comprise administering Compound A or a pharmaceutically acceptable salt thereof once every other week (QOW).

[0085] In some embodiments, provided combination therapies comprise administering Compound A or a pharmaceutically acceptable salt thereof in a dose of about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg.

[0086] In some embodiments, Compound A or a pharmaceutically acceptable salt is administered to a patient in need thereof in a therapeutically effective dose amount and at dose intervals that achieve target exposure over an (approximate) 100 nM threshold for about 30-50% of the time between doses. For example, in some embodiments, Compound A or

pharmaceutically acceptable salt thereof is administered as a total dose of about 150 mg - 300 mg (e.g., 150 mg, 200 mg, 250 mg, or 300 mg) of Compound A every week (QW). In some embodiments, Compound A or pharmaceutically acceptable salt thereof is administered to a patient in need thereof at a total dose of about 200 mg - 400 mg (e.g., 200 mg, 250 mg, 300 mg, 350 mg or 400 mg) of Compound A every other week (Q2W or QOW).

[0087] The dose of Compound A can be optionally increased in successive administrations, when given in combination with a hypomethylating agent. For example, in some embodiments, 150 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof on the first day of treatment, in combination with azacitidine (e.g., 75 mg/m ² ). Subsequently, the same daily dose of azacitidine can be administered to the patient for a total of 7 consecutive days. The following day, a once daily dose of 150 mg - 300 mg (e.g., 150 mg,

200 mg, 250 mg, or 300 mg) of Compound A or a pharmaceutically acceptable salt thereof can be administered to the patient without azacitidine (i.e., about 24 hours after the most recent prior administration of azacitidine).

[0088] The present disclosure also provides that Compound A or a pharmaceutically acceptable salt thereof can be administered in a dosing regimen in combination with a hypomethylating agent. A hypomethylating agent is a therapeutic agent that inhibits DNA methylation, preferably azacitidine or decitabine. In some embodiments, a hypomethylating agent is administered in a 28 day treatment cycle. The decitabine (DAC) can be administered at a dose of 20 mg/m ² x 5 days, every 28 days. In some embodiments, the present disclosure provides a method of treating a patient comprising administering a therapeutically effective amount of a BET Inhibitor Compound (e.g., Compound A) about 24 hours after administration of a hypomethylating agent. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered in a dosing regimen with azacitidine during a 28-day cycle. In some embodiments, a 28-day cycle is repeated. In some embodiments, azacitidine is administered during days 1 - 7 of a 28-day cycle, and Compound A or a pharmaceutically acceptable salt thereof is administered during days 8 - 28 of a 28-day cycle (e.g., on Day 8, Day 15, and Day 22). In some embodiments, patients receive 75 mg/m ² of azacitidine QD on days 1 - 7. In some embodiments, patients receive 150 mg - 300 mg QW Compound A or a pharmaceutically acceptable salt thereof on days 1, 8, 15 and 22 every 28 days, or 200 mg to 400 mg QOW Compound A or a pharmaceutically acceptable salt thereof on days 1 and 15 every 28 days.

[0089] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient who is receiving or has received azacitidine. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof (e.g., about 150 mg to about 400 mg) is administered to a patient who is receiving or has received 75 mg/m ² azacitidine once per day for the first seven consecutive days of a 28-day course of treatment. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof (e.g., about 150 mg to about 400 mg) is administered to a patient who is receiving or has received 75 mg/m ² azacitidine once per day for the first seven consecutive days of a 28-day course of treatment and wherein Compound A or a pharmaceutically acceptable salt thereof is administered at least about 24 hours after the seventh dose of azacitidine and prior to any subsequent dose of azacitidine after the 28-day course of treatment. In some such methods, Compound A or a pharmaceutically acceptable salt thereof (e.g., 150 mg or 200 mg) is administered on the first day of the 28-day course of treatment and on the same day as the first dose of azacitidine, and then is subsequently administered once every week (e.g., 300 mg QW) or once every other week (e.g., 400 mg QOW) throughout the 28-day course of treatment.

[0090] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a hypomethylating agent (e.g., azacitidine) to a patient in need thereof at a dose of about 50% of the MTD at least once about 24 hours (or greater than 24 hours) after administering the final dose of the hypomethylating agent every 28 days to the patient in need thereof. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered once weekly or once every other week in a dose that achieves target exposure over an (approximate) 100 nM threshold for about 30-50% of the time between doses (“TOT”). For example, Compound A or a pharmaceutically acceptable salt thereof can be administered in a total dose of about 150 mg - 400 mg, once every week or once every other week.

[0091] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per week (QW) in combination with azacitidine on at least one day and on at least one day that is without azacitidine administration but within about 24 hours after the last prior dose of azacitidine. In some embodiments, the first QW dose of Compound A or a pharmaceutically acceptable salt thereof is a first dose of 150 mg, and subsequent doses that are the same or higher, preferably within the range of 150 mg - 300 mg per dose. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per week (QW) in an amount of 300 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to the patient in need thereof once every week. For example, in some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered in a total dose of about 150 mg - 300 mg (e.g., 150 mg, 200 mg, 250, mg, or 300 mg) once every week or 200 mg to 400 mg (e.g., 200 mg, 300 mg or 400 mg) once every other week, depending on the patient being treated, when administered in combination with azacitidine, as disclosed herein. In some embodiments, patients diagnosed with AML/MDS are treated by administering an initial dose of 150 mg of Compound A or a pharmaceutically acceptable salt thereof every week (QW), and optionally increasing the individual dose of Compound A or a pharmaceutically acceptable salt thereof administered in subsequent doses QW up to 300 mg (e.g., subsequent doses of 150 mg-300 mg, including doses of 150 mg, 200 mg, 250, mg, or 300 mg). In some embodiments, patients diagnosed with AML, MDS or NHL are treated with an initial dose of 150 mg - 300 mg (e.g.,

150 mg) of Compound A or a pharmaceutically acceptable salt thereof in combination with azacitidine on the same day, followed by six consecutive days of receiving the azacitidine without Compound A, followed by a second dose of Compound A or a pharmaceutically acceptable salt thereof about 24 hours after the seventh dose of azacitidine.

[0092] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once every other week (QOW) in combination with azacitidine on at least one day and on at least one day that is without azacitidine administration but greater than about 24 hours after the last prior dose of azacitidine. In some embodiments, the first QOW dose of Compound A or a pharmaceutically acceptable salt thereof is a first dose of 200 mg, and subsequent doses that are the same or higher, preferably within the range of 200 mg - 400 mg per dose. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once every other week (QOW) in an amount of 400 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to the patient in need thereof once every other week. For example, in some embodiments, 200 mg to 400 mg (e.g., 200 mg, 300 mg or 400 mg) of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient once every other week, depending on the patient being treated, when administered in combination with azacitidine, as disclosed herein. In some embodiments, patients diagnosed with AML/MDS or NHL are treated by administering an initial dose of 200 mg of Compound A or a pharmaceutically acceptable salt thereof every other week (QOW), and optionally increasing the individual dose of Compound A administered in subsequent doses QOW up to 400 mg (e.g., subsequent doses of 200 mg-400 mg, including doses of 200 mg or 300 mg or 400 mg, each given QOW) of Compound A every week (QOW).

Subjects to be Treated

[0093] In some embodiments, patients are selected to receive Compound A as described herein based on one or more markers and/or characteristics, such as, for example, diagnosis, response to prior therapy and/or mutation status.

[0094] In some embodiments, a patient is suffering from a cancer (e.g., AML/MDS or NHL) that is relapsed or refractory to standard therapies. In some embodiments, a patient has received one or more prior therapies (e.g., prior chemotherapies).

[0095] In some embodiments, a patient is suffering from AML/MDS. In some embodiments, a patient is suffering from relapsed or refractory AML (e.g., with intermediate or unfavorable risk cytogenetics and/or lacking FLT3 ITD or TKD alterations). In some embodiments, a patient is suffering from AML characterized by a FLT3 mutation.

[0096] In some embodiments, a patient is suffering from NHL.

[0097] In some embodiments, patients are selected based on one or more inclusion criteria.

