HALILOVIC ENSAR (US)
MENSSEN HANS DIETRICH RICHARD (CH)
PATHAK DHRUBAJYOTI (CH)
WO2020128892A1 | 2020-06-25 | |||
WO2021079188A1 | 2021-04-29 | |||
WO2013111105A1 | 2013-08-01 |
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CLAIMS 1. An MDM2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of a haematological malignancy, wherein the treatment further comprises administration of a BCL2 inhibitor or a pharmaceutically acceptable salt thereof and a hypomethylating agent or a pharmaceutically acceptable salt thereof. 2. A BCL2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of a haematological malignancy, wherein the treatment further comprises administration of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a hypomethylating agent or a pharmaceutically acceptable salt thereof. 3. A hypomethylating agent or a pharmaceutically acceptable salt thereof for use in the treatment of a haematological malignancy, wherein the treatment further comprises administration of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor or a pharmaceutically acceptable salt thereof. 4. A method of treating a haematological malignancy in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of a BCL2 inhibitor or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a hypomethylating agent or a pharmaceutically acceptable salt thereof. 5. A combination comprising an MDM2 inhibitor or a pharmaceutically acceptable salt thereof, a BCL2 inhibitor or a pharmaceutically acceptable salt thereof and a hypomethylating agent or a pharmaceutically acceptable salt thereof. 6. The MDM2 inhibitor for use according to Claim 1, the BCL2 inhibitor for use according to Claim 2, the hypomethylating agent for use according to Claim 3, the method according to Claim 4, or the combination according to Claim 5, wherein the MDM2 inhibitor is HDM201. 7. The MDM2 inhibitor for use according to Claim 1 or Claim 6, the BCL2 inhibitor for use according to Claim 2 or Claim 6, the hypomethylating agent for use according to Claim 3 or Claim 6, the method according to Claim 4 or Claim 6, or the combination according to Claim 5 or Claim 6, wherein the BCL2 inhibitor is navitoclax or venetoclax. 8. The MDM2 inhibitor for use according to Claim 7, the BCL2 inhibitor for use according to Claim 7, the hypomethylating agent for use according to Claim 7, the method according to Claim 7, or the combination according to Claim 7, wherein the BCL2 inhibitor is venetoclax. 9. The MDM2 inhibitor for use according to any one of Claims 1 and 6 to 8, the BCL2 inhibitor for use according to any one of Claims 2 and 6 to 8, the hypomethylating agent for use according to any one of Claims 3 and 6 to 8 or the method according to any one of Claims 4 and 6 to 8, wherein the MDM2 inhibitor is administered orally. 10. The MDM2 inhibitor for use according to any one of Claims 1 and 6 to 9, the BCL2 inhibitor for use according to any one of Claims 2 and 6 to 9, the hypomethylating agent for use according to any one of Claims 3 and 6 to 9 or the method according to any one of Claims 4 and 6 to 9, wherein the MDM2 inhibitor is administered on each of the first 5 days of a 28 day treatment cycle, and wherein the treatment comprises at least two treatment cycles. 11. The MDM2 inhibitor for use according to Claim 10, the BCL2 inhibitor for use according to Claim 10, the hypomethylating agent for use according to Claim 10 or the method according to Claim 10, wherein the daily dose of the MDM2 inhibitor on each of the first 5 days of the 28 day treatment cycle is from 10 to 50 mg. 12. The MDM2 inhibitor for use according to Claim 11, the BCL2 inhibitor for use according to Claim 11, the hypomethylating agent for use according to Claim 11 or the method according to Claim 11, wherein the daily dose of MDM2 inhibitor on each of the first 5 days of the 28 day treatment cycle is 20, 30 or 40 mg. 13. The MDM2 inhibitor for use according to any one of Claims 1 and 6 to 12, the BCL2 inhibitor for use according to any one of Claims 2 and 6 to 12, the hypomethylating agent for use according to any one of Claims 3 and 6 to 12, the method according to any one of Claims 4 and 6 to 12, or the combination according to any one of Claims 5 to 7, wherein the hypomethylating agent is azacitidine or decitabine. 14. The MDM2 inhibitor for use according to any one of Claims 1 and 6 to 13, the BCL2 inhibitor for use according to any one of Claims 2 and 6 to 13, the hypomethylating agent for use according to any one of Claims 3 and 6 to 13 or the method according to any one of Claims 4 and 6 to 13, wherein the hypomethylating agent is administered subcutaneously or intravenously. 15. The MDM2 inhibitor for use according to any one of Claims 1 and 6 to 14, the BCL2 inhibitor for use according to any one of Claims 2 and 6 to 14, the hypomethylating agent for use according to any one of Claims 3 and 6 to 14 or the method according to any one of Claims 4 and 6 to 14, wherein the BCL2 inhibitor is administered orally. 