TW202329968A - Pharmaceutical combinations comprising an mdm2 inhibitor, a bcl2 inhibitor and a hypomethylating agent and uses thereof for the treatment of haematological malignancies - Google Patents

Abstract

The invention relates to a pharmaceutical combination comprising an MDM2 inhibitor, a BCL2 inhibitor and a hypomethylating agent. The present invention also relates to methods of treating haematological malignancies involving said combination.

Description

Pharmaceutical combination comprising an MDM2 inhibitor, a BCL2 inhibitor and a hypomethylating agent and its use for the treatment of hematological malignancies

The present invention relates to a pharmaceutical combination comprising an MDM2 inhibitor, a BCL2 inhibitor and a hypomethylating agent. The present invention also relates to methods of treatment of hematological malignancies with respect to said combination.

HDM201

p53 is induced and activated by a number of potentially tumorigenic processes including aberrant growth signals, DNA damage, ultraviolet light, and protein kinase inhibitors (Millard M et al. Curr Pharm Design 2011;17:536-559), and regulates genes controlling cell growth arrest, DNA repair, apoptosis and angiogenesis (Bullock AN and Fersht AR. Nat Rev Cancer 2001;1:6876; Vogelstein B et al. Nature Education 2010; 3(9):6).

Human Double Minute-2 (HDM2) is one of the most important regulators of p53. Human double minute-2 binds directly to p53, thereby inhibiting the transactivation of p53, and subsequently directing p53 to cytoplasmic degradation (Zhang Y et al. Nucleic Acid Res 2010;38:6544-6554).

p53 is one of the most commonly inactivated proteins in human cancers through direct mutation of the TP53 gene (found in about 50% of all human cancers) (Vogelstein, B et al. Nature 2000;408:307-310) Or inactivation via inhibitory mechanisms such as overexpression of HDM2 (Zhao Y et al BioDiscovery 2013;8:4).

Proven potent and selective inhibitors of the HDM2-p53 interaction (also known as HDM2 inhibitors or MDM2 inhibitors, such as NVP-HDM201 (herein referred to as HDM201), and also known as siremadlin) Restoration of p53 function in preclinical cells and in vivo models (Holzer P et al. Poster at AACR 2016, abstract number 4855, Holzer P, Chimia [Chemistry] 2017, 71(10), 716-721). The HDM2 inhibitor HDM201, namely (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-benzene Base)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4- Ketones, and methods for their preparation are disclosed in WO 2013/111105 (Example 102). Venetoc

Venetoclax is a potent and selective inhibitor of B-cell lymphoma (BCL)-2, an anti-apoptotic protein. Venetoclax directly binds to the BH3-binding groove of BCL-2, displacing pro-apoptotic proteins (such as BIM) containing BH3 motifs to activate mitochondrial outer membrane permeabilization (MOMP), caspase activation , and programmed cell death. Bcl-2 is an anti-apoptotic protein of the Bcl-2 protein family, including Mcl-1 and Bcl-xL. Bcl-2 (such as Mcl-1 and Bcl-xL) can bind pro-apoptotic effector molecules (such as Bax/Bak) and prevent their oligomerization and formation of transmembrane pores in mitochondrial membranes. By doing so, Bcl-2 prevents the release of cytochrome c, thereby blocking the activation of caspases and subsequently inhibiting apoptosis. Escape from apoptosis is one of the hallmarks of cancer, and thus anti-apoptotic proteins such as Bcl-2 (facilitators of this escape) represent powerful therapeutic targets (Certo et al. 2006). Venetoclax is a highly selective orally bioavailable small molecule inhibitor of Bcl-2 that exhibits activity in Bcl-2-dependent leukemia and lymphoma cell lines (Souers et al 2013). Venetoclax induces apoptotic cell death in AML/MDS cell lines (primary AML/MDS subject samples) both in vitro and in mouse xenograft models (Pan et al. 2014).

Venetoclax monotherapy is FDA-approved for the treatment of CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma), with or without 17p deletion, who have received at least one prior therapy [Veenetoclax US Pl ]. In Europe, venetoclax has been approved by the EMA for the treatment of CLL with 17p deletion or TP53 mutation in adult subjects who are not suitable for B cell receptor pathway inhibitors or who have failed treatment with B cell receptor pathway inhibitors; Treatment of CLL without 17p deletion or TP53 mutation [venetoclax EU SmPC] in adult subjects who have failed chemoimmunotherapy and B-cell receptor pathway inhibitors.

Venetoclax had modest activity as monotherapy, with a CR/CRi rate of 19% (6/32 subjects) in R/R or chemotherapy-ineligible AML subjects (Konopleva et al 2016). Hypomethylating agent in combination with venetoclax

Hypomethylating agents (also known as demethylating agents) such as azacitidine and decitabine reduce the amount of DNA methylation in cells and increase the expression of tumor suppressor genes.

Hypomethylating agents have been used in combination with venetoclax for the treatment of newly diagnosed inappropriate AML patients, and this combination is increasingly considered the standard of care for this patient group. Venetoclax 400 mg showed significant activity in combination with azacitidine or decitabine, with CR/CRi rates of 71% and 74%, respectively (Jonas et al., Leukemia, 33, 2795-2804 , 2019). The combination of venetoclax and azacitidine received full FDA approval in 2020 for the treatment of ineligible AML (i.e. AML patients who are not eligible for standard intensive induction chemotherapy).

However, only 23.4% of patients could achieve MRD (minimal residual disease)-negative CR, disease resistance inevitably emerged over time, and long-term survival remained poor. Thus, despite recent improvements in the standard of care, there remains a significant unmet medical need in AML, especially unfit AML. (DiNardo, C. D., B. A. Jonas, V. Pullarkat, M. J. Thirman, J. S. Garcia, A. H. Wei, M. Konopleva, H. Döhner, A. Letai, P. Fenaux, E. Koller, V. Havelange, B. Leber, J. . Esteve, J. Wang, V. Pejsa, R. Hájek, K. Porkka, Á. Illés, D. Lavie, R. M. Lemoli, K. Yamamoto, S.-S. Yoon, J.-H. Jang, S. -P. Yeh, M. Turgut, W.-J. Hong, Y. Zhou, J. Potluri, and K. W. Pratz (2020). "Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia Azacitidine and venetoclax in [New England Journal of Medicine] 383(7): 617-629.)

The combination of venetoclax and azacitidine has also been studied for the treatment of high-risk MDS (myelometaplastic syndrome). The combination was found to result in improved overall survival (OS) compared to azacitidine monotherapy. (JS Garcia, Abstract No. 656, presented at the ASH Annual Meeting, December 7, 2020). However, disease progression remains common and significant unmet needs remain.

It is an object of the present invention to provide a drug combination to improve the treatment of hematologic malignancies such as MDS or AML such as AML such as unsuitable AML.

It is believed that a drug combination comprising: i) an MDM2 inhibitor or a pharmaceutically acceptable salt thereof; ii) a BCL2 inhibitor or a pharmaceutically acceptable salt thereof; and iii) a hypomethylating agent or its pharmaceutically acceptable salt.

Therefore, according to a first aspect of the present invention, there is hereby provided herein an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of hematological malignancies, wherein the treatment further comprises administering a BCL2 inhibitor or a pharmaceutically acceptable salt thereof. Acceptable salts and hypomethylating agents or pharmaceutically acceptable salts thereof.

According to the second aspect of the present invention, there is hereby provided a BCL2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of hematological malignancies, wherein the treatment further comprises administration of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof salts and hypomethylating agents or pharmaceutically acceptable salts thereof.

According to the third aspect of the present invention, there is hereby provided a hypomethylating agent or a pharmaceutically acceptable salt thereof for use in the treatment of hematologic malignancies, wherein the treatment further comprises administering an MDM2 inhibitor or a pharmaceutically acceptable salt thereof. An acceptable salt and a BCL2 inhibitor or a pharmaceutically acceptable salt thereof.