One or more (preferably, all) of the following inclusion criteria can be used in selecting patients: • Patients > 18 years old

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

• No prior organ allograft

• Acceptable liver function: Bilirubin < 1.5 times upper limit of normal (ULN); and

aspartate transaminase (AST, also referred to as SGOT), alanine transaminase (ALT, also referred to as SGPT) and alkaline

• Acceptable renal function: Serum creatinine < 1.5 times ULN or calculated creatinine clearance > 50 mL/min (Cockcroft and Gault 1976)

• Recovery from the non-hematologic toxic effects of prior treatment to grade < 1, or

baseline value according to NCI CTCAE v. 4.0 classification (excluding infertility, alopecia or Grade 1 neuropathy)

• Negative pregnancy test if female of childbearing potential

[0098] In some methods, patients diagnosed with AML/MDS can be selected to receive a BET Inhibitor Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) as a single agent based on the presence of histologically or cytologically proven AML or intermediate risk, high risk, or very high-risk MDS as defined by the World Health Organization (WHO) criteria and Revised International Prognostic Scoring System (IPSS-R), respectively, that is relapsed/refractory (R/R) to standard therapy or for whom standard treatments are

contraindicated. In other methods, patients diagnosed with AML/MDS can be selected to receive a BET Inhibitor Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) as a single agent based on the presence of histologically or cytologically proven AML with a FLT3 internal tandem duplication (FLT3-ITD) or tyrosine kinase domain (FLT3-TKD) mutation previously determined by local testing that is R/R to standard therapy or for whom standard treatments are contraindicated. In other methods, patients diagnosed with AML/MDS can be selected to receive a BET Inhibitor Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) as a single agent based on the presence of histologically or cytologically proven AML with intermediate or unfavorable risk cytogenetics in the absence of a detectable FLT3 ITD or TKD mutation as previously determined by local testing that is R/R to standard therapy or for whom standard treatments are contraindicated.

[0099] For methods of treating NHL with a BET Inhibitor Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) as a single agent, patients can be selected based on either or both criteria: (a) Mature B-cell NHL as defined by WHO (2008) with the following histologies: follicular, marginal zone (splenic, nodal, and extranodal), mantle cell, primary mediastinal, diffuse large B-cell (DLBCL, including Richter’s transformation and follicular grade 3b) lymphomas, and B-cell lymphomas not specified (with features of DLBCL/Burkitt’s lymphoma), that is R/R to standard therapy and for whom standard treatments are

contraindicated or unavailable; and/or (b) adequate bone marrow function defined by absolute neutrophil count (ANC) > 750 cells/mm ³ , platelet count > 75,000/mm ³ , and hemoglobin (Hgb) > 8 g/dL at screening. In some embodiments, patients who are on chronic red blood cell (RBC) transfusions or erythropoietin to maintain a Hgb of > 8 g/dL are eligible.

[0100] For methods of treating NHL with a BET Inhibitor Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) as a single agent, patients can be selected based on the criteria: Mature B-cell NHL as defined by WHO (2008) with the following histologies:

primary mediastinal lymphoma, diffuse large B-cell lymphoma (DLBCL) (including Richter’s transformation and follicular grade 3b), and B-cell lymphomas not specified (with features of DLBCL/Burkitt’s lymphoma), that is R/R to standard therapy and for whom standard treatments are contraindicated or unavailable.

[0101] For methods of treating NHL with a BET Inhibitor Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) as a single agent, patients can be selected based on the criteria: measurable lymph node or tumor mass > 1.5 cm in at least 1 dimension by computed tomography (CT) or magnetic resonance imaging (MRI) requiring treatment at the discretion of the Investigator.

[0102] For methods of treating AML/MDS with a combination of a BET Inhibitor

Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) and azacitidine, patients can be selected based on the criteria of histologically or cytologically proven AML or MDS (intermediate risk, high-risk or very high risk) as defined by the WHO criteria and IPSS-R, respectively, that is: (a) R/R to standard therapy, or (b) AML: who are unfit for, or unwilling to receive standard induction therapy, or (c) MDS: eligible to receive azacitidine.

[0103] In some embodiments, the methods of treatment disclosed herein exclude the treatment of patients who meet one or more of the following exclusion criteria: • Considered surgically cured. Patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses) provided these are definitively treated prior to enrollment

• Uncontrolled disseminated intravascular coagulation with associated sequelae (bleeding, impaired renal function, etc.)

• Patients with symptomatic central nervous system (CNS) metastases or other tumor location (such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone fracture, etc.) necessitating an urgent therapeutic intervention, palliative care, surgery or radiation therapy

• Patients with previous allogeneic stem cell transplant (SCT) if they meet any of the

following criteria: < 100 days from time of SCT; active acute or chronic graft vs host disease (GvHD) or receiving immunosuppressive therapy as treatment or prophylaxis against GvHD within the last 7 days

• Treatment with major surgery (requiring general anesthesia) within one month prior to study entry

• Treatment with small molecule anti-cancer therapeutic within 5 half-lives of the agent or within 21 days if the half-life is unknown. Hydroxyurea given to control

hyperleukocystosis must be stopped prior to start of study drug

• Treatment with chemotherapy within 2 weeks OR have not recovered from any adverse events (AEs)

• Treatment with an anti-cancer therapeutic antibody less than 4 weeks before first dose of study drug

• Treatment with other experimental therapies or participation in another clinical trial within a period of time that is less than the cycle length or within 21 days prior to starting study drug whichever is shorter

• Previous treatment with any prior BET inhibitor therapy

• Patients unable to swallow oral medications, or patients with gastrointestinal conditions (e.g., malabsorption, gastric or small bowel resection, etc.) deemed to jeopardize intestinal absorption • Congestive heart failure (New York Heart Association Class III or IV) or unstable angina pectoris. Previous history of myocardial infarction within 1 year prior to study entry, uncontrolled hypertension or uncontrolled arrhythmias

• Baseline QTcF > 480 msec (QTcF=QT interval corrected using Fridericia’s formula; average of the QTcF values from screening triplicate ECGs). This criterion does not apply to patients with bundle branch block.

• Pulmonary disease (e.g., chronic obstructive pulmonary disease [COPD], asthma, etc.) that is not controlled (moderate to severe symptoms) with current medication

• Known HIV positivity

• Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy (Prophylactic systemic antimicrobials permitted)

• Uncontrolled disease-related metabolic disorder (e.g., hypercalcemia)

• Concurrent treatment with chronic corticosteroids except if chronic treatment with < 20 mg of methylprednisolone daily or equivalent (pulse steroids for treatment or prophylaxis are allowed [e.g., for transfusion or medication reactions])

• Concomitant medication(s) known to cause Torsades de Pointes initiated less than 4 weeks before first dose of study drug

• Pregnant or nursing women or women of childbearing potential not using adequate

contraception. Male patients not using adequate contraception.

• Serious nonmalignant disease

• Patients who have exhibited allergic reactions to compounds structurally similar to

Compound A

• Medical, psychiatric, cognitive, or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study

[0104] In some embodiments, patients with leukocytosis at baseline or who develop leukocytosis after initiation of therapy with Compound A may receive hydroxyurea. Suggested guidelines for administering hydroxyurea are as follows:

• For a white blood cell count (WBC) 10 - 50 x 10 ⁹ /L consider administering hydroxyurea 500 mg four times a day;

• For a WBC > 50 x 10 ⁹ /L consider administering hydroxyurea 1000 mg four times a day; • Hydroxyurea should be tapered/discontinued when WBC count is < 10 xl0 ⁹ /L

[0105] Patients who enroll in the study requiring CNS prophylaxis due to prior CNS involvement and remain asymptomatic may receive intrathecal chemotherapy at the discretion of the Investigator. Patients may receive premedication for nausea and/or vomiting at the discretion of the Investigator. All concomitant medications and supportive therapy administered, starting the first day prior to the first dose and until 28 days after the last dose of a BET Inhibitor Compound (e.g., Compound A), must be recorded on the appropriate electronic case report form (eCRF). No other investigational medicinal products will be allowed during this study. Initiation of an agent known to prolong the QTcF interval will not be allowed within in 4 weeks of Cycle 1 Day 1. In some embodiments, no concomitant anticancer therapy with the exceptions

(hydroxyurea or CNS prophylaxis) noted above, is administered to patients receiving a BET Inhibitor Compound (e.g., Compound A).