16. The MDM2 inhibitor for use according to any one of Claims 1 and 6 to 15, the BCL2 inhibitor for use according to any one of Claims 2 and 6 to 15, the hypomethylating agent for use according to any one of Claims 3 and 6 to 15, the method according to any one of Claims 4 and 6 to 15, or the combination according to any one of Claims 5 to 7 and 13, wherein the MDM2 inhibitor, the BCL2 inhibitor and the hypomethylating agent are in the form of a non-fixed combination. 17. The MDM2 inhibitor for use according to any one of Claims 1 and 6 to 16, the BCL2 inhibitor for use according to any one of Claims 2 and 6 to 16, the hypomethylating agent for use according to any one of Claims 3 and 6 to 16, or the method according to any one of Claims 4 and 6 to 16, wherein the MDM2 inhibitor, the BCL2 inhibitor and the hypomethylating agent are for simultaneous or sequential use. 18. The MDM2 inhibitor for use according to any one of Claims 1 and 6 to 17, the BCL2 inhibitor for use according to any one of Claims 2 and 6 to 17, the hypomethylating agent for use according to any one of Claims 3 and 6 to 17 or the method according to any one of Claims 4 and 6 to 17, wherein the haematological malignancy is AML or MDS. 19. The MDM2 inhibitor for use according to Claim 18, the BCL2 inhibitor for use according to Claim 18, the hypomethylating agent for use according to Claim 18 or the method according to Claim 18, wherein the haematological malignancy is AML. 20. The MDM2 inhibitor for use according to Claim 19, the BCL2 inhibitor for use according to Claim 19, the hypomethylating agent for use according to Claim 19 or the method according to Claim 19, wherein the AML is unfit AML. 21. The MDM2 inhibitor for use according to Claim 19 or Claim 20, the BCL2 inhibitor for use according to Claim 19 or Claim 20, the hypomethylating agent for use according to Claim 19 or Claim 20 or the method according to Claim 19 or Claim 20, wherein the treatment is administered to a subject who is: i) 75 years of age or older, or ii) from 18 to 74 years of age with at least one of the following co-morbidities: a) an ECOG performance Status 2 or 3; b) a cardiac history of congestive heart failure requiring treatment, or Ejection Fraction ≤ 50%, or chronic stable Angina; and c) DLCO ≤ 65% or FEV1% ≤ 65%. 22. The MDM2 inhibitor for use according to any one of Claims 19 to 21, the BCL2 inhibitor for use according to any one of Claims 19 to 21, the hypomethylating agent for use according to any one of Claims 19 to 21 or the method according to any one of Claims 19 to 21, wherein the AML is TP53 wild-type AML. 23. The MDM2 inhibitor for use according to any one of Claims 19 to 22, the BCL2 inhibitor for use according to any one of Claims 19 to 22, the hypomethylating agent for use according to any one of Claims 19 to 22 or the method according to any one of Claims 19 to 22, wherein the treatment comprises from two to six complete treatment cycles of the MDM2 inhibitor, the BCL2 inhibitor and the hypomethylating agent, and wherein following said two to six complete treatment cycles: i) the complete remission (CR) rate is ≥ 30%; and/or ii) the posterior probability that the CR rate is ≥ 15% is at least 97.5%; and/or iii) the CR rate is ≥ 30%, and the posterior probability that CR rate is ≥ 15% is at least 97.5%. 24. The MDM2 inhibitor for use according to any one of Claims 19 to 23, the BCL2 inhibitor for use according to any one of Claims 19 to 23, the hypomethylating agent for use according to any one of Claims 19 to 23 or the method according to any one of Claims 19 to 23, wherein the treatment is administered to a subject who has previously received therapy with a combination of a BCL2 inhibitor and a hypomethylating agent. 25. The MDM2 inhibitor for use according to any one of Claims 19 to 23, the BCL2 inhibitor for use according to any one of Claims 19 to 23, the hypomethylating agent for use according to any one of Claims 19 to 23 or the method according to any one of Claims 19 to 23, wherein the treatment is first line (1L) treatment. 26. The MDM2 inhibitor for use according to any one of Claims 19 to 25, the BCL2 inhibitor for use according to any one of Claims 19 to 25, the hypomethylating agent for use according to any one of Claims 19 to 25 or the method according to any one of Claims 19 to 25, wherein the AML is TP53 wildtype AML with adverse genetic risk stratification according to ELN 2017. 27. The MDM2 inhibitor for use according to any one of Claims 1 and 6 to 26, the BCL2 inhibitor for use according to any one of Claims 2 and 6 to 26, the hypomethylating agent for use according to any one of Claims 3 and 6 to 26 or the method according to any one of Claims 4 and 6 to 26, wherein the hypomethylating agent is azacitidine and the azacitidine is administered on each of the first 7 days of a 28 day treatment cycle or on days 1 to 5, 8 and 9 of a 28 day treatment cycle, and wherein the treatment comprises at least two treatment cycles. 