According to a fourth aspect of the present invention, there is provided herein a method of treating a hematological 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 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.

According to the fifth aspect of the present invention, there is provided herein a drug 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 combination.

As stated above, it is an object of the present invention to find new combination therapies effective in the treatment of hematological malignancies.

Accordingly, the present invention provides the following numbered embodiments:

Embodiment 1. An MDM2 inhibitor or a pharmaceutically acceptable salt thereof is used in the treatment of hematologic malignancies, wherein the treatment further includes administering a BCL2 inhibitor or a pharmaceutically acceptable salt thereof and a hypomethylating agent or a pharmaceutically acceptable salt thereof.

Embodiment 2. A BCL2 inhibitor or a pharmaceutically acceptable salt thereof is used in the treatment of hematologic malignancies, wherein the treatment further includes administering an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a hypomethylating agent or a pharmaceutically acceptable salt thereof.

Embodiment 3. A hypomethylating agent or a pharmaceutically acceptable salt thereof is used in the treatment of hematological malignancies, wherein the treatment further includes administering an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor or a pharmaceutically acceptable salt thereof.

Embodiment 4. A method of treating a hematological malignancy of 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 and a therapeutically effective amount of A combination 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.

Embodiment 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.

Embodiment 5a. The combination as described in embodiment 5 for use in the treatment of hematological malignancies, eg AML, eg incompatible AML, eg TP53 wild type incompatible AML.

Embodiment 6. The MDM2 inhibitor used as described in Embodiment 1, the BCL2 inhibitor used as described in Embodiment 2, the hypomethylation agent used as described in Embodiment 3, the method as described in Embodiment 4 . The combination of embodiment 5 or embodiment 5a, wherein the MDM2 inhibitor is HDM201.

Embodiment 7. The MDM2 inhibitor used as described in Embodiment 1 or Embodiment 6, the BCL2 inhibitor used as described in Embodiment 2 or Embodiment 6, the hypothyroidism used as described in Embodiment 3 or Embodiment 6 BCL2 inhibitor, the method as described in Embodiment 4 or Embodiment 6, or the combination as described in Embodiment 5, Embodiment 5a or Embodiment 6, wherein the BCL2 inhibitor is navitoclax or vitamin naitok.

Embodiment 8. The MDM2 inhibitor used as described in Embodiment 7, the BCL2 inhibitor used as described in Embodiment 7, the hypomethylation agent used as described in Embodiment 7, the method as described in Embodiment 7 . The combination according to embodiment 7, wherein the BCL2 inhibitor is venetoclax.

Embodiment 9. The MDM2 inhibitor used as described in any one of Embodiments 1 and 6 to 8, the BCL2 inhibitor used as described in any one of Embodiments 2 and 6 to 8, as described in Embodiments 3 and 6 The hypomethylating agent used in any one of embodiments 4 and 6 to 8, wherein the MDM2 inhibitor is administered orally.

Embodiment 10. MDM2 inhibitor used as described in any one of embodiments 1 and 6 to 9, BCL2 inhibitor used as described in any one of embodiments 2 and 6 to 9, as described in embodiments 3 and 6 The hypomethylating agent used according to any one of to 9 or the method according to any one of embodiments 4 and 6 to 9, wherein the MDM2 inhibitor is used on each of the first 5 days of a 28-day treatment cycle administered, and wherein the treatment comprises at least two treatment cycles.

Embodiment 11. The MDM2 inhibitor used as described in Embodiment 10, the BCL2 inhibitor used as described in Embodiment 10, the hypomethylating agent used as described in Embodiment 10, or the method described in Embodiment 10 , wherein the daily dose of the MDM2 inhibitor is 10 to 50 mg for each of the first 5 days of a 28-day treatment cycle.

Embodiment 12. The MDM2 inhibitor used as described in Embodiment 11, the BCL2 inhibitor used as described in Embodiment 11, the hypomethylating agent used as described in Embodiment 11, or the method described in Embodiment 11 , wherein the daily dose of the MDM2 inhibitor is 20, 30 or 40 mg on each of the first 5 days of a 28-day treatment cycle.

Embodiment 13. MDM2 inhibitor for use as described in any one of embodiments 1 and 6 to 12, BCL2 inhibitor for use as described in any one of embodiments 2 and 6 to 12, as described in embodiments 3 and 6 The hypomethylating agent used in any one of 12, the method as described in any one of embodiments 4 and 6 to 12, or the combination as described in any one of embodiments 5 to 7, wherein The hypomethylating agent is azacitidine or decitabine, such as azacitidine.

Embodiment 14. MDM2 inhibitor for use as described in any one of embodiments 1 and 6 to 13, BCL2 inhibitor for use as described in any one of embodiments 2 and 6 to 13, as described in embodiments 3 and 6 The hypomethylating agent used according to any one of embodiments 4 and 6 to 13 or the method according to any one of embodiments 4 and 6 to 13, wherein the hypomethylating agent is administered subcutaneously or intravenously, for example subcutaneously .

Embodiment 15. MDM2 inhibitor for use as described in any one of embodiments 1 and 6 to 14, BCL2 inhibitor for use as described in any one of embodiments 2 and 6 to 14, as described in embodiments 3 and 6 The hypomethylating agent used in any one of embodiments 4 and 6 to 14, wherein the BCL2 inhibitor is administered orally.

Embodiment 16. MDM2 inhibitor for use as described in any one of embodiments 1 and 6 to 15, BCL2 inhibitor for use as described in any one of embodiments 2 and 6 to 15, as described in embodiments 3 and 6 The hypomethylating agent used as described in any one of to 15, the method as described in any one of Embodiments 4 and 6 to 15, or the combination as described in any one of Embodiments 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.

Embodiment 17. MDM2 inhibitor for use as described in any one of embodiments 1 and 6 to 16, BCL2 inhibitor for use as described in any one of embodiments 2 and 6 to 16, as described in embodiments 3 and 6 The hypomethylating agent used in any one of to 16 or the method as described in any one of embodiments 4 and 6 to 16, wherein the MDM2 inhibitor, the BCL2 inhibitor and the hypomethylating agent Use simultaneously or sequentially.

Embodiment 18. MDM2 inhibitor for use as described in any one of embodiments 1 and 6 to 17, BCL2 inhibitor for use as described in any one of embodiments 2 and 6 to 17, as described in embodiments 3 and 6 The hypomethylating agent used according to any one of embodiments 4 and 6 to 17, wherein the hematological malignancy is AML or MDS.

Embodiment 19. The MDM2 inhibitor used as described in Embodiment 18, the BCL2 inhibitor used as described in Embodiment 18, the hypomethylating agent used as described in Embodiment 18, or the method described in Embodiment 18 , wherein the hematological malignancy is AML.

Embodiment 20. The MDM2 inhibitor used as described in Embodiment 19, the BCL2 inhibitor used as described in Embodiment 19, the hypomethylating agent used as described in Embodiment 19, or the method described in Embodiment 19 , where the AML is unsuitable (for standard induction chemotherapy) AML.

Embodiment 21. The MDM2 inhibitor used as described in Embodiment 19 or Embodiment 20, the BCL2 inhibitor used as described in Embodiment 19 or Embodiment 20, the hypothyroidism used as described in Embodiment 19 or Embodiment 20 The alkylating agent or the method of embodiment 19 or embodiment 20, wherein the treatment is administered to a subject who: i) aged 75 years or over, or ii) Aged from 18 to 74 years old, with at least one of the following comorbidities: a) ECOG performance status is 2 or 3; b) Heart disease history of congestive heart failure requiring treatment, or ejection fraction ≤ 50%, or chronic stable angina; c) Pulmonary comorbidities (e.g. DLCO ≤ 65% or FEV1% ≤ 65%); and d) Any other comorbidities incompatible with standard induction chemotherapy according to the physician's assessment.