Exemplary Embodiments

[0106] The present disclosure also contemplates, among other things, the following numbered embodiments:

A1. A method of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program, the method comprising administering to the patient in need thereof a therapeutically effective dose of Compound A every week in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.

A2. A method of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program, the method comprising administering to the patient in need thereof a therapeutically effective dose of Compound A every other week in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.

A3. A method of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program, the method comprising administering to the patient in need thereof a therapeutically effective dose of Compound A every 4 weeks in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.

A4. The method of any one of embodiments A1-A3, wherein the therapeutically effective amount is a total of 300 mg of Compound A administered in each dose. A5. The method of any one of embodiments A1-A3, wherein the therapeutically effective amount is a total of 400 mg of Compound A administered in each dose.

A6. The method of any one of embodiments A1-A3, wherein the therapeutically effective amount is a total of 300 - 400 mg of Compound A administered in each dose.

A7. A method of treating a patient diagnosed with relapsed or refractory hematologic cancer malignancies, the method comprising administering to the patient in need thereof 400 mg of Compound A every other week (QOW) or 300 mg of Compound A every week (QW).

A8. The method of any one of embodiments A1-A7, wherein the patient is diagnosed with Acute myelogenous leukemia (AML), MDS or Non-Hodgkin lymphoma (NHL).

A9. The method of any one of embodiments A1-A8, wherein the patient in need thereof is administered a dose of 300 mg or 400 mg of Compound A.

A10. The method of any one of embodiments A1-A8, wherein the patient in need thereof is administered a dose of 400 mg of Compound A once every other week (QOW).

A11. The method of any one of embodiments A1-A8, wherein the patient in need thereof is administered a dose of 400 mg of Compound A once every other week (QOW).

A12. The method of any one of embodiments A1-A8, wherein the patient in need thereof is administered a dose of 300 mg of Compound A once every week (QW).

A13. A method of treating a patient diagnosed with an acute leukemia or

relapsed/refractory mature B-cell non-Hodgkin’s lymphoma, the method comprising administering to the patient in need thereof a total of about a 400 mg dose of (S)-(5- cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)- 3,4-dihydroquinolin-l(2H)- yl)(cyclopropyl)methanone or a pharmaceutically acceptable salt thereof, once every other week (QOW) to the patient in need thereof.

A14. A method of treating a patient diagnosed with an acute leukemia or

relapsed/refractory mature B-cell non-Hodgkin’s lymphoma, the method comprising administering to the patient in need thereof a total of about a 400 mg dose of Compound A:

Compound A

or a pharmaceutically acceptable salt thereof, once every other week (QOW) to the patient in need thereof.

A15. A method of treating a patient diagnosed with an acute leukemia or

relapsed/refractory mature B-cell non-Hodgkin’s lymphoma, the method comprising administering to the patient in need thereof a total of about a 300 mg dose of (S)-(5- cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)- 3,4-dihydroquinolin-l(2H)- yl)(cyclopropyl)methanone or a pharmaceutically acceptable salt thereof, once every week (QW) to the patient in need thereof.

A16. A method of treating a patient diagnosed with an acute leukemia or

relapsed/refractory mature B-cell non-Hodgkin’s lymphoma, the method comprising administering to the patient in need thereof a total of about a 300 mg dose of Compound A:

Compound A

or a pharmaceutically acceptable salt thereof, once every week (QW) to the patient in need thereof.

A17. The method of any one of embodiments A13-A16, wherein the patient is diagnosed with AML.

[0107] The present disclosure also contemplates, among other things, the following numbered embodiments:

B 1. A method of treating a patient diagnosed with acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS) or non-Hodgkin lymphoma (NHL), the method comprising administering to the patient in need thereof a therapeutically effective amount of Compound A every other week throughout a course of treatment.

B2. The method of embodiment B 1, wherein the therapeutically effective dose of

Compound A is about 400 mg of Compound A administered to the patient in need thereof once every other week (QOW).

B3. The method of embodiment Bl, wherein Compound A is administered as a succinate salt of Compound A.

B4. A method of treating a patient diagnosed with acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS) or non-Hodgkin lymphoma (NHL), the method comprising administering to the patient in need thereof a therapeutically effective amount of Compound A as a pharmaceutically acceptable succinate salt every other week throughout a course of treatment.

B5. The method of embodiment B4, wherein the therapeutically effective dose of

Compound A is about 400 mg of Compound A administered to the patient in need thereof once every other week (QOW).

B6. A method of treating a patient diagnosed with acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS) or non-Hodgkin lymphoma (NHL), the method comprising administering to the patient in need thereof a total dose of 400 mg of

Compound A as a pharmaceutically acceptable succinate salt once every other week throughout a course of treatment.

B7. The method of any one of embodiments B1-B6, wherein about 400 mg of Compound A is administered once per day to the patient in need thereof, once every other week.

B8. A method of treating a patient diagnosed with acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS) or non-Hodgkin lymphoma (NHL), the method comprising administering to the patient in need thereof a total of about 400 mg of

Compound A or a pharmaceutically acceptable salt thereof, one day every other week throughout a course of treatment:

(Compound A).

B9. The method of embodiment B8, wherein a pharmaceutically acceptable succinate salt of Compound A is administered to the patient in need thereof.

BIO. The method of any one of embodiments B8-B9, wherein Compound A is

administered once per day and once every other week to the patient in need thereof.

B 11. A method of treating a patient diagnosed with acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS) or non-Hodgkin lymphoma (NHL), the method comprising administering to the patient in need thereof a total of about 400 mg of (S)-(5- cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)- 3,4-dihydroquinolin-l(2H)- yl)(cyclopropyl)methanone, or a pharmaceutically acceptable salt thereof, one day every other week throughout a course of treatment.

B12. The method of embodiments B11, wherein (S)-(5-cyclobutoxy-2-methyl-6-(l- (piperidin-4-yl)-lH-pyrazol-4-yl)-3,4-dihydroquinolin-l(2H)- yl)(cyclopropyl)methanone succinate salt is administered to the patient in need thereof.

B13. The method of any one of embodiments B11-B12, wherein (S)-(5-cyclobutoxy-2- methyl-6-( 1 -(piperidin-4-yl)- lH-pyrazol-4-yl)-3 ,4-dihydroquinolin- 1 (2H)- yl)(cyclopropyl)methanone or a pharmaceutically acceptable salt thereof is administered once per day and once every other week to the patient in need thereof.

B14. The method of any one of embodiments Bl-B 13, wherein the patient is diagnosed with AML.

B15. The method of any one of embodiments Bl-B 13, wherein the patient is diagnosed with MDS.

B16. The method of any one of embodiments Bl-B 13, wherein the patient is diagnosed with NHL.

B17. A method of treating a patient diagnosed with acute myelogenous leukemia (AML), the method comprising administering to the patient in need thereof a total of about 400 mg of (S)-(5-cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol -4-yl)-3,4-dihydroquinolin- l(2H)-yl)(cyclopropyl)methanone succinate, once every other week.

[0108] The present disclosure also contemplates, among other things, the following numbered embodiments:

Cl . A method of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program, the method comprising administering to the patient in need thereof a therapeutically effective dose of a BET Inhibitor Compound every week in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.

C2. A method of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program, the method comprising administering to the patient in need thereof a therapeutically effective dose of a BET Inhibitor Compound every other week in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.

C3. A method of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program, the method comprising administering to the patient in need thereof a therapeutically effective dose of a BET Inhibitor Compound every 4 weeks in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.

C4. The method of any one of embodiments C1-C3, wherein the BET Inhibitor

Compound is selected from the group consisting of BET Inhibitor Compound A, B, C, D,

E, F, G, H, I, J, K, L, M, N, O and P.

C5. The method of any one of embodiments C1-C4, wherein the BET Inhibitor

Compound is administered once every week to the patient in need thereof.

C6. The method of any one of embodiments C1-C4, wherein the BET Inhibitor

Compound is administered once every other week to the patient in need thereof.

C7. The method of any one of embodiments C1-C6, wherein the dose is selected from a dose schedule listed in Example 21.

C8. The method of any one of embodiments C1-C7, wherein the patient is diagnosed with a cancer selected from the group consisting of AML, MDS and NHL. C9. The method of any one of embodiments C1-C8, wherein the patient is diagnosed with AML.