28. The MDM2 inhibitor for use according to claim 27, the BCL2 inhibitor for use according to claim 27, the hypomethylating agent for use according to claim 27 or the method according to claim 27, wherein the azacitidine is administered at from 20 to 200 mg/m2 on i) each of the first 7 days of each 28 day treatment cycle, or ii) on each of days 1 to 5, 8 and 9 of each 28 day treatment cycle. 29. The MDM2 inhibitor for use according to Claim 28, the BCL2 inhibitor for use according to Claim 28, the hypomethylating agent for use according to Claim 28 or the method according to Claim 28, wherein the azacitidine is administered at 75 mg/m2 on i) each of the first 7 days of each 28 day treatment cycle, or ii) on each of days 1 to 5, 8 and 9 of each 28 day treatment cycle. 30. The MDM2 inhibitor for use according to any one of Claims 1 and 6 to 29, the BCL2 inhibitor for use according to any one of Claims 2 and 6 to 29, the hypomethylating agent for use according to any one of Claims 3 and 6 to 29 or the method according to any one of Claims 4 and 6 to 29, wherein the BCL2 inhibitor is venetoclax and the venetoclax is administered at 100 mg on the first day of the first 28 day treatment cycle, 200 mg on the second day of the first 28 day treatment cycle, and 400 mg on each of the third to twenty-eighth days of the first 28 day treatment cycle. 31. The MDM2 inhibitor for use according to Claim 30, the BCL2 inhibitor for use according to Claim 30, the hypomethylating agent for use according to Claim 30 or the method according to Claim 30, wherein the venetoclax is administered at 400mg daily of the second and any subsequent 28 day treatment cycles. 32. The MDM2 inhibitor for use according to any one of Claims 1 and 6 to 29, the BCL2 inhibitor for use according to any one of Claims 2 and 6 to 29, the hypomethylating agent for use according to any one of Claims 3 and 6 to 29 or the method according to any one of Claims 4 and 6 to 29, wherein the BCL2 inhibitor is venetoclax and the venetoclax is administered at 400 mg on each of the first to twenty-eighth days of a 28 day treatment cycle, and wherein the treatment comprises at least two treatment cycles. |
In addition, complete remission with partial hematological recovery (CRh) may be assessed following the below criteria: ● Bone marrow: less than 5% blasts and no blasts with Auer rods; and ● Peripheral Blood: Neutrophils greater than 0.5x10 9 /L and/or platelets > 50x10 9 /L; and ● No evidence of extramedullary disease (such as CNS or soft tissue involvement) Of note, subject who is assessed as CRh would also fulfill the criteria of CRi. However, not all subjects who are assessed as CRi would automatically fulfill the criteria of CRh. In an embodiment, in each of the from two to four 28 day doublet treatment cycles of combined BCL2i (e.g. venetoclax) and hypomethylating agent therapy (without further combination with an MDM2i), the hypomethylating agent used in the doublet treatment cycles was either azacitidine or decitabine, for example wherein: i) Azacitidine was administered on each of the first 7 days of the 28 day doublet treatment cycle (e.g. subcutaneously or intravenously); or ii) Decitabine was administered on each of the first 5 days of the 28 day doublet treatment cycle (e.g. subcutaneously or intravenously). In an embodiment, in the 28 day doublet treatment cycles of combined BCL2i and hypomethylating agent therapy (without further combination with an MDM2i), the BCL2i in the doublet was venetoclax, and the venetoclax was administered in each of 28 days of the 28 day doublet treatment cycle (e.g. orally). In an embodiment, the venetoclax was administered at 100 mg on the first day of the first 28 day doublet treatment cycle, 200 mg on the second day of the first 28 day doublet treatment cycle, 300 mg on the third day of the first 28 day doublet treatment cycle and 400 mg on each of the fourth to twenty-eighth days of the first 28 day doublet treatment cycle. In an embodiment, the venetoclax was administered 400 mg daily on the second and any subsequent doublet treatment cycles. In an alternative embodiment, the treatment is first line (1L) treatment (e.g. in newly diagnosed AML) (wherein the AML includes both de novo and secondary AML). In an embodiment, the AML is TP53 wildtype AML and has adverse genetic risk stratification according to ELN (European LeukemiaNet) 2017. In an embodiment, the AML has one or more of the genetic abnormalities: i) t(6;9)(p23;q34.1); DEK-NUP214; ii) t(v;11q23.3); KMT2A rearranged; iii) t(9;22)(q34.1;q11.2); BCR-ABL1; iv) inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1); v) −5 or del(5q); −7; −17/abn(17p); vi) Complex karyotype,§ monosomal karyotype||; vii) Wild-type NPM1 and FLT3-ITDhigh † ; viii) Mutated RUNX1¶ ; and