Embodiment 22. The MDM2 inhibitor for use according to any one of embodiments 19 to 21, the BCL2 inhibitor for use as described in any one of embodiments 19 to 21, any one of embodiments 19 to 21 The hypomethylating agent used or the method according to any one of embodiments 19 to 21, wherein the AML is TP53 wild-type AML.

Embodiment 23. An MDM2 inhibitor for use as described in any one of embodiments 19 to 22, a BCL2 inhibitor for use as described in any one of embodiments 19 to 22, any one of embodiments 19 to 22 The hypomethylating agent used or the method according to any one of embodiments 19 to 22, wherein the treatment comprises two to six complete treatment cycles of an MDM2 inhibitor, a BCL2 inhibitor, and a hypomethylating agent (e.g. 28-day treatment cycle), and wherein after said two to six complete treatment cycles: i) Complete response (CR) rate ≥ 30%; and/or ii) The posterior probability of a CR rate ≥ 15% is at least 97.5%; and/or iii) CR rate ≥ 30%, the posterior probability of CR rate ≥ 15% is at least 97.5%.

Embodiment 24. MDM2 inhibitor for use as described in any one of embodiments 19 to 23, BCL2 inhibitor for use as described in any one of embodiments 19 to 23, any one of embodiments 19 to 23 The use of a hypomethylating agent or the method of any one of embodiments 19 to 23, wherein the treatment is administered to a patient who previously received a BCL2 inhibitor (e.g., venetoclax) and a hypomethylating agent (e.g. azacitidine or decitabine, e.g. azacitidine) without further combination therapy with an MDM2 inhibitor.

Embodiment 24a. The MDM2 inhibitor used as described in Embodiment 24, the BCL2 inhibitor used as described in Embodiment 24, the hypomethylating agent used as described in Embodiment 24, or the method described in Embodiment 24 , wherein following therapy with a combination of a BCL2 inhibitor and a hypomethylating agent, the patient fails to achieve any of the following: a) complete remission (CR); b) Complete remission (CRi) with incomplete hematological response; c) CR with partial recovery of peripheral blood counts (CRh); and d) Morphological leukemia-free status (MLFS).

Embodiment 24b. The MDM2 inhibitor used as described in Embodiment 24 or Embodiment 24a, the BCL2 inhibitor used as described in Embodiment 24 or Embodiment 24a, the hypothyroidism used as described in Embodiment 24 or Embodiment 24a A methylating agent or the method of embodiment 24 or embodiment 24a, wherein the combination therapy of the BCL2 inhibitor and hypomethylating agent comprises two to four complete treatment cycles of the BCL2 inhibitor and hypomethylating agent (e.g. 28-day treatment cycle).

Embodiment 24c. The MDM2 inhibitor used as described in Embodiment 24, Embodiment 24a or Embodiment 24b, the BCL2 inhibitor used as described in Embodiment 24, Embodiment 24a or Embodiment 24b, as described in Embodiment 24, Embodiment The hypomethylating agent for use as described in Embodiment 24a or Embodiment 24b or the method as described in Embodiment 24, Embodiment 24a or Embodiment 24b, wherein the treatment is administered to a patient who has previously received a BCL2 inhibitor and a hypomethylating agent. combination therapy with an MDM2 inhibitor, a BCL2 inhibitor, and a hypomethylating agent, and wherein treatment with a MDM2 inhibitor, a BCL2 inhibitor, and a hypomethylating agent is followed by a combination therapy with a BCL2 inhibitor and a hypomethylating agent (i.e., where the MDM2 inhibitor, BCL2 Day 1 of the first treatment cycle (e.g., 28-day treatment cycle) with a BCL2 inhibitor and a hypomethylating agent is after the last day (e.g., day 28) of the last cycle of therapy with a BCL2 inhibitor and a hypomethylating agent first day).

Embodiment 25. MDM2 inhibitor for use as described in any one of embodiments 19 to 23, BCL2 inhibitor for use as described in any one of embodiments 19 to 23, any one of embodiments 19 to 23 The use of a hypomethylating agent or the method of any one of embodiments 19 to 23, wherein the treatment is first-line (1L) treatment (eg, including both primary and secondary AML).

Embodiment 26. MDM2 inhibitor for use as described in any one of embodiments 19 to 25, BCL2 inhibitor for use as described in any one of embodiments 19 to 25, any one of embodiments 19 to 25 The hypomethylating agent used or the method according to any one of embodiments 19 to 25, wherein the AML is TP53 wild-type AML with poor genetic risk stratification according to ELN 2017.

Embodiment 27. MDM2 inhibitor for use as described in any one of embodiments 1 and 6 to 26, BCL2 inhibitor for use as described in any one of embodiments 2 and 6 to 26, as described in embodiments 3 and 6 The hypomethylating agent used in any one of to 26 or the method as described in any one of embodiments 4 and 6 to 26, wherein the hypomethylating agent is azacitidine, and the azacitidine Cytidine is administered on each of the first 7 days of the 28-day treatment cycle or on days 1 to 5, 8, and 9 of the 28-day treatment cycle, and wherein the treatment comprises at least two treatment cycles.

Embodiment 28. An MDM2 inhibitor for use as described in embodiment 27, a BCL2 inhibitor for use as described in embodiment 27, a hypomethylating agent for use as described in embodiment 27, or a method as described in embodiment 27 , wherein the azacitidine is administered at 20 to 200 mg/m ² on i) each of the first 7 days of each 28-day cycle, or ii) on days 1 to 5, 8, and 8 of each 28-day treatment cycle Dose each day for 9 days.

Embodiment 29. An MDM2 inhibitor for use as described in embodiment 28, a BCL2 inhibitor for use as described in embodiment 28, a hypomethylating agent for use as described in embodiment 28, or a method as described in embodiment 28 , wherein the azacitidine is given at 75 mg/m ² on i) each of the first 7 days of each 28-day cycle, or ii) on days 1 to 5, 8, and 9 of each 28-day treatment cycle every day of giving.

Embodiment 30. MDM2 inhibitor for use as described in any one of embodiments 1 and 6 to 29, BCL2 inhibitor for use as described in any one of embodiments 2 and 6 to 29, as described in embodiments 3 and 6 The hypomethylating agent used according to any one of 29 or the method according to any one of embodiments 4 and 6 to 29, wherein the BCL2 inhibitor is venetoclax, and the venetoclax Administer 100 mg on Day 1 of the first 28-day treatment cycle, 200 mg on Day 2 of the first 28-day treatment cycle, and from Day 3 to 400 mg is administered each day for twenty-eight days, eg, wherein the treatment comprises at least two treatment cycles.

Embodiment 31. An MDM2 inhibitor for use as described in embodiment 30, a BCL2 inhibitor for use as described in embodiment 30, a hypomethylating agent for use as described in embodiment 30, or a method as described in embodiment 30 , wherein the venetoclax is administered at 400 mg per day (i.e., on days 1 to 28) in the second and any subsequent 28-day treatment cycle.

Embodiment 32. MDM2 inhibitor for use as described in any one of embodiments 1 and 6 to 29, BCL2 inhibitor for use as described in any one of embodiments 2 and 6 to 29, as described in embodiments 3 and 6 The hypomethylating agent used according to any one of 29 or the method according to any one of embodiments 4 and 6 to 29, wherein the BCL2 inhibitor is venetoclax, and the venetoclax Administer at 400 mg each day on Days 1 through 28 of a 28-day treatment cycle, and wherein the treatment comprises at least two treatment cycles.