[0109] The present disclosure also contemplates, among other things, the following numbered embodiments:

D1. A method of treating a patient diagnosed with cancer, the method comprising

administering to the patient in need thereof every 28 days:

a. 75 mg/m ² azacitidine to the patient once per day for the first seven consecutive days of the 28 days, followed by

b. about 150 mg-400 mg of Compound A or a pharmaceutically acceptable salt thereof to the patient at least about 24 hours of the seventh dose of azacitidine and prior to any subsequent dose of azacitidine after the 28 days.

D2. The method of embodiment Dl, wherein Compound A is further administered on the first day of the 28 days on the same day as the first dose of azacitidine, and then

subsequently administered once every week throughout a repeated 28-day treatment cycle, and the azacitidine is administered for seven consecutive days during the first week of each of the 28-day treatment cycles.

D3. The method of embodiment D2, wherein 150 mg - 300 mg of Compound A or a

pharmaceutically acceptable salt thereof is administered to the patient.

D4. The method of embodiment D2, wherein 150 mg of Compound A or a

pharmaceutically acceptable salt thereof and azacitidine are both administered to the patient on day 1 of a first treatment cycle.

D5. The method of any one of embodiments D3-D4, wherein 150 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient without azacitidine on days 8, 15 and 22 of the 28-day treatment cycle.

D6. The method of any one of embodiments D3-D4, wherein 150 mg - 300 mg of

Compound A or a pharmaceutically acceptable salt thereof is administered to the patient without azacitidine on days 8, 15 and 22 of the 28-day treatment cycle.

D7. The method of any one of embodiments D3-D4, wherein 300 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient without azacitidine on days 8, 15 and 22 of the 28-day treatment cycle.

D8. The method of any one of embodiments D2-D7, wherein a. 150 mg of Compound A or a pharmaceutically acceptable salt thereof and azacitidine are both administered to the patient on day 1 of a first 28-day treatment cycle; and

b. 300 mg of Compound A or a pharmaceutically acceptable salt thereof is

administered to the patient without azacitidine on days 8, 15 and 22 of the first 28- day treatment cycle.

D9. The method of any one of embodiments D1-D8, wherein Compound A or a

pharmaceutically acceptable salt thereof is only administered to the patient on days 1, 8, 15 and 22 of the 28-day treatment cycle.

D10. The method of any one of embodiments D1-D9, wherein Compound A or a

pharmaceutically acceptable salt thereof is only administered to the patient on days 1, 8, 15 and 22 of the 28-day treatment cycle, and azacitidine is only administered to the patient on days 1-7 of the 28-day treatment cycle.

Dl l. The method of embodiment Dl, wherein Compound A is administered once every other week throughout a 28-day treatment cycle, and the azacitidine is administered for seven consecutive days during the first week of the 28-day treatment cycle.

D12. The method of embodiment Dl l, wherein 200 mg - 400 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient.

D13. The method of embodiment Dl l, wherein 200 mg of Compound A or a

pharmaceutically acceptable salt thereof and azacitidine are both administered to the patient on day 1 of a first treatment cycle.

D14. The method of any one of embodiments Dl 1-D12, wherein 200 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient without azacitidine on day 15 of the 28-day treatment cycle.

D15. The method of any one of embodiments Dl 1-D12, wherein 200 mg - 400 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient without azacitidine on day 15 of the 28-day treatment cycle.

D16. The method of any one of embodiments Dl 1-D12, wherein 400 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient without azacitidine on day 15 of the 28-day treatment cycle.

D17. The method of any one of embodiments Dl 1-D16, wherein a. 200 mg of Compound A or a pharmaceutically acceptable salt thereof and azacitidine are both administered to the patient on day 1 of a first 28-day treatment cycle; and

b. 400 mg of Compound A or a pharmaceutically acceptable salt thereof is

administered to the patient without azacitidine on day 15 of the first 28-day treatment cycle.

D18. The method of any one of embodiments D11-D17, wherein Compound A or a

pharmaceutically acceptable salt thereof is only administered to the patient on days 1 and 15 of the 28-day treatment cycle.

D19. The method of any one of embodiments D11-D18, wherein Compound A or a

pharmaceutically acceptable salt thereof is only administered to the patient on days 1 and 15 of the 28-day treatment cycle, and azacitidine is only administered to the patient on days 1-7 of the 28-day treatment cycle.

D20. The method of any one of embodiments D1-D19, wherein Compound A is further administered to the patient on the first day of the 28 days, on the same day as the first dose of azacitidine.

D21. The method of any one of embodiments D1-D20, wherein Compound A is

administered as the succinate salt of Compound A.

D22. A method of treating a patient diagnosed with cancer selected from the group

consisting of AML, MDS and NHL, the method comprising administering to the patient in need thereof a hypomethylating agent in combination with a BET inhibitor, wherein the BET inhibitor is administered throughout a course of treatment of at least 28 consecutive days, and wherein the BET inhibitor is administered to the patient:

a. in a dose effective to achieve target exposure over an about 100 nM threshold for about 30-50% of the time between doses; and

b. at least about 24 hours after the final dose of the hypomethylating agent and prior to any subsequent dose of the hypomethylating agent during the course of treatment.

D23. The method of embodiment D22, wherein the BET inhibitor is Compound A.

D24. The method of any one of embodiments D22-D23, wherein the hypomethylating agent is azacitidine. D25. The method of any one of embodiments D22-D24, wherein the BET inhibitor is further administered to the patient with the hypomethylating agent on the first day of the course of treatment.

D26. The method of any one of embodiments D22-D25, wherein the BET inhibitor is only administered to the patient on the same day as the hypomethylating agent on the first day of every 28 consecutive days throughout the course of treatment.

D27. The method of embodiment D26, wherein the dose of the BET inhibitor is lower when administered on days when the hypomethylating agent is administered, than the dose of the BET inhibitor administered on days when the hypomethylating agent is not administered.

D28. The method of any one of embodiments D1-D27, wherein the patient is diagnosed with AML.

D29. The method of any one of embodiments D1-D27, wherein the patient is diagnosed with MDS.

D30. The method of any one of embodiments D1-D27, wherein the patient is diagnosed with NHL.

EXAMPLES

[0110] The small molecule (S)-(5-cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol -4- yl)-3,4-dihydroquinolin-l(2H)-yl)(cyclopropyl)methanone (Compound A) has a molecular and formula weight of 434.58 Da, and a melting point of 80.9 °C (DSC). Compound A has potent and equivalent biochemical activity against all 4 BET family members (BRD2, BRD3, BRD4, BRDT), and shows additional activity towards several non-BET bromodomain proteins

(including CECR2 and BRD9). Compound A is a BET bromodomain inhibitor that exhibits significant anti -tumor activity in vivo in mouse xenograft models of human leukemia/lymphoma. Importantly, optimal activity and tolerability were observed on intermittent dosing schedules. These data support the clinical trial of Compound A in leukemias/lymphomas.

[0111] Members of the BET family regulate chromatin structure and gene expression. In particular, BET family member BRD4 has been shown to positively regulate transcription of the oncogene MYC through its localization to super-enhancer transcriptional regulatory elements. [0112] The safety and tolerability of Compound A has been assessed in a number of in vitro and multi-dosing in vivo experiments, suggesting that the therapeutic index can be modulated through dose and schedule. Compound A was active in in vivo xenograft models under a variety of schedules, in both solid and hematological tumors. Notably, Compound A has shown superior efficacy to comparative BET inhibitor OTX015 in the AML model MV-4-11, showing regressions, whereas the best response observed with competitor molecules has been tumor stasis.

Example 1: Synthesis of Compound A

[0113] As shown in Figure 1, Compound A can be obtained by a series of synthetic reactions using commercially available materials. Oxidative cyclization of 2-chloro-5-methoxyaniline (i), and crotonaldehyde, using chloranil as the oxidant, afforded methoxyquinoline (ii) as its hydrochloride salt. Catalytic hydrogenation in the presence of base reductively removed the chlorine to provide (iii) in good yield. Catalytic asymmetric hydrogenation of the quinoline with a chiral ?’-arene-N-tosylethylenediamine-Ru(II) complex at high pressure afforded the desired (iv). Subsequent acylation with cyclopropanecarbonyl chloride yielded (v) and demethylation with boron tribromide yielded phenol (vi) in good overall yield. Regioselective bromination with N-bromosuccinimide (NBS) provided (vii) as the major product, and alkylation with

cyclobutylbromide gave arylbromide (viii). Palladium catalyzed Suzuki cross-coupling using the commercially available tert-butyl 4-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl]piperidine-l-carboxylate (ix) afforded penultimate N-Boc intermediate (x) which was deprotected with trifluoroacetic acid to give Compound A.