ix) Mutated ASXL1¶ § Three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated recurring translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); AML with BCR-ABL1. || Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 additional monosomy or structural chromosome abnormality (excluding core-binding factor AML). † Low, low allelic ratio (<0.5); high, high allelic ratio (≥0.5); semiquantitative assessment of FLT3-ITD allelic ratio (using DNA fragment analysis) is determined as ratio of the area under the curve “FLT3-ITD” divided by area under the curve “FLT3-wild type”; ¶ These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML subtypes. Favourable-risk AML subtypes include: a) t(8;21)(q22;q22.1); RUNX1-RUNX1T1; b) inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11; c) Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow † ; and d) Biallelic mutated CEBPA † Low, low allelic ratio (<0.5); high, high allelic ratio (≥0.5); semiquantitative assessment of FLT3-ITD allelic ratio (using DNA fragment analysis) is determined as ratio of the area under the curve “FLT3-ITD” divided by area under the curve “FLT3-wild type”; As used herein, the term “first line treatment” simply means the first treatment for treating the disease from a temporal perspective. In an embodiment, the AML has the genetic abnormality t(6;9)(p23;q34.1); DEK-NUP214. In an embodiment, the AML has the genetic abnormality t(v;11q23.3); KMT2A rearranged. In an embodiment, the AML has the genetic abnormality t(9;22)(q34.1;q11.2); BCR-ABL1. In an embodiment, the AML has the genetic abnormality inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1). In an embodiment, the AML has the genetic abnormality −5 or del(5q); −7; −17/abn(17p). In an embodiment, the AML has the genetic abnormality Complex karyotype,§ monosomal karyotype||. In an embodiment, the AML has the genetic abnormality Wild-type NPM1 and FLT3-ITDhigh † . In an embodiment, the AML has the genetic abnormality Mutated RUNX1¶ . In an embodiment, the AML has the genetic abnormality Mutated ASXL1¶. The terms "a" and "an" and "the" and similar references in the context of describing the invention (especially in the context of the following claims and preceding embodiments) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural form is used for compounds, patients, cancers and the like, this is taken to mean also a single compound, patient, or the like. References in this specification to "the invention" are intended to reflect embodiments of the several inventions disclosed in this specification, and should not be taken as unnecessarily limiting of the claimed subject matter. The term "synergistic effect" as used herein refers to action of two or three therapeutic agents producing an effect, for example, slowing the progression of a proliferative disease, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves. A synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet.6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol.114: 313-326 (1926)) and the median effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul.22: 27-55 (1984)). Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of a drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compound and which typically are not biologically or otherwise undesirable. The compound may be capable of forming acid addition salts by virtue of the presence of an amino group. Unless otherwise specified, or clearly indicated by the text, reference to therapeutic agents useful in the pharmaceutical combination of the present invention includes both the free base of the compounds, and all pharmaceutically acceptable salts of the compounds. The term “combination” or “pharmaceutical combination” is defined herein to refer to either a fixed combination in one dosage unit form, a non-fixed combination or a kit of parts for the combined administration where the therapeutic agents may be administered together, independently at the same time or separately within time intervals, which preferably allows that the combination partners show a cooperative, e.g. synergistic effect. Thus, the single compounds of the pharmaceutical combination of the present invention could be administered simultaneously or sequentially. Furthermore, the pharmaceutical combination of the present invention may be in the form of a fixed combination or in the form of a non-fixed combination. The term “fixed combination” means that the therapeutic agents, e.g., the single compounds of the combination, are in the form of a single entity or dosage form. The term “non-fixed combination” means that the therapeutic agents, e.g., the single compounds of the combination, are administered to a patient as separate entities or dosage forms either simultaneously or sequentially with no specific time limits, wherein preferably such administration provides therapeutically effective levels of the two therapeutic