Embodiments 1 to 32 above and embodiments A to W below all relate to the combination of MDM2 inhibitors, BCL2 inhibitors and hypomethylating agents, or their use in the treatment of hematological malignancies, such as AML or MDS, such as AML, such as unsuitable Use in AML. The following combinations (not limited to the following combinations) and their uses specified in the above embodiments are covered in the present invention (including their pharmaceutically acceptable salts): HDM201 + venetoclax + azacitidine HDM201 + venetoclax + decitabine KRT-232 + venetoclax + azacitidine KRT-232 + venetoclax + decitabine Edanulin + venetoclax + azacitidine Edanulin + venetoclax + decitabine RAIN-32 + venetoclax + azacitidine RAIN-32 + venetoclax + decitabine APG-115 + venetoclax + azacitidine APG-115 + venetoclax + decitabine BI907828 + venetoclax + azacitidine BI907828 + venetoclax + decitabine

The above list merely exemplifies the combinations of the invention and should not be considered as limiting the scope of the invention. The present invention includes additional combinations not exemplified above.

Additional embodiments of the invention include:

Embodiment A. A method of treating TP53 wild-type incompatible AML in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of HDM201 or a pharmaceutically acceptable salt thereof and a therapeutically effective amount A combination of venetoclax or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of azacitidine or a pharmaceutically acceptable salt thereof.

Embodiment B. The method as described in embodiment A, wherein the subject is: i) aged 75 years or over, or ii) Aged 18 to 74 years with at least one of the following comorbidities: a) ECOG performance status 2 or 3; b) cardiac history of congestive heart failure requiring treatment, or ejection fraction ≤ 50%, or Chronic stable angina; and c) DLCO ≤ 65% or FEV1% ≤ 65%.

Embodiment C. The method as described in embodiment A or embodiment B, wherein the treatment is administered with a combination of a BCL2 inhibitor such as venetoclax and a hypomethylating agent such as azacitidine or Citabine, such as azacitidine), without further combination therapy with an MDM2 inhibitor, where the patient fails to achieve any of the following: a) complete remission (CR); b) Complete remission (CRi) with incomplete hematological response; c) CR with partial recovery of peripheral blood counts (CRh); and d) Morphological leukemia-free status (MLFS).

Embodiment C1: The method of embodiment C, wherein the combination therapy with the BCL2 inhibitor and hypomethylating agent comprises two to four complete treatment cycles (e.g., 28 days) of the BCL2 inhibitor and hypomethylating agent treatment cycle).

Embodiment C2: The method of Embodiment C or Embodiment C1, wherein treatment with an MDM2 inhibitor, a BCL2 inhibitor, and a hypomethylating agent is followed by therapy with a combination of a BCL2 inhibitor and a hypomethylating agent (i.e. where day 1 of the first cycle of treatment with an MDM2 inhibitor, a BCL2 inhibitor, and a hypomethylating agent is the last day of the last cycle of therapy with a BCL2 inhibitor and a hypomethylating agent (e.g., day 28 days) after the first day).

Embodiment D. The method of embodiment A or embodiment B, wherein the combination of HDM201, venetoclax, and azacitidine is first-line (1L) therapy (including both primary and secondary AML) .

Embodiment E. The method of embodiment D, wherein the subject has poor genetic risk stratification according to ELN 2017.

Embodiment F. The method of embodiment E, wherein the AML has the genetic abnormality t(6;9)(p23;q34.1); DEK-NUP214.

Embodiment G. The method of embodiment E, wherein the AML has the genetic abnormality t(v;11q23.3); KMT2A rearrangement.

Embodiment H. The method of embodiment E, wherein the AML has the genetic abnormality t(9;22)(q34.1;q11.2); BCR-ABL1.

Embodiment I. The method of embodiment E, wherein the AML has the genetic abnormality inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM (EVI1).

Embodiment J. The method of embodiment E, wherein the AML has the genetic abnormality −5 or del(5q); −7; −17/abn(17p).

Embodiment K. The method of embodiment E, wherein the AML has a genetically abnormal complex karyotype or a monosomal karyotype.

Embodiment L. The method of embodiment E, wherein the AML is genetically abnormal wild-type NPM1 and FLT3-ITD high.

Embodiment M. The method of embodiment E, wherein the AML has a genetically abnormal mutation of RUNX1.

Embodiment N. The method of embodiment E, wherein the AML has a genetically abnormal mutation of ASXL1.

Embodiment O. The method of any one of embodiments A to N, wherein the subject is 75 years of age or older.

Embodiment P. The method of embodiment O, wherein the subject has an ECOG performance status of 0 to 2.

Embodiment Q. The method of any one of Embodiments A to N, wherein the subject is 18 to 74 years old.

Embodiment R. The method of embodiment Q, wherein the subject has an ECOG performance status of 0 to 3.

Embodiment S. The method of Embodiment Q or Embodiment R, wherein the subject has chronic stable angina.

Embodiment T. The method of Embodiment Q or Embodiment R, wherein the subject has a cardiac history of congestive heart failure in need of treatment.

Embodiment U. The method of Embodiment Q or Embodiment R, wherein the subject has a left ventricular ejection fraction of less than or equal to 50%.

Embodiment V. The method of Embodiment Q or Embodiment R, wherein the subject has a DLCO of less than or equal to 65%.

Embodiment W. The method of Embodiment Q or Embodiment R, wherein the subject has an FEV1% of less than or equal to 65%.

It is believed that the combinations of the invention are useful in the effective treatment of hematological malignancies, such as MDS or AML, eg due to a synergistic effect in inhibiting cell proliferation and/or inducing apoptosis.

The MDM2 inhibitor is preferably administered on each of the first 5 days of a 28-day treatment cycle, wherein the treatment includes at least two treatment cycles.

In an embodiment, the treatment cycles are consecutive, ie directly following each other, with no gaps. With only two treatment cycles, this corresponds to: Day 1-5: Administration of MDM2 inhibitor (administration day) Days 6-28: No MDM2 inhibitor administration Day 29-33: Administration of MDM2 inhibitor (administration day) Days 34-56: No MDM2 inhibitor administered.

In alternative embodiments, there is an optional interval of up to 28 days between treatment cycles (MDM2i and/or BCL2i and/or hypomethylating agents). Interval may be recovery from toxicity. Ideally, however, the treatment cycles (preferably for all MDM2i, BCL2i and hypomethylating agents) are consecutive, ie directly following each other with no gaps.

Preferably, the MDM2 inhibitor is HDM201.

Preferably, the daily dose of HDM201 on each administration day is 10 to 50 mg, such as 10 mg to 40 mg (expressed as HDM201 free base). Most preferably, the daily dose of HDM201 is 20, 30 or 40 mg (expressed as HDM201 free base) on each day of administration. Preferably, HDM201 is administered orally. Preferably, HDM201 is HDM201 succinic acid eutectic.

The BCL2 inhibitor is preferably administered orally.

Preferably, the BCL2 inhibitor is venetoclax.

In an embodiment, the BCL2 inhibitor is venetoclax, and venetoclax is administered at 100 mg on the first day of the first 28-day treatment cycle and at 200 mg on the second day of the first 28-day treatment cycle. , and administered at 400 mg each of days three to twenty-eight of the first 28-day treatment cycle. In an embodiment, venetoclax is administered at 400 mg per day in each subsequent 28-day treatment cycle, where there is at least one subsequent 28-day treatment cycle (ie, a total of at least two 28-day treatment cycles).