[0114] A Compound A succinate salt was prepared according to the following method. Compound A was slurried in acetone with succinic acid (1 : 1 molar ratio) and solid was isolated at 4 °C. About 20 mg of resulting solid was suspended in 0.3 mL of a solvent. The suspension was stirred for 6 days at room temperature, and the solids were isolated. The X-ray powder diffraction pattern of the crystalline Compound A Succinate is summarized below:

2 theta d-spacing

4.4 20.1

6.8 13.0

7.7 11.4

8.7 10.1 35.2 2.6

36.1 2.5

36.6 2.5

38.8 2.3

[0115] The finished product, Compound A Capsules, used in human clinical trials described in the remaining Examples is Compound A succinate active pharmaceutical ingredient (API) powder filled in empty, hard gelatin, opaque, plain (or unmarked) capsules. Compound A Capsules were initially presented as three unit strengths for oral administration. The capsules contain 5, 20, or 100 mg Compound A fill weight per capsule. Each dose strength was filled in capsules that have distinctive size and color combinations. Compound A Capsules were presented for oral administration. The capsules had distinctive sizes and colors to designate the capsule strength: 5 mg capsules; 20 mg capsules; and 100 mg capsules.

Example 2: In vitro cell assay testing of Compound A

[0116] The binding of Compound A to BRD4 Bromodomain 1 (BD1) and BRD4

Bromodomain 2 (BD2) was measured using AlphaScreen assay technology. His-BRD4 BD1 and His-BRD4 BD2 binding and inhibition was assessed by monitoring the engagement of biotinylated Histone H4 (1-21) K5/8/12/16 tetra-acetylated (H4K4) peptide with the targets. Compound A inhibited BRD4 BD1 binding to the H4K4 peptide with an ICso of < 1.0 micromolar and inhibited BRD4 BD2 binding to the H4K4 peptide with an ICso of < 0.1 micromolar. The testing of Compound A in an alternative ligand binding competition assay, which showed equipotent binding activity of Compound A for BRD4, BD1, and BD2.

[0117] Compound A was further profiled in a bromodomain assay panel (BROMOscan, DiscoveRx) to determine its selectivity against other bromodomain-containing proteins using a ligand binding site-directed competition assay to quantitatively measure interactions between test compound and bromodomains. Compound A was screened at a primary screening concentration of 10 micromolar against thirty -two bromodomains. Compound A bound six non-BET bromodomains in the panel with sub -micromolar affinity: CECR2, BRD9, BRD7, CREBBP, BRPF1 and EP300.

[0118] The impact of Compound A on human cancer cell proliferation was determined using MV-4-11 Acute Myeloid Leukemia cell line in a 72 hour proliferation assay. The amounts of viable cells were determined using the CellTiter-Glo Luminescent Cell Viability Assay. Values for the concentration that inhibited cell growth by 50% (Gbo) between the DMSO control and background control (no cells) were determined using either IDBS Activity Base software with a four parameter logistic curve fit or GraphPad Prism 6 software with a non-linear regression curve fit. Compound A exhibits sub -micromolar GLo values against MV-4-11 cells (n=l 15). The MV- 4-11 AML cell line was utilized as a standard model for further preclinical testing: MV-4-11 is sensitive to BET inhibitors in general and this model has been commonly used both in vitro and in vivo.

[0119] The impact of Compound A on the suppression of MYC expression was determined using a sandwich enzyme-linked immunosorbent assay (ELISA) assay measuring MYC protein levels from MV-4-11 cellular lysates. MV-4-11 cells were treated with Compound A for 24 hours, followed by ELISA detection of MYC protein. Compound A was shown to downregulate MYC in MV-4-11 with an ICso of <1 micromolar (n=6). The MYC downregulation in MV-4-11 closely correlates to the anti-proliferative activity in the MV-4-11 cellular proliferation assay, suggesting that the anti-proliferative effect of Compound A may be associated with the suppression of MYC protein levels.

Example 3: MV-4-11 Murine Xenograft Testing of Compound A

[0120] MV-4-11 xenografted nude mice were dosed with Compound A at various doses and schedules (Compound A 15 mg/kg QD x 3, 55 mg/kg single dose, 100 mg/kg single dose), followed by collection of plasma and tumors at several time points. MYC downregulation (mRNA), free plasma and tumor levels (total tumor levels corrected for plasma fraction unbound) of Compound A were then compared. The data from these experiments suggest that MYC expression was reduced in MV-4-11 tumors (in comparison to vehicle treated tumors) by approximately 60 to 80% by Compound A at 4 h post final dose, at all dose levels. Interestingly, the extent of MYC suppression was consistent with the in vitro experiments described above. At these dose levels with Compound A, the MYC downregulation increased only marginally in going from 15 mg/kg to 55 mg/kg, with suppression plateauing at around 80% for the 55 mg/kg and 100 mg/kg doses. The ratio of free tumor (assuming corrections for binding are equivalent to plasma protein binding) versus free plasma concentrations was consistent with the higher volume of distribution observed for Compound A (Vss 8.9 L/kg). [0121] This analysis was extended to longer time points post dose. At the 15 mg/kg dose level of Compound A, the level of MYC downregulation was sustained at levels greater than 50% between 12-24 hours. When the dose of Compound A was increased from 15 mg/kg to 55 mg/kg, and then to 100 mg/kg, the extent of MYC downregulation increased at later time points. The MYC downregulation appeared to be associated with the free plasma levels, as it was evident that as the compound was cleared, the MYC mRNA levels began to rise back towards vehicle treated levels.

[0122] When comparing free plasma levels of Compound A to the cellular anti-proliferative effect for MV-4-11 (GEo < 1 micromolar), it was evident that when free plasma levels were at or slightly above the GIso (1 - 2 fold), this was associated with significant (70 - 80%) MYC suppression, and that when free compound levels dropped below this threshold the MYC levels began to return to untreated levels. In summary, these experiments suggest that Compound A produces MYC suppression in vivo.

[0123] An extended duration of MYC suppression was observed with Compound A. For the 15 mg/kg once daily dosing schedule, the extent of MYC suppression in the MV-4-11 xenograft was approximately 80% for an eight hour period. This time frame also coincided with the free plasma exposure of Compound A being at or slightly above the GEo for the cellular anti proliferative activity (MV-4-11 GEo < 1 micromolar). This delivered significant anti-tumor activity, including regressions. After this eight hour time period, the unbound plasma levels fell below the cellular GEo and the MYC levels began to recover towards untreated levels, and presumably therefore the dose was tolerated. Therefore, it seems maintaining unbound plasma levels at or slightly above this threshold for some period of time was key to driving maximal MYC suppression (-80%), and in turn anti -tumor effect, but also managing the time below this threshold to allow MYC to recover, and the dose to be tolerated, was also important. Similar trends were observed for the less frequent dosing schedules, such as 55 mg/kg Q3D and 100 mg/kg Q7D. In these less frequent dosing schedules a longer time over threshold was evident, but a longer holiday under the threshold was also required for the regimen to be tolerated and active.

[0124] Figure 2 is a graph showing the effect of treatment on tumor volume in MV-4-11 human tumor xenograft model (MLL-fusion, Flt3-ITD+) described in Example 4. The in vivo anti-tumor activity of Compound A was investigated as a single agent in the MV-4-11 acute myeloid leukemia human (subcutaneous tumor) xenograft model in mice. MV-4-11 was chosen as a model that is MYC-dependent, sensitive to Compound A in vitro.

[0125] Several doses and schedules of Compound A were compared to the reported optimal dose/schedule for OTX015 (100 mg/kg QDx21) in MV-4-11 xenografted nude mice over multiple separate studies. Significant tumor growth inhibition was observed with Compound A in a number of studies and with a number of different doses and schedules over a 21 day period. The once daily dosing schedule was run with either 15 or 22.5 mg/kg dose levels, in five separate studies, with tumor stasis observed on several occasions, and significant regressions observed in a similar number of other experiments. In one study, Compound A 15 mg/kg once daily dosing was compared to OTX015 100 mg/kg once daily dosing. In this experiment Compound A demonstrated significant tumor regression, with OTX015 showing tumor stasis. In addition, when dosing was discontinued, Compound A-treated tumors exhibited a slower growth rebound when compared to the OTXO 15 -treated tumors (Figure 2).