agents in the body of the subject, e.g., a mammal or human in need thereof. The pharmaceutical combinations can further comprise at least one pharmaceutically acceptable carrier. Thus, the present invention relates to a pharmaceutical composition comprising the pharmaceutical combination of the present invention and at least one pharmaceutically acceptable carrier. As used herein, the term “carrier” or "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Generally, the term “pharmaceutical composition” is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human. The present pharmaceutical combinations can be formulated in a suitable pharmaceutical composition for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulating, sugar-coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units. The pharmaceutical composition may contain, from about 0.1 % to about 99.9%, preferably from about 1 % to about 60 %, of the therapeutic agent(s). One of ordinary skill in the art may select one or more of the aforementioned carriers with respect to the particular desired properties of the dosage form by routine experimentation and without any undue burden. The amount of each carriers used may vary within ranges conventional in the art. The following references disclose techniques and excipients used to formulate oral dosage forms. See The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003). These optional additional conventional carriers may be incorporated into the oral dosage form either by incorporating the one or more conventional carriers into the initial mixture before or during granulation or by combining the one or more conventional carriers with granules comprising the combination of agents or individual agents of the combination of agents in the oral dosage form. In the latter embodiment, the combined mixture may be further blended, e.g., through a V-blender, and subsequently compressed or molded into a tablet, for example a monolithic tablet, encapsulated by a capsule, or filled into a sachet. Clearly, the pharmaceutical combinations of the present invention can be used to manufacture a medicine. The present invention relates to such pharmaceutical combinations or pharmaceutical compositions that are particularly useful as a medicine. Specifically, the combinations or compositions of the present invention can be applied in the treatment of haematological malignancies, e.g. AML or MDS, e.g. AML, e.g. unfit AML. The present invention also relates to use of pharmaceutical combinations or pharmaceutical compositions of the present invention for the preparation of a medicament for the treatment of a haematological malignancies, e.g. AML or MDS, e.g. AML, e.g. unfit AML, and to a method for treating haematological malignancies, e.g. AML or MDS, e.g. AML, e.g. unfit AML, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination according to the present invention, or the pharmaceutical composition according to the present invention. The term “treatment” as used herein comprises a treatment relieving, reducing or alleviating at least one symptom in a subject, increasing progression-free survival, overall survival, extending duration of response or delaying progression of a disease. For example, treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer. Within the meaning of the present invention, the term “treatment” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease in a patient, e.g., a mammal, particularly the patient is a human. The term “treatment” as used herein comprises an inhibition of the growth of a tumor incorporating a direct inhibition of a primary tumor growth and / or the systemic inhibition of metastatic cancer cells. A "subject," "individual" or "patient" is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, mice, simians, humans, farm animals, sport animals, and pets. The term "a therapeutically effective amount" of a compound (e.g. chemical entity or biologic agent) of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one embodiment a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg. As used herein, the term “inhibit”, "inhibition" or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. The optimal dosage of each combination partner for treatment of a cancer can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known in the art. The amount of each combination partner that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the particular mode of administration. In some embodiments the unit dosage forms containing the combination of agents as described herein will contain the amounts of each agent of the combination that are typically administered when the agents are administered alone. Frequency of dosage may vary depending on the compound used and the particular condition to be treated or prevented. In general, the use of the minimum dosage that is sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art.