In an alternative embodiment, for example, wherein the treatment is directed towards dual combination therapy (eg, two to four 28-day dual combinations) with the BCL2 inhibitor venetoclax and a hypomethylating agent (eg, azacitidine) treatment cycle), the daily dose of venetoclax on all administration days is 400 mg, starting from the first treatment cycle, a total of at least two 28-day treatment cycles (MDM2 inhibitors, vitamin netoclax and hypomethylating agents). In an embodiment, the MDM2 inhibitor, the BCL2 inhibitor venetoclax is on Day 1 of the first 28-day treatment cycle (e.g., wherein there are at least two treatment cycles), and the hypomethylating agent is a BCL2 inhibitor The day after day 28 of the last 28-day dual treatment cycle of treatment with a hypomethylating agent (preferably a total of two to four 28-day dual treatment cycles, more preferably a total of two or three a 28-day dual treatment cycle). In an embodiment, after the last 28-day dual treatment cycle of treatment with a BCL2 inhibitor and a hypomethylating agent, the patient fails to achieve any of the following: a) complete remission (CR); b) Complete remission (CRi) with incomplete hematological response; c) CR with partial recovery of peripheral blood counts (CRh); and d) Morphological leukemia-free status (MLFS).

Preferably, the hypomethylating agent is azacitidine or decitabine, most preferably azacitidine.

The hypomethylating agent is preferably administered subcutaneously or intravenously, eg subcutaneously.

Preferably, the hypomethylating agent is azacitidine and azacitidine is administered each day for the first 7 days of a 28-day treatment cycle, and wherein the treatment comprises at least two treatment cycles, or wherein azacitidine Cytidine is administered on each of the first 5 days and on days 8 and 9 of a 28-day treatment cycle, and wherein the treatment comprises at least two treatment cycles. Preferably, azacitidine is administered at 20-200 mg/m ² on the day of administration. More preferably, azacitidine is administered at 50-100 mg/ ^m2 on the day of administration, most preferably about 75 mg/ ^m2 on the day of administration.

Where the hypomethylating agent is decitabine, preferably decitabine 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. When the hypomethylating agent is decitabine, it is preferable to administer decitabine at 20 mg/m ² on the administration day.

Preferably, the 28-day treatment cycles of MDM2i (such as HDM201), BCL2i (such as venetoclax) and hypomethylating agents (such as azacitidine) are all aligned. That is to say, the first day of the MDM2i treatment cycle is the first day of the BCL2i treatment cycle and the first day of the hypomethylating agent treatment cycle.

MDM2i, BCL2i and hypomethylating agent are preferably in a non-fixed combination. However, in another (less preferred) aspect of the invention, MDM2i, BCL2i and hypomethylating agent are provided in a fixed combination.

MDM2i, BCL2i and hypomethylating agents can be used simultaneously or sequentially.

As used herein, the term "hypomethylating agent" refers to a drug that inhibits DNA methylation, and includes azacitidine, decitabine, and guadectabine. Preferably, the "hypomethylating agent" of the present invention is azacitidine or decitabine, most preferably azacitidine.

As used herein, the term "MDM2i" or "MDM2 inhibitor" refers herein to an MDM2i inhibitor at a concentration of less than 10 μM, preferably less than 1 μM, preferably at nM (e.g. less than 500 nM, e.g. less than 250 nM, e.g. less than Any compound that inhibits the HDM-2/p53 or HDM-4/p53 interaction (preferably the HDM-2/p53 interaction) with an IC ₅₀ in the range of 100 nM), the inhibition of which is determined by time-resolved Measured by fluorescence energy transfer (TR-FRET) assay. Inhibition of p53-Hdm2 and p53-Hdm4 interactions was measured by time-resolved fluorescence energy transfer (TR-FRET). Fluorescence energy transfer (or fluorescence resonance energy transfer) describes the energy transfer between donor and acceptor fluorescent molecules. For this assay, MDM2 protein (amino acids 2-188) and MDM4 protein (amino acids 2-185) labeled with a C-terminal biotin moiety were combined with europium-labeled streptavidin as a donor fluorophore. Avidin (Perkin Elmer, Inc., Waltham, MA, USA) was used in combination. The p53-derived Cy5-labeled peptide Cy5-TFSDLWKLL (p53 aa18-26) is an energy acceptor. After excitation of the donor molecule at 340 nm, the binding interaction between MDM2 or MDM4 and the p53 peptide induces energy transfer and an enhanced response at the acceptor emission wavelength at 665 nm. Disruption of p53-MDM2 or p53-MDM4 complex formation due to binding of the inhibitor molecule to the p53-binding site of MDM2 or MDM4 results in increased donor emission at 615 nm. Ratiometric FRET assay readouts (count rate 665 nm/count rate 615 nm x 1000) were calculated from the raw data of two different fluorescent signals measured in time-resolved mode. The assay can be carried out according to the following procedure: The test is carried out in the following manner: in a white 1536w microtiter plate (Greiner Bio-One Company (Greiner Bio-One GmbH), Frickenhausen (Frickenhausen, Germany) with 3.1 μL The total volume of , by adding in reaction buffer (PBS, 125 mM NaCl, 0.001% Novexin (composed of carbohydrate polymers (Novexin polymers) designed to increase protein solubility and stability; Novexin Ltd. (Novexin Ltd., Cambridgeshire, UK), 0.01% gelatin, 0.2% Pluronic (from a block copolymer of ethylene oxide and propylene oxide, BASF, Ludwigshafen, Germany) , 1 mM OTT), combine 100 nl of compound diluted in 90% DMSO/10% HO (3.2% final DMSO concentration) with 2 μL of europium-labeled streptavidin (final concentration 2.5 nM) , after which 0. μL of MDM2-Bio or MDM4-Bio diluted in assay buffer (final concentration 10 nM) was added. The solution was pre-incubated for 15 min at room temperature before adding 0.5 μL of Cy5-p53 peptide in assay buffer (final concentration 20 nM). Incubate for 10 min at room temperature before reading the plate. To measure samples, an Analyst GT Multimode Microplate Reader (Molecular Devices) was used with the following settings: dichroic mirror 380 nm, excitation 330 nm, emission donor 615 nm and emission acceptor 665 nm . IC50 values were calculated by curve fitting using XLfit. If not specified, reagents were purchased from Sigma Chemical Co, St. Louis, MO, USA.

The terms "Bcl2 inhibitor" or "BCL2i" or "BCL2 inhibitor" or "BCL-2 inhibitor" or "Bcl-2 inhibitor" etc. are defined herein to mean a compound which targets, reduces or Inhibits anti-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1 and/or Bcl-B).

The term "hematologic malignancies" is used synonymously with "blood neoplasms" and refers herein to cancers that start in blood-forming tissues (such as bone marrow) or cells of the immune system. Examples of hematological tumors are leukemia, lymphoma, and multiple myeloma. They are also commonly called blood cancers.

A preferred hematological tumor of the present invention is leukemia. More preferably, the hematological tumor is selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL). Even more preferably, the hematological tumor is AML and/or MDS. A particularly preferred hematological tumor of the present invention is a TP53 wild-type hematological tumor. More preferably, the TP53 wild-type blood tumor of the present invention is TP53 wild-type leukemia. Even more preferably, the TP53 wild type hematologic tumor is selected from TP53 wild type acute myeloid leukemia (AML), TP53 wild type myelometaplastic syndrome (MDS), and TP53 wild type acute lymphoblastic leukemia (ALL). Even more preferably, the TP53 wild type hematological tumor is TP53 wild type AML and/or MDS. Most preferably, the TP53 wild-type blood tumor is TP53 wild-type AML.

Preferably, the AML (eg TP53 wild-type AML) is unsuitable (for standard induction chemotherapy) AML, eg as determined by a physician.

As used herein, AML refers to AML based on the WHO 2016 classification.

As used herein, ineligible AML refers to AML ineligible for (standard induction) chemotherapy based on the WHO 2016 classification.

As used herein, de novo AML refers to AML in a patient with no previous clinical history of a myeloid malignancy such as MDS or myeloproliferative disorder.