[0126] For the MV-4-11 xenograft model, it was evident that targeting unbound plasma exposures of one to two fold of the cellular GFo would translate into approximately 80% MYC suppression, which in turn translated into significant anti-tumor activity. Managing the time over this threshold through dose and schedule is hypothesized to be key for maximizing anti-tumor activity and tolerability.

[0127] The efficacy and tolerability of Compound A in the MV-4-11 xenograft mouse models suggested that a Q3D schedule was tolerable and produced significant anti-tumor efficacy (TGI) when free plasma exposures were over the cellular GFo (MV-4-11 GFo <1 micromolar) for about two thirds (48 hours) of the dosing period, followed by a one third period (24 hours) under this threshold. Similar experiments with both QD and Q7D schedules pointed to a time over threshold of about one third, and a holiday for two thirds of the dosing period.

Human dose can be modeled to produce unbound plasma concentrations over this threshold for one third of the dosing period, for the Q7D dose. For the Q7D schedule, a time period over threshold of 56 hours (1/3 of dosing period) can be selected.

Example 4: Human Toxicity Clinical Trial of Compound A

[0128] The initial human use of Compound A is disclosed as BET Inhibitor FT-1101 in human clinical trials under clinical trial identifier NCT02543879 at the website clinicaltrials.gov. The results of 28-day definitive toxicity studies were used to calculate a safe clinical starting dose for Compound A in the proposed Phase 1 trial. The clinical starting dose for the proposed Phase 1 trial was 10 mg administered orally once weekly (Schedule 1 in Example 5). Based on an analysis of the preliminary PK profiles of the initial patients receiving at least one 10 mg dose of Compound A (n=8), alternative dosing schedules of every month (QM, Schedule 2 in

Example 5) and every other week (QOW, Schedule 3 in Example 5) involving less frequent dosing will be explored.

[0129] In some methods provided herein, Compound A can be administered as a single agent (SA) in patients with relapsed or refractory (R/R) AML/MDS or R/R non-Hodgkin lymphomas (NHL).

[0130] AML/MDS or NHL patients are evaluated in separate hematologic malignancy treatment cohorts. Single agent (SA) Compound A can be administered via one or more intermittent dosing schedules. A single schedule of Compound A administered in combination will be selected from schedules (and doses) disclosed herein.

Example 5: Dose Escalation of Single Agent Compound A in Phase 1 Human Clinical Trial

[0131] Dose escalation studies are initiated with SA Compound A with each hematologic malignancy treatment cohort evaluated utilizing a 3+3 strategy. Once an MTD is identified for a treatment cohort, additional patients may be enrolled in expansion cohorts each of select populations of patients with either AML/MDS or NHL. On the initial schedule for each treatment cohort, study drug will be taken once weekly in 28-day continuous cycles from Day 1 until study withdrawal criteria are met.

[0132] A human clinical trial study evaluates multiple potential schedules for SA Compound A in separate hematologic malignancy treatment cohorts: an AML/MDS treatment cohort and an NHL treatment cohort.

[0133] A Compound A dosing schedule (Schedule 1) for each treatment cohort of

AML/MDS or NHL patients consists of Compound A given orally according to a level and schedule shown in Table 2 below. In some embodiments, Compound A is administered between 10-400 mg QW. In some embodiments, Compound A is administered between 20-400 mg QM.

In some embodiments, Compound A is administered between 40-900 mg QOW. Table 2

Q monthly; QOW = every other week; QW = weekly.

[0134] Compound A shows consistent pharmacokinetics across various doses in human clinical trials. Figure 3 A shows the day 1, dose normalized (Cmax/dose in ng/mL/(mg)) ratio measured in patients receiving Compound A according to certain doses provided in Table 2. Figures 3 A-3D are graphs showing the ratio of measured AUC values (Figure 3B), and plasma concentrations (Figure 3C and Figure 3D) for the administration of various doses of Compound A (80-400 mg in Figure 3A; 400 mg in Figure 3C and 260 mg in Figure 3D) in a human clinical trial.

[0135] The SA dose escalation portion of the clinical trial allows a dose increase of 100% with the dose escalation from Dose Level 1 to Dose Level 2 for each dose schedule. Thereafter, a maximum of up to -50% increase (adjusted based on pill strength) between dose-escalation cohorts within a schedule is allowed until the MTD is determined. Intermediate dose levels from those proposed above may be explored based on AEs, tolerability, PK, other clinical data as clinically indicated, or on available pill strengths and sizes.

[0136] The MTD is the highest dose level within a schedule that does not meet the dose limiting toxicity (DLT) dose level definition for a treatment cohort (AML/MDS or NHL). The DLT dose level is defined as the lowest dose level at which a DLT is experienced in > 2 patients out of a maximum of 6 evaluable patients within a treatment cohort (AML/MDS or NHL).

[0137] Dose escalation to define a SA MTD may occur in 1 or more selected schedules for each treatment cohort. Each dose level must be evaluated and found to be safe by at least 1 treatment cohort before dose escalation can occur. For any treatment cohort, a within-schedule dose level may be skipped if the dose level was previously tolerated by the other treatment cohort or the dose level was previously tolerated in a more frequent dosing schedule. [0138] In the SA dose-escalation phase, for each schedule proposed, patients from at least 1 treatment cohort (AML/MDS or NHL) can initially be enrolled at that dose level. If exactly 1 of the initial 3 evaluable patients has a DLT before the end of Cycle 1, the dose level is expanded to up to 6 evaluable patients. If 5 of a total of <6 evaluable patients complete the full cycle absent a DLT, escalation may continue.

[0139] For a given dose level, once > 2 patients have a DLT, further enrollment/treatment for that cohort halts, along with dose escalation. The dose level at which > 2 of up to 6 evaluable patients have a DLT is at least 1 dose level above the MTD for that treatment cohort. The next lower dose is more fully evaluated by treating a total of up to 6 evaluable patients. If > 2 patients have a DLT at this lower dose level, de-escalation continues until a dose level is identified at which 0 or 1 of a total of 6 patients has a DLT. This is identified as the MTD for the schedule evaluated for that treatment cohort. The recommended phase II dose (RP2D) may be a dose level equivalent or lower than the MTD.

[0140] Treatment of evaluable subjects included AML patients on treatment through 7 treatment cycles with stable disease (n=2).

Example 6. Results of Dose Escalation of Single Agent Compound A in Phase 1 Human Clinical Trial

[0141] A Phase 1 study evaluated the safety, PK/PD, and clinical activity of Compound A in patients with relapsed/refractory (R/R) AML/MDS, or non-Hodgkin lymphoma (NHL). Dose escalation evaluated a range of dose levels, from 10 mg to 600 mg, oral Compound A in three different oral dosing schedules: weekly (QW), every other week (QOW), and once a month (QM). A summary of dose escalation is provided in Figure 4.

[0142] A total of 84 AML/MDS patients and 10 NHL patients received Compound A in a dose escalation study. Patients received Compound A in dose escalation with a median of 2 (range: 1-13) treatment cycles and a median exposure of 43 (range: 1-401) days for AML/MDS patients and 51.5 (range: 1-183) days for NHL patients. Most AML/MDS patients (n=80) received Compound A as a single agent. Disease characteristics of the patient population are summarized in Table 3. Table 3

*4% of AML/MDS population were other disease types.

[0143] Efficacy (response) was assessed in evaluable patients. Evaluable patients were defined as having at least one post-baseline disease assessment or those who discontinued prior to first-baseline assessment due to death, AE, or early clinical progression. Among evaluable AML/MDS patients who received >180 mg Compound A monotherapy (n=30), one patient (3%) on the 400 mg QOW schedule achieved complete remission with incomplete hematologic recovery (CRi) and 19 patients (63%) achieved stable disease (SD), including 2 patients receiving > 7 cycles of treatment. (Dose level cut-off of >180 mg was applied based on lowest dose that showed robust modulation of PD biomarkers.) Among evaluable NHL patients who received >180 mg Compound A monotherapy (n=3), one patient (33%) achieved SD. All patients who received Compound A monotherapy stopped treatment. Reasons for treatment discontinuation included disease progression (40 patients, 43%), withdrawal of patient (16 patients, 17%), physician decision (12 patients, 13%), death (10 patients, 11%), adverse event (5 patients, 5%), and other reasons (7 patients, 7%) which included lack of response, hospice, and relocation. Figure 5 summarizes time on treatment for patients receiving certain dosing schedules of Compound A.

[0144] Pharmacokinetic parameters were assessed. Concentration-time profiles were constructed from plasma samples obtained at certain time points through the course of a treatment cycle. Estimates of AUC and slope of terminal decay phase were used to calculate values of pharmacokinetic parameters, including Tmax and ti/2. Plasma profiles were fitted by nonlinear regression analysis whenever possible. Figure 6 is a plot of mean concentration of Compound A (ng/mL) at various time points after first oral dose. As can be seen in Figure 6, Compound A demonstrated dose-proportional pharmacokinetics (PK) across the range of doses evaluated (10-600 mg). Median Tmax ranged from 2-4 hrs and geometric mean ti/2 ranged from 30-61 hrs. Geometric mean AUC ₍ o-i ₆₈₎ and Cmax values ranged from 795-97100 ng*h/mL and from 18-1220 ng/mL, respectively. A summary of pharmacokinetic parameters (mean AU o- 168), mean Cmax, and mean ti/2) is provided in Table 4.

Table 4

[0145] Pharmacodynamic biomarkers (CCR1 and HEXIM1 mRNA expression) were assessed in whole blood collected at certain time points through a course of treatment using quantitative real-time PCR. Pharmacodynamic responses correlated with Compound A concentrations, and dose-dependent PD biomarker modulation QCCR 1 and†HEXIM1) was observed for Compound A doses >180 mg. Figure 7A is a box-and-whisker plot of CCR1 modulation at 4 hrs post-dose for various doses (80-600 mg) of Compound A. Figure 7B is a box-and-whisker plot of HEXIM1 modulation at 4 hrs post-dose for various doses (80-600 mg) of Compound A. As can be seen from Figures 7A and 7B, both CCR1 and HEXIM1 levels were modulated in a dose-dependent manner (e.g., for doses >180 mg) after a single dose of

Compound A.

[0146] Furthermore, pharmacodynamics biomarkers (CCR1 and HEXIM1) were shown to correlate with the plasma pharmacokinetic profile in patients receiving a single 300 mg oral dose of Compound A (n=7). Figure 8A is a plot of mean concentration of Compound A (ng/mL) at various time points after a single 300 mg oral dose of Compound A. Figure 8B is a plot of HEXIM1 expression (relative quantification (RQ)) over time after a single 300 mg oral dose of Compound A. Figure 8C is a plot of CCR1 expression (relative quantification (RQ)) over time after a single 300 mg oral dose of Compound A. As can be seen by Figures 8A-8C, levels of the PD biomarkers CCR1 and HEXIM1 tracked with plasma pharmacokinetics. The

pharmacodynamic maximum observed effect for both HEXIM1 and CCR1, as well as plasma Cmax were observed at 4 hrs post dose.

[0147] Pharmacodynamic activity (e.g., CCR1 suppression and HEXIM1 upregulation) was consistent with preclinical observations indicating antitumor activity (e.g., Example 3). Thus, intermittent dosing (e.g., QOW) within a tolerable range is effective for eliciting desirable PD activity as described herein.

[0148] Safety was assessed via treatment-emergent adverse events (TEAEs) for all patients. All adverse events were recorded and categorized by severity according to the NCI CTCAE guidelines (http://ctep.cancer.gov/reporting/ctc.html). The most common TEAEs were diarrhea (32%), fatigue (30%), dyspnea (29%), nausea (27%), and anemia (24%) among AML/MDS patients, and diarrhea (60%) among NHL patients. The most common severe (> grade 3) TEAEs were anemia (21%), decreased platelets (19%), pneumonia (16%), and sepsis (13%) among AML/MDS patients, and pleural effusion and disease progression (20% each) among NHL patients. 22 AML/MDS patients (26%) had at least one AE leading to treatment discontinuation (5 discontinuations due to disease progression, and 3 AEs assessed as related to treatment). 2 NHL patients (20%) had at least one AE leading to treatment discontinuation, both for disease progression. Twenty AML/MDS patients (24%) and 2 NHL patients (20%) died due to AEs, all of which were assessed as unrelated to study treatment. Disease progression was the most common fatal TEAE in AML/MDS and NHL patients (10% and 20%, respectively). Compound A as a single agent showed acceptable safety in R/R AML/MDS and NHL patients.

Gastrointestinal toxicity was mostly low-grade, and higher-grade gastrointestinal AEs occurred in <5% of AML/MDS patients and in 0% of NHL patients. TEAEs are summarized in Table 5.

Table 5

[0149] Based on the dose escalation study of this Example, the maximum tolerated dose (MTD) on the QOW schedule was 400 mg Compound A, though MTD was not determined for other dosing schedules (QW and QM). Some clinical activity was observed in R/R AML/MDS patients, wherein one patient (3%) achieved CRi and 19 patients (63%) achieved SD, including 2 patients receiving >7 cycles of treatment.

Example 7. Effect of Dosing Compound A and Azacitidine

[0150] Compound A and azacitidine exhibit a combinatorial effect. The combinatorial effects of Compound A and azacitidine were assessed using a Cell Titer Glo readout assay (Promega). Kasumi-1 and MV-4-11 cells were plated in white flat bottom 96 well plates.

Dilution series were made for each compound (10 mM top dose, 8 points, 1 :3 dilution in DMSO) and added to cells after plating. Compounds were also added individually, and some wells were treated with DMSO only. Cells were treated as follows: compounds were added according to the diagram in Figure 9. Compounds were initially added at the same time. MV-4-11 cells were treated for 72 hours and Kasumi-1 were treated for 120 hours. Cell Titer Glo was added at the end and viability was read out on the Envision Multilabel Reader. Data was analyzed using online software from Horizon (http://chalice.horizondiscovery.com/analyzer- server/cwr/analyze.jsp). Same-time addition did not provide evidence of synergy, so pre treatments were done. Plate setup was the same as before, but each cell line was pretreated with either azacitidine or Compound A for 4 or 24 hours, before addition of second compound. Total assay time remained the same for both cells lines, except for two MV-4-11 plates, which were given 72 hours total time after secondary compound addition. The results are reported below in Table 6. Synergy scores > 3 are considered to show a synergistic effect. 24 hour pretreatment with azaciditine consistently showed strong synergistic effects for both AML cell lines tested.

Table 6

Example 8: Combination of Compound A and Azacitidine in Phase 1 Human Clinical Trial

[0151] In some methods provided herein, Compound A can be administered in combination with azacitidine (for example, in patients with R/R AML/MDS or AML who are unfit for, or unwilling to receive, standard induction therapy, or in patients with MDS eligible to receive azacitidine).

[0152] BET proteins are believed to mediate resistance to azacitidine. Strong synergy between azacitidine and Compound A in AML cell lines. Based on immune surveillance data, azacitidine is believed to upregulate PD-L-1/PD-L2 in AML, while Compound A down regulates PDL-l/PDL-2 expression in TME (M2 and MDSC).

[0153] Azacitidine is supplied as a lyophilized powder in 100 mg single-use vials containing no preservative and is packaged in cartons of one vial. Unreconstituted vials of azacitidine must be stored according to storage conditions provided in the VIDAZA® package insert. Azacitidine should be reconstituted aseptically with 4 mL of sterile water for injection. The resulting suspension will contain azacitidine, 25 mg/mL. Azacitidine will be administered via

subcutaneous injection or intravenous infusion at approximately the same time on scheduled dose days, in accordance with the azacitidine dosing instructions.

[0154] Compound A in combination with azacitidine is synergistic in vitro in human leukemia cell lines. Upregulation of PD-L1/PD-L2 after HMA treatment in both AML and MDS patients has been reported, indicating a diminished response to azacitidine therapy via immunotolerance may play a role in HMA treatment failures in AML/MDS.

[0155] The hypomethylating agent (HMA) azacitidine is approved for the treatment of subtypes of myelodysplastic syndrome (MDS) and is a recommended treatment option in acute myelogenous leukemia (AML) patients who are not candidates for or who have failed intensive cytotoxic induction/consolidation regimens. Resistance to azacitidine therapy in AML has been shown to be mediated by BET proteins. [0156] The starting dose of Compound A in combination is administered on Day 1 of each 28-day treatment cycle and will be a dose approximately < 50% the MTD identified for the AML/MDS SA treatment cohorts in that schedule. The standard dose of azacitidine, 75 mg/m ² is administered via subcutaneous injection or intravenous infusion for seven days starting on Day 1 of each 28-day treatment cycle. A 48-hour dose-interruption of the azacitidine for weekends or holidays is allowed. Alternate schedules of azacitidine dosing (e.g., starting azacitidine dosing on Day 8 of each treatment cycle) can be used if concurrent dosing of Compound A/azacitidine on Day 1 of each treatment cycle is found to be intolerable.

[0157] Further, as reported in Example 6, azacitidine administration about 24 hours prior to administration of Compound A exhibited a synergistic effect. Accordingly, a dosing regimen is administered to a patient where azacitidine is administered on days 1 - 7 of a 28-day cycle followed by Compound A administration on days 8 - 28 of a 28-day cycle. The standard dose of azacitidine (75 mg/m ² ) is administered via subcutaneous injection or intravenous infusion each day on days 1 - 7 of a 28 day cycle. On Day 8, about 24 hours after the final dose of azacitidine (of a 28 day cycle), Compound A is administered. During days 8 - 28, Compound A is administered on Day 8, Day 15, and Day 22. The 28-day cycle can be repeated as needed.

[0158] Sample QW dosing schedules include the following (* indicates neither azacitidine nor Compound A is administered on days 9-14 or days 16-21; N/A indicates not administered): Example Dosing Regimen A*:

Example Dosing Regimen B*:

Example Dosing Regimen C*: [0159] Sample QOW dosing schedules include the following (N/A indicates not administered):

Example Dosing Regimen D:

Example Dosing Regimen E:

[0160] Dose 0, Dose 1, Dose 2, and Dose 3 can be the same or different. In some

embodiments, Dose 1 is greater than Dose 0, Dose 2 is greater than Dose 1 and Dose 3 is greater than Dose 2. For example, Dose 0 and Dose 1 can be any one of the following combinations for QOW dosing:

[0161] For example, the method of treatment can be the following QOW dosing schedule:

[0162] Another method of treatment can be the following QW dosing schedule:

[0163] For a given dose level, once > 2 patients have a DLT, further enrollment/treatment for that cohort will halt, as will dose escalation. The dose level at which > 2 of up to 6 evaluable patients have a DLT is considered to be at least 1 dose level above the MTD for that treatment cohort. The next lower dose is then evaluated by treating a total of up to 6 evaluable patients. If > 2 patients have a DLT at this lower dose level, de-escalation will continue until a dose level is identified at which 0 or 1 of a total of 6 patients has a DLT. This identifies the MTD for the combination treatment cohort. The RP2D can be a dose level equivalent or lower than the MTD.

Example 9: Dosing of Compound B

[0164] A Compound B intermittent dosing schedule for treatment of AML or metastatic castration-resistant prostate cancer comprises administering to a patient in need thereof an amount of Compound B sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. For example, 1-500 mg of Compound B is administered every week to a patient in need thereof. In another example, 1-500 mg of Compound B is administered every other week to a patient in need thereof.

Example 10: Dosing of Compound C

[0165] A Compound C intermittent dosing schedule for treatment of AML, MM, breast cancer, NSCLC, prostate cancer, SCLC, or NHL comprises administering to a patient in need thereof an amount of Compound C sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. For example, 1-500 mg of Compound C is administered every week to a patient in need thereof. In another example, 1-500 mg of Compound C is administered every other week to a patient in need thereof.

Example 11: Dosing of Compound D

[0166] A Compound D intermittent dosing schedule for treatment of solid tumors, lymphoma, or ovarian CA expansion comprises administering to a patient in need thereof an amount of Compound D sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. For example, 1-80 mg of Compound D is administered every week to a patient in need thereof. In another example, 1-80 mg of Compound D is administered every other week to a patient in need thereof.

Example 12: Dosing of Compound E

[0167] A Compound E intermittent dosing schedule for treatment of HCC, NMC, melanoma, or lymphoma comprises administering to a patient in need thereof an amount of Compound E sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. For example, 1-80 mg of Compound E is administered every week to a patient in need thereof. In another example, 1-80 mg of Compound E is administered every other week to a patient in need thereof.

Example 13: Dosing of Compound F

[0168] A Compound F intermittent dosing schedule for treatment of TNBC, ovarian cancer (serous histology for expansion phase), SCLC, or other solid tumors comprises administering to a patient in need thereof an amount of Compound F sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. For example, 1-500 mg of Compound F is administered every week to a patient in need thereof. In another example, 1-500 mg of

Compound F is administered every other week to a patient in need thereof.

Example 14: Dosing of Compound G

[0169] A Compound G intermittent dosing schedule for treatment of MM, lymphoma, leukemia, MDS, MPN, or nerve sheath tumors comprises administering to a patient in need thereof an amount of Compound G sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. For example, 1-200 mg of Compound G is administered every week to a patient in need thereof. In another example, 1-200 mg of Compound G is administered every other week to a patient in need thereof.

Example 15: Dosing of Compound H

[0170] A Compound H intermittent dosing schedule for treatment of breast cancer or diffuse large B cell lymphoma comprises administering to a patient in need thereof an amount of Compound H sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. For example, 1-500 mg of Compound H is administered every week to a patient in need thereof. In another example, 1-500 mg of Compound H is administered every other week to a patient in need thereof. Example 16: Dosing of Compound I

[0171] A Compound I intermittent dosing schedule for treatment of AML, SCLC, NSCLC, colorectal cancer, TNBC, ER+ BrCA, CRPC, MYC-amp solids, or ras-mutant solid tumors comprises administering to a patient in need thereof an amount of Compound I sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. For example, 1-50 mg of Compound I is administered every week to a patient in need thereof. In another example, 1-50 mg of Compound I is administered every other week to a patient in need thereof.

Example 17: Dosing of Compound J

[0172] A Compound J intermittent dosing schedule for treatment of lymphoma, solid tumors, AML, MDS, MF, or MM comprises administering to a patient in need thereof an amount of Compound J sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. For example, 1-70 mg of Compound J is administered every week to a patient in need thereof. In another example, 1-70 mg of Compound J is administered every other week to a patient in need thereof.

Example 18: Dosing of Compound K

[0173] A Compound K intermittent dosing schedule for treatment of solid and heme escalation comprises administering to a patient in need thereof an amount of Compound K sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. For example, 1-500 mg of Compound K is administered every week to a patient in need thereof. In another example, 1-500 mg of Compound K is administered every other week to a patient in need thereof.

Example 19: Dosing of Compound L

[0174] A Compound L intermittent dosing schedule for treatment of AML/DLBCL, solid tumors (NMC, TNBC, NSCLC, CRPC), heme, glioblastoma multiforme, lymphoma, or MDS comprises administering to a patient in need thereof an amount of Compound L sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. For example, 1-200 mg of Compound L is administered every week to a patient in need thereof. In another example, 1-200 mg of Compound L is administered every other week to a patient in need thereof.

Example 20: Dosing of Compound M

[0175] A Compound M intermittent dosing schedule for treatment of solid tumors, lymphoma, MDS, or AML comprises administering to a patient in need thereof an amount of Compound M sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. For example, 1-500 mg of Compound M is administered every week to a patient in need thereof. In another example, 1-500 mg of Compound M is administered every other week to a patient in need thereof.

Example 21: BET Inhibitor Dosing Schedules

[0176] A BET Inhibitor Compound is administered to a patient in need thereof according to a dosing schedule described in Table 7, e.g., according to a dosing schedule sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.

Table 7

[0177] The foregoing has been a description of certain non-limiting embodiments of the invention. Accordingly, it is to be understood that the embodiments of the invention herein described are merely illustrative of the application of the principles of the invention. Reference herein to details of the illustrated embodiments is not intended to limit the scope of the claims.