Examples Example 1 In vivo pharmacology of HDM201 and venetoclax (ABT-199) combination HDM201 was shown to enhance antitumor activity of the selective Bcl-2 inhibitor venetoclax (also known as ABT-199) in vivo in multiple AML patient derived orthotopic models. In mice harboring the mutant IDH1/FLT3-ITD, HDM201 treatment alone exhibited minimal anti-cancer activity (92%T/C, p>0.05). In contrast, HDM201 in combination with venetoclax induced complete tumor regressions (-100%Reg), while only partial tumor regressions were observed with venetoclax alone (-9 to -52%Reg). See Figures 1 and 2. Consistent with the observation in peripheral blood, the depletion of leukemic cells in spleen was also observed by spleen weight and IHC staining of IDH1 R132H positive leukemic cells. HDM201 as a single agent led to a modest reduction of spleen size and leukemic density. In contrast, HDM201 in combination with venetoclax resulted in a near complete depletion of the leukemic cells in spleen and significant reduction of spleen size comparable to naïve animals, while venetoclax alone exhibited partial reduction of spleen size and leukemic density as compared to the vehicle control (See Figure 1). In an additional study, HDM201 was tested at three dose levels (5, 10, and 20 mg/kg HDM201) in combination with venetoclax. HDM201 given at a 4 fold lower dose (5 mg/kg vs 20 mg/kg) in venetoclax combination, improved the platelet counts to the levels comparable to non-treated animals, while still maintaining the high degree of tumor regression (-75%Reg) (see Figure 2). These data suggest that potential overlapping hematological toxicities of the combination could be mitigated with administration of lower doses of HDM201 while maintaining the anti-tumor activity. Example 2 CHDM201I12201 Clinical Study Rationale and design for study investigating HDM201 in combination with venetoclax and azacitidine: The study will be a phase Ib/II open label dose confirmation, proof of concept study of siremadlin (HDM201) in combination with venetoclax plus azacitidine in Unfit Adult AML participants. The primary purpose of this study is to assess whether siremadlin in combination with venetoclax plus azacitidine can enhance the clinical response in unfit AML patients without unacceptable levels of treatment-emergent toxicities. Two subpopulations of adult participants with unfit AML will be evaluated in separate arms. Arm 1: participants who responded sub-optimally to first-line venetoclax plus azacitidine treatment, and Arm 2: participants with newly diagnosed untreated AML with adverse genetic risk stratification according to ELN 2017 (excluding mutant TP53). The study treatment (siremadlin in combination with venetoclax plus azacitidine) will be administered in cycles with a planned duration of 28 days and will continue until the participants experience disease progression/relapse or unacceptable toxicity. The study will enroll approximately 55 participants and will be conducted in two parts: Part 1 is the safety run in part with the objective to determine the recommended dose for expansion (RDE) of siremadlin when administered in combination with venetoclax plus azacitidine. Part 2 is the Expansion part to further asses the efficacy and safety of siremadlin RDE in combination with venetoclax plus azacitidine. Study treatment will be administered in cycles with a planned duration of 28 days. Any participant who does not achieve at least Partial Response (PR) after taking siremadlin in combination with venetoclax plus azacitidine for a maximum of 4 cycles will discontinue study treatment. In each cycle, siremadlin will be administered orally once daily from Day 1 to Day 5, venetoclax will be administered orally once daily at 400mg starting on Day 1 (following a ramp-up in Arm 2 only, as per the following table) Azacitidine will be administered intravenously or subcutaneously at 75 mg/m 2 either from Days 1 to 7 or from Days 1 to 5, followed by administration Days 8 and 9 (at the discretion of the investigator following local institutional practice). In Arm 1, the participants will continue receiving their venetoclax and azacitidine doses that were evaluated as tolerable prior to study enrollment. For both arms: the siremadlin starting dose (dose level 1) will be 20 mg QD with dose level -1 at siremadlin 10 mg QD and dose level +1 and +2 respectively 30 and 40 mg QD. For each dose level, once the required number of evaluable participants has been confirmed, enrollment will be halted in order to allow the participants to have completed the DLT observation period (1 cycle) and a Safety Review Meeting has been conducted. The participating investigators and the Novartis Team will make decisions regarding siremadlin dose as guided by a Bayesian Logistic Regression model (BLRM). For a dose level to be considered for RDE, at least 6 evaluable participants are required in each arm independently. Based on the data generated in in at least 9-15 evaluable participants in each arm, the RDE will be determined separately (including safety data from the other arm, if available). Upon confirmation of the applicable RDE in each arm, Novartis will provide notification to the investigational sites indicating that Part 2 (expansion) is open to enrollment. Enrollment to Part 2 will continue until a total of 25 evaluable participants (including those in the safety run-in) are enrolled at the RDE in Arm 1. An additional 6 participants (approximately) will be enrolled in the expansion part of Arm 2. The assignment of a participant to a treatment arm and dose cohort will be captured in the interactive response technology (IRT) system and coordinated by Novartis. For participants enrolled in Arm 2, hospitalization is required from Cycle 1 Day 1 (C1D1) to Cycle 1 Day 3 (C1D3) (3 days) in order to closely monitor the chemistry parameters, in particular to detect occurrence of tumor lysis syndrome (TLS), and thereafter at the discretion of the investigator. At any time during the study, participants unable to tolerate one or two of the study drugs may continue to receive only the tolerated drug(s) considering the participants benefits/risk balance of continuing the drug(s) as per the investigator’s judgement. All participants will also be followed for safety for 30 days after the last dose of study treatment. All participants who discontinued study treatment will enter a long-term follow-up (for efficacy and/or survival status) as described in the study flow diagram of Figure 3. Study Flow The study flow is comprised of 3 periods: Pre-treatment (screening), treatment and follow-up. Participants will undergo assessments during screening and periodically during treatment and follow-up as shown in the study flow chart of Figure 4. Rationale Siremadlin is a novel investigational agent with single-agent activity in AML participants. Studies have shown that there is rationale to combine siremadlin with other agents such as selective Bcl- 2 inhibitors in AML to improve single agent anti-leukemic activity. The planned clinical trial will seek to extend these preliminary findings of efficacy by evaluating siremadlin in combination with the Bcl-2 inhibitor venetoclax and the HMA (hypomethylating agent) azacitidine. The combination of venetoclax and azacitidine has demonstrated improved efficacy relative to azacitidine alone in early Phase 1b trials, and has received full approval by the FDA for treatment of unfit AML. Despite the improved efficacy of the venetoclax/HMA regimen, significant unmet medical need remains, as a substantial number of patients fail to achieve a CR (complete remission) and the CRs which are observed are only of limited duration. It is hypothesised that addition of HDM201 to the venetoclax and azacitidine combination can enhance the clinical response in unfit AML patients without unacceptable levels of treatment- emergent toxicities. This is the first trial that will evaluate the combination of siremadlin with venetoclax plus azacitidine. The combination of siremadlin and venetoclax is currently being evaluated in a Phase 1b, multi-arm, open level study [CHDM201H12101C] in adult patients with AML or high risk MDS. In this study, the selection of the dose and regimen for siremadlin is based on the currently available preclinical and clinical safety, efficacy, and PK information from the single agent first-in- human clinical trial [CHDM201X2101] and [CHDM201H12101C], while for venetoclax, the dose and regimen are selected from clinical data available for venetoclax trials in AML (i) Konopleva M, Pollyea DA, Potluri, J, et al (2016) Efficacy and Biological Correlates of Response in a Phase II study of venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia models. J Hematl Oncol p. 50. and (ii) DiNardo CD, Jonas BA, Pullarkat V, et al (2020) Azacitidine and venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med p. 617-29. In the ongoing [CHDM201H12101C] trial, dose escalation is performed in the siremadlin plus venetoclax arm following the first cycle of treatment and based on the participant’s safety data and supporting PK data. In study [CHDM201H12101C], the PK exposures and parameters of siremadlin at doses of 20 mg and 30 mg on days 1 to 5 of each cycle in combination with venetoclax (400 mg QD) were comparable to historical siremadlin single agent data [CHDM201X2101]. Study Population The study population will include approximately 55 patients with AML who are ineligible for chemotherapy, and who either responded sub-optimally to first line venetoclax plus azacitidine treatment or have newly diagnosed untreated AML presenting with high-risk clinical features. Inclusion Criteria 1. Signed Informed consent must be obtained prior to participation in the study 2. Age greater than or equal to 18 years at the date of signing the informed consent form (ICF) 3. Participants with AML based on WHO 2016 classification who are ineligible for chemotherapy and: a. Arm 1 (sub-optimal responders): have received at least 2 cycles and not more than 4 cycles of first-line venetoclax plus azacitidine treatment and have not achieved a CR, CRi, CRh or MLFS (based on IWG; ELN 2017). A participant can be enrolled in the study after two cycles only if the participant is no better than SD at the end of the cycle of venetoclax plus azacitidine treatment. Otherwise, the participants should be enrolled after cycle 3 of venetoclax plus azacitidine treatment. b. Arm 2 (newly diagnosed AML presenting with high-risk clinical features: newly diagnosed AML with adverse genetic risk stratification (according to ELN 2017) (except TP53 mutation positive participants). 4. Participants in both arms must be considered ineligible for standard of care standard (intensive) induction chemotherapy. Ineligibility is defined by the following: - 75 years of age or greater OR - from 18 to 74 years of age with at least one of the following co-morbidities: i) Eastern Cooperative Oncology (ECOG) Performance Status of 2 or 3; ii) Cardiac History of congestive heart failure requiring treatment or Ejection Fraction less than or equal to 50%, or chronic stable angina; iii) DLCO less than or equal to 65% or FEV1 less than or equal to 65% 5. Participants with antecedent of myelodysplastic syndromes (MDS), myelofibrosis, essential thrombocythemia, polycythemia vera or therapy related AML may be included in the study, provided no prior therapy, as specified in the exclusion criteria. 6. Participants must have an ECOG performance status of from 0 to 2 if greater than or equal to 75 years of age; or from 0 to 3 for participants from 18 years of age to 74 years of age. 7. AST and ALT ≤ 3 x upper limit of normal (ULN). 8. Total bilirubin ≤ 1.5 x ULN (except in the setting of isolated Gilbert syndrome, in which case higher total bilirubin is allowed provided that conjugated bilirubin is ≤ 3.0 x ULN). 9. Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73 m 2 (estimation based on Modification of Diet in Renal Disease (MDRD) formula, by local laboratory). 10. WBC < 25x10 9 /L (may be reduced with leukopheresis or hyroxyurea). 11. Participant is able to communicate with the investigator, and has the ability to comply with the requirements of the study procedures. Key Exclusion Criteria Participants meeting any of the following criteria are not eligible for inclusion in this study. 1. Prior exposure to MDM-inhibitor therapy at any time. 2. Participants with TP53 mutation positive, as defined by local TP53 testing. 3. Participants with del17p. 4. Previous treatment at any time, with any of the following antineoplastic agents, approved or investigational; checkpoint inhibitors, venetoclax and hypomethylating agents (HMAs) such as decitabine or azacitidine. Previous treatment for AML, MDS, myelofibrosis, essential thrombocytopenia or polycythemia vera, with the exception of hydroxyurea, growth factors, ruxolitinib, and supportive care. In Arm 1, as defined in the inclusion criteria pre-treatment with venetoclax and azacitidine is allowed provided the participant is enrolled in the study within 28 days from their last dose of venetoclax and/or azacitidine treatment. 5. Participants with AML-M3 / APL (acute promyelocytic leukemia) with PM-RARA (promyelocytic leukemia / retinoic acid receptor alpha) or with AML secondary to Down’s syndrome. 6. Participants treated with FLT3 inhibitors. 7. Participants with known active central nervous system (CNS) leukemia or neurologic symptoms suggestive of CNS leukemia (unless CNS leukemia has been excluded by at least one lumbar puncture showing negativity prior to starting protocol therapy). 8. Participants with concurrent or prior malignancy, except - Participant with history of MDS, myelofibrosis, essential thrombocythemia, polycythemia vera, aplastic anaemia, or other antecedent hematologic disorder - Participant with history of adequately treated malignancy for which the participant has been disease free (absence of residual disease) for at least 1 year and no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the course of the study. Participants who are receiving adjuvant therapy such as hormonal therapy or long-term maintenance therapy who have no residual disease for at least 1 year are eligible. Treatment Duration A participant may continue study treatment as scheduled unless: - They fail to achieve at least PR after taking siremadlin in combination with venetoclax plus azacitidine for a maximum of 4 cycles Or until: - They experience progressive disease, or relapse from CR or CRi - They experience unacceptable toxicity - The initiation of a treatment cycle is delayed due to toxicities by more than 28 days (measured from the intended start date of the new cycle (i.e. measure from Day 29 of the previous cycle) - They are scheduled to receive Hematopoietic Stem Cell Transplant (HSCT) or intensive chemotherapy at any time during the course of the study - They fail to adhere to the protocol At any time during the study, participants unable to tolerate one or two of the study drugs may continue to receive only the tolerated drug(s) considering the participants benefits/risk balance of continuing the drug(s) as per the investigator’s judgement.