As used herein, secondary AML refers to AML in a patient with a prior clinical history of myeloid malignancy (eg, MDS or myeloproliferative disorder) that transforms into AML.

Preferably, treatment is administered to subjects who are 18 years of age or older.

In an embodiment, treatment is administered to subjects who are or have been determined to be unsuitable (i.e. not eligible for standard induction chemotherapy) because they: i) aged 75 years or over, or ii) Aged from 18 to 74 years old, with at least one of the following comorbidities: a) ECOG performance status of 2 (ambulatory and capable of all self-care, but unable to perform any work activities; up and about for more than 50% of waking hours) or 3 (only limited self-care; restricted for more than 50% of waking hours on a bed or chair); b) Cardiac history of congestive heart failure requiring treatment, or (ventricular (eg, left ventricular) ejection fraction) ≤ 50%, or chronic stable angina; c) Pulmonary comorbidities (eg DLCO ≤ 65% or FEV1% ≤ 65%); and d) Any other comorbidities incompatible with standard induction chemotherapy according to the physician's assessment.

In the case of the hematologic malignancy to be treated is MDS, according to the International Prognostic Grading System for MDS (IWG-PM), it is preferred that the MDS be moderate risk, high risk or very high risk, more preferably high risk or Very high risk.

The (left) ventricular ejection fraction is the total amount of blood pumped by the (left) ventricle per heartbeat. A range of 55%-70% is normal. A reading below 50% indicates that the heart's pumping capacity is below normal. The ejection fraction can be measured using an echocardiogram, a magnetic resonance imaging (MRI) scan of the heart, or a nuclear medicine scan of the heart (nuclear stress test).

DLCO refers to the ability of the lungs to diffuse carbon monoxide, also known as carbon monoxide transfer factor (TLCO), a lung function test that measures the ability of the lungs to transfer inhaled air to red blood cells in the pulmonary capillaries. DLCO criteria can be found in: Am Rev Respir Dis. [American Review of Respiratory Diseases] 1987; 136(5):1299., Eur Respir J. [European Respiratory Journal] 2005; 26(4):720, and Eur Respir J. [European Respiratory Journal] 2017;49(1) Epub 3 Jan 2017.

FEV1% (also known as the FEV1/FVC ratio, also known as the Tiffeneau-Pinelli index) refers to the percentage of a subject's vital capacity (the maximum volume of air that a person can expel from the lungs after a maximal inhalation) that they are able to The first second of gas is released. FEV1% is used to assess obstructive and restrictive lung diseases such as COPD. The normal FEV1% value is c. 70%-80%. Less than 65% indicates decreased lung function. The Tiffeneau-Pinelli index can be routinely calculated using a spirometer.

In an embodiment, the treatment is administered to a subject who is 75 years of age or older and has an ECOG performance status of 0 to 2, or a subject who is 18 to 74 years of age and has an ECOG performance status of 0 to 3.

In an embodiment, treatment is administered to a subject who is 75 years of age or older, or 18 to 74 years of age and has at least one of the following comorbidities: a) ECOG performance status is 2 or 3; b) Cardiac history of congestive heart failure requiring treatment, or (ventricular, e.g. left ventricular) ejection fraction) ≤ 50%, or chronic stable angina; and c) Pulmonary comorbidities, such as DLCO ≤ 65% or FEV1% ≤ 65%.

As used herein, ECOG performance status refers to the following:

In an embodiment, treatment is administered to a subject aged 18 to 74 years with a cardiac history of congestive heart failure requiring treatment.

In an embodiment, treatment is administered to subjects aged 18 to 74 years with a left ventricular ejection fraction ≤ 50%.

In an embodiment, treatment is administered to a subject aged 18 to 74 years with chronic stable angina.

In an embodiment, treatment is administered to a subject who is 18 to 74 years old and has a DLCO≦65%.

In an embodiment, the treatment is administered to a subject aged 18 to 74 years with FEV1% ≤ 65%.

In an embodiment, the treatment is administered to a subject with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN).

In an embodiment, treatment is administered to a subject with total bilirubin < 1.5 x ULN. In an alternative embodiment, the subject has isolated Jabel syndrome, and the subject has < 3.0 x ULN.

In an embodiment, the treatment is administered to a subject with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 ^m2 based on the Modification of Diet in Renal Disease (MDRD) formula.

In an embodiment, the treatment is administered to a subject with <25 x 10 ⁹ /L white blood cells (WBC).

In an embodiment, treatment is administered to a subject without del17p.

In an embodiment, the AML is not AML-M3/APL/acute promyeloid leukemia with PM-RARA (promyelocytic leukemia/retinoic acid receptor alpha/PML-RARA t(15;17)(q22;q12 )).

In an embodiment, the AML is not AML secondary to Down syndrome.

In an embodiment, treatment is administered to a subject who has not (concurrently) been treated with a FLT3 inhibitor.

In an embodiment, the treatment is administered to a subject who does not have active CNS leukemia.

In an embodiment, treatment is administered to subjects without neurologic symptoms suspicious of CNS leukemia, unless CNS leukemia has been ruled out by at least one negative lumbar puncture.

Preferably, after 2 to 6 complete (28 days) treatment cycles with a combination of MDM2i (eg HDM201), BCL2i (eg venetoclax) and a hypomethylating agent (eg azacitidine), Complete remission (CR) rate ≥ 30%.

In an embodiment, the treatment is administered to a subject with no additional concurrent or prior malignancies other than prior MDS, myelofibrosis, essential thrombocythemia, polycythemia vera, aplastic anemia or other previous blood disorders.

In an alternative embodiment, treatment is administered to a subject with a history of additional malignancy, who has been disease-free (no residual disease) for at least 1 year, and in whom there is no ongoing chemotherapy, radiotherapy or surgery.

In an embodiment, the subject with a history of additional malignancy is from a subject who has been free of the disease (no residual disease) for at least 1 year and in which no ongoing chemotherapy, radiotherapy or surgery is receiving adjuvant therapy. In an embodiment, the adjuvant therapy is hormone therapy or long-term maintenance therapy.

In an embodiment, treatment is administered to subjects who have not received hematopoietic stem cell transplantation (HSCT) or intensive chemotherapy during any 28-day treatment cycle (combination MDM2i, BCL2i, and hypomethylating agent therapy).

In an embodiment, for example, a CR rate ≥ A posterior probability of 15% is at least 90%, such as at least 92.5%, such as at least 95%, such as at least 97.5%. In an embodiment, the CR rate after 2 to 6 complete 28-day treatment cycles with a combination of MDM2i (eg, HDM201), BCL2i (eg, venetoclax), and a hypomethylating agent (eg, azacitidine) The posterior probability of ≥ 15% is at least 97.5%.

In an embodiment, CR following 2 to 6 complete 28-day treatment cycles with a combination of MDM2i (eg, HDM201), BCL2i (eg, venetoclax), and a hypomethylating agent (eg, azacitidine) rate ≥ 30%, and the posterior probability of CR rate ≥ 15% is at least 97.5%. In an embodiment, after 2 to 6 complete 28-day treatment cycles with a combination of MDM2i (eg, HDM201), BCL2i (eg, venetoclax), and a hypomethylating agent (eg, azacitidine), after The posterior probability of a median CR rate ≥ 30% and a CR rate ≥ 15% is at least 97.5%.

As used herein, posterior probability refers to Bayesian posterior probability. In Bayesian posterior probability, hypothesis B occurs , the posterior probability of A occurring can be expressed as: , where P ( A ) is the probability of A occurring, P ( B ) is the probability of B occurring, and P ( B l A ) is the probability of B occurring assuming A is true.

As used herein, the term "standard induction chemotherapy" is a term of the art and refers to high-dose chemotherapy typically used in the initial treatment of "suitable" AML. Standard induction chemotherapy in AML is usually a combination of cytarabine and an anthracycline such as daunomycin or idarubicin. Inductions tend to be short (usually around a week) but intense and can cause serious side effects, so they are not recommended in "unsuitable" AML patients who may not be able to cope with the resulting toxicity. Even in "suitable" AML patients, standard induction chemotherapy is usually given in the hospital so that patients can be monitored for serious side effects.

In an embodiment, the treatment is administered with a combination of a BCL2 inhibitor such as venetoclax and a hypomethylating agent such as azacitidine or decitabine such as azacitidine, Subjects without further combination therapy with an MDM2 inhibitor (referred to herein as dual therapy, dual combination, etc.). In an embodiment, following dual combination therapy with a BCL2 inhibitor and a hypomethylating agent, the patient fails to achieve any of the following: a) complete remission (CR); b) Complete remission (CRi) with incomplete hematological response; c) CR with partial recovery of peripheral blood counts (CRh); and d) Morphological leukemia-free status (MLFS).

In an embodiment, therapy with a dual combination of a BCL2 inhibitor and a hypomethylating agent comprises two to four complete treatment cycles (e.g., 28-day treatment cycles) of a BCL2 inhibitor and a hypomethylating agent, preferably Two or three full 28-day treatment cycles. In this embodiment, it is preferred that the 28-day treatment cycle of the BCL2 inhibitor and the hypomethylating agent in the dual combination is consistent, that is, the first day of the BCL2 inhibitor treatment cycle is the hypomethylating agent treatment cycle Day 1 of .

In an embodiment, the treatment is administered to those who have previously received a dual combination therapy with a BCL2 inhibitor and a hypomethylating agent, and wherein treatment with an MDM2 inhibitor, a BCL2 inhibitor and a hypomethylating agent is followed by treatment with a BCL2 Dual combination therapy of an inhibitor and a hypomethylating agent (i.e., where Day 1 of the first treatment cycle of each of the MDM2 inhibitor, BCL2 inhibitor, and hypomethylating agent is a dual combination (i.e., BCL2 inhibitor and hypomethylating agents) on the first day after the last day of the last cycle of therapy (e.g. day 28). In an embodiment, preferably two to four double treatment cycles, most preferably a total of two or three double treatment cycles. Preferably, each double treatment cycle is 28 days.

That is, Day X - the last (preferably second, third or fourth, more preferably second or third) cycle of therapy with a dual combination of a BCL2 inhibitor and a hypomethylating agent The last day of the (eg day 28).

Day X+1 - Day 1 of treatment with MDM2 inhibitor, BCL2i inhibitor, and hypomethylating agent (eg, 28-day treatment cycle).

In an embodiment, treatment is administered to a subject previously treated with a combination of MDM2i (e.g. HDM201), BCL2i (e.g. venetoclax) and a hypomethylating agent (e.g. azacitidine), Two to four (preferably is two or three) 28-day dual treatment cycles, but fails to achieve the following (based on IWG; ELN 2017): a) complete remission (CR); b) Complete remission (CRi) with incomplete hematological response; c) CR with partial recovery of peripheral blood counts (CRh); or d) Morphological leukemia-free status (MLFS).

In an embodiment, prior to treatment with the combination of the invention, treatment is administered to a patient previously treated with BCL2i (eg, venetoclax) and hypomethylating agent therapy (eg, azacitidine or decitabine, compared to Subjects with two 28-day dual therapy cycles of combination therapy preferably azacitidine) and with stable disease, PD or relapsed from CR or CRi. In an alternative embodiment, treatment is administered with a combination of BCL2i (e.g. venetoclax) and hypomethylating agent therapy (e.g. azacitidine or decitabine, preferably azacitidine). Zacitidine) in three 28-day dual treatment cycles and achieved a partial response (PR).

As used herein, a response class in AML can be defined as follows:

In addition, complete remission (CRh) with partial hematologic recovery can be assessed according to the following criteria: • bone marrow: less than 5% blasts and no blasts containing Auer bodies; and • peripheral blood: neutrophils greater than 0.5 x 10 ⁹ /L and/or platelets >50 x 10 ⁹ /L; and • No evidence of extramedullary disease (eg, CNS or soft tissue involvement)

Of note, subjects assessed as CRh will also meet the criteria for CRi. However, not all subjects assessed as CRi will automatically meet the criteria for CRh.

In an embodiment, in each of two to four 28-day dual treatment cycles of combined BCL2i (e.g., venetoclax) and hypomethylating agent therapy (without further combination with MDM2i), used in the dual treatment cycles The hypomethylating agent is azacitidine or decitabine, for example where: i) azacitidine administered (e.g., subcutaneously or intravenously) on each of the first 7 days of a 28-day dual treatment cycle; or ii) Decitabine is administered (eg, subcutaneously or intravenously) on each of the first 5 days of the 28-day dual treatment cycle.

In an embodiment, in a 28-day dual treatment cycle of combined BCL2i and hypomethylating agent therapy (without further combination with MDM2i), the BCL2i in the dual is venetoclax, and venetoclax is given in the 28-day dual Administered (eg, orally) each day of the 28-day treatment cycle. In an embodiment, venetoclax is administered as 100 mg on the first day of the first 28-day dual treatment cycle, 200 mg on the second day of the first 28-day dual treatment cycle, 300 mg on day three of the treatment cycle, and 400 mg each day on day four and twenty-eight of the first 28-day dual treatment cycle. In an embodiment, venetoclax is administered at 400 mg per day for the second and any subsequent dual treatment cycle.

In an alternative embodiment, the treatment is first-line (1L) treatment (eg, newly diagnosed AML) (wherein AML includes both primary and secondary AML).

In an embodiment, the AML is TP53 wild-type AML and has unfavorable genetic risk stratification according to ELN (European LeukemiaNet) 2017.

In an embodiment, AML has one or more of the following genetic abnormalities: i) t(6;9)(p23;q34.1); DEK-NUP214; ii) t(v;11q23.3); KMT2A rearrangement ; 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, § monomeric karyotype||; vii) wild-type NPM1 and FLT3-ITD high ^† ; viii) mutated RUNX1¶; and ix) mutated ASXL1¶

^§ Three or more unrelated chromosomal abnormalities in the absence of 1 of the WHO-specified repeat translocations or inversions, ie 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 as the presence of 1 single monosomy (excluding deletions of X or Y) associated with at least 1 additional monosomy or structural chromosomal abnormality (excluding core binding factor AML).

^† Low, low allele ratio (<0.5); high, high allele ratio (≥0.5); semi-quantitative assessment of FLT3 -ITD allele ratio (using DNA fragment analysis) determined as under the curve " FLT3 -ITD" The ratio of the area divided by the area under the curve " FLT3 -wild type";

^¶Such markers should not be used as poor prognostic markers if they occur with favorable risk AML subtypes.

Favorable 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 allele ratio (<0.5); high, high allele ratio (≥0.5); semi-quantitative assessment of FLT3 -ITD allele ratio (using DNA fragment analysis) determined as under the curve " FLT3 -ITD" The ratio of the area divided by the area under the curve " FLT3 -wild type";

As used herein, the term "first-line therapy" simply means the first therapy that treats the disease temporally.

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 rearrangement. 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 a genetically abnormal complex karyotype, §monosomal karyotype||. In an embodiment, the AML has genetic abnormalities wild type NPM1 and FLT3-ITD high ^† . In an embodiment, the AML has a genetically abnormal mutation of RUNX1¶. In an embodiment, the AML has a genetically abnormally mutated ASXL1¶.

Unless otherwise indicated herein or clearly contradicted by context, the terms "a/an" and "the ” and similar designations shall be construed to include both the singular and the plural. When the plural is used for compound, patient, cancer, etc., this also means the singular compound, patient, etc.

References to "the present invention" in this specification are intended to reflect implementations of the several inventions disclosed in this specification and should not be viewed as unnecessarily limiting of the claimed subject matter.

As used herein, the term "synergy" refers to the action of two or three therapeutic agents that produce an effect, such as slowing the progression of a proliferative disease, particularly cancer or a symptom thereof, that is more effective than each of the therapeutic agents administered on its own. The simple sum of the drug's effects is greater. Synergistic effects can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. [Clinical Pharmacokinet.] 6: 429-453 (1981)), Loewe The additivity equation (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. [Archives of Experimental Pathology and Pharmacology] 114: 313-326 (1926)) and the intermediate effect equation (Chou, T. C. and Talalay , P., Adv. Enzyme Regul. [Progress in Enzyme Regulation Research] 22: 27-55 (1984)). Each of the equations mentioned above can be applied to experimental data to generate corresponding plots to illustrate the effects of evaluating drug combinations. The corresponding graphs associated with the above mentioned equations are concentration-effect curves, isobologram curves and combination index curves, respectively.

The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compound and is typically not biologically or otherwise undesirable. Due to the presence of the amine group, the compounds may be capable of forming acid addition salts.

References to therapeutic agents useful in the pharmaceutical combinations of the present invention include the free bases of the compounds and all pharmaceutically acceptable salts of the compounds unless otherwise stated or expressly indicated by the context.

The term "combination" or "pharmaceutical combination" is defined herein to mean a fixed combination in the form of a dosage unit, a non-fixed combination for combined administration, or a kit, wherein the therapeutic agents are simultaneously independently or Administered together separately over time intervals, this preferably allows the combination partners to exhibit synergy, eg a synergistic effect. Thus, the individual compounds of the pharmaceutical combination of the present invention may be administered simultaneously or sequentially.

In addition, 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 (eg, individual compounds in combination) are presented as a single entity or dosage form.

The term "non-fixed combination" means that the therapeutic agents (e.g., individual compounds in a combination) are administered to a patient simultaneously or sequentially as separate entities or dosage forms, with no specific time limit, where preferably such administration is A subject, such as a mammal or human in need thereof, is provided with therapeutically effective levels of both therapeutic agents.

The pharmaceutical combination may further comprise at least one pharmaceutically acceptable carrier. Therefore, 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, antifungal), etc. Osmotic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrating agents, lubricants, sweeteners, flavoring agents, dyes, etc. and combinations thereof, as those familiar with the art can understand (See eg, Remington's Pharmaceutical Sciences [Remington's Pharmaceutical Sciences], 18th ed., Mack Printing Company, 1990, pp. 1289-1329). Except where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

As used herein, the phrase "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, or other problems or complications. , those compounds, materials, compositions and/or dosage forms commensurate with a reasonable benefit/risk ratio.

In general, the term "pharmaceutical composition" is defined herein to mean a mixture or solution containing at least one therapeutic agent to be administered to a subject (eg, mammal or human). The pharmaceutical combinations of the invention may be formulated as pharmaceutical compositions suitable for enteral or parenteral administration, for example those in unit dosage form, such as sugar-coated tablets, tablets, capsules or suppositories or ampoules. If not otherwise stated, the preparations are carried out in a manner known per se, for example by means of various conventional methods of mixing, pulverizing, direct compression, granulating, sugar-coating, dissolving, lyophilization or by means of the methods known to those skilled in the art. Obvious manufacturing techniques. It should be understood that the unit content of the combination partner contained in the individual doses of each dosage form need not in itself constitute an effective amount, since the necessary effective amount can be achieved by administering multiple dosage units. Pharmaceutical compositions may contain from about 0.1% to about 99.9%, preferably from about 1% to about 60%, of one or more therapeutic agents. One or more of the aforementioned carriers can be selected by one skilled in the art by routine experimentation without any undue burden as to the particular desired properties of the dosage form. The amount of each carrier used may vary within the range conventional in the art. The following references disclose techniques and excipients for formulating oral dosage forms. See The Handbook of Pharmaceutical Excipients, 4th ed., edited by Rowe et al., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy. and Practice], 20th ed., edited by Gennaro, Lippincott Williams & Wilkins [Wilkins] (2003). It can be prepared by incorporating one or more conventional carriers into the initial mixture before or during granulation, or by combining one or more conventional carriers with granules comprising the combination of agents or the individual agents of the combination of agents in an oral dosage form. Such optional additional conventional carriers are incorporated into oral dosage forms. In the latter embodiment, the combined mixture can be further blended, eg, by a V-blender, and then compressed or molded into tablets (eg, monolithic tablets), encapsulated, or filled into sachets. Obviously, the pharmaceutical combination of the present invention can be used in the manufacture of medicaments.

The present invention relates to such pharmaceutical combinations or pharmaceutical compositions, in particular for use as medicaments.

In particular, the combinations or compositions of the invention are useful in the treatment of hematological malignancies, such as AML or MDS, such as AML, such as unsuitable AML.

The present invention also relates to the use of the pharmaceutical combination or pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of hematological malignancies (such as AML or MDS, such as AML, such as unsuitable AML), and for the treatment of hematological malignancies (such as A method for AML or MDS, eg AML, eg unsuitable AML), comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination according to the invention or a pharmaceutical composition according to the invention in a subject in need thereof.

As used herein, the term "treatment" includes treatment that relieves, alleviates or alleviates at least one symptom, increases progression-free survival, overall survival, prolongs the duration of response, or delays disease progression in a subject. For example, treatment can reduce one or several symptoms of a disorder or completely eradicate a disorder (eg, cancer). Within the meaning of the present invention, the term "treatment" also means arresting, delaying the onset of a disease (i.e. the time period preceding the clinical manifestation of the disease) and/or reducing Risk of disease development or worsening. As used herein, the term "treatment" includes inhibition of tumor growth, including direct inhibition of primary tumor growth and/or systemic inhibition of metastatic cancer cells.

"Subject", "individual" or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, mice, apes, humans, farm animals, sport animals, and pets.

The term "therapeutically effective amount" of a compound of the invention (eg, chemical entity or biological agent) means that the compound of the invention will cause a biological or medical response (eg, reduction or inhibition of enzyme or protein activity) in a subject, or Amount to improve symptoms, alleviate symptoms, slow down or delay disease progression, or prevent disease, etc. In one embodiment, the therapeutically effective amount in vivo may range between about 0.1-500 mg/kg, or between about 1-100 mg/kg, depending on the route of administration.

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 reduction in the baseline activity of a biological activity or process.

The optimal dosage of each combination partner for the treatment of cancer can be determined empirically for each individual using known methods and will depend on a variety of factors including, but not limited to: the extent of the disease; the age of the individual , weight, general health, sex, and diet; time and route of administration; and other medications the individual is taking. Optimum dosages can be determined using routine testing and procedures well known in the art. The amount of each combination partner that can be combined with a carrier material to produce a single dosage form will vary depending upon the individual being treated and the particular mode of administration. In some embodiments, unit dosage forms containing combinations of agents as described herein will contain amounts of each agent in the combination that are typically administered when the agents are administered alone.

The frequency of dosage will vary depending on the compound employed and the particular condition to be treated or prevented. In general, it is preferred to use the smallest dose sufficient to provide effective therapy. Treatment effectiveness in patients can generally be monitored using assays appropriate to the condition being treated or prevented and which will be familiar to those skilled in the art. EXAMPLES Example 1 In vivo pharmacology of combination of HDM201 and venetoclax (ABT-199)

In multiple AML patient-derived orthotopic models, HDM201 was shown to enhance the in vivo antitumor activity of the selective Bcl-2 inhibitor venetoclax (also known as ABT-199). In mice with mutant IDH1/FLT3-ITD , HDM201 treatment alone exhibited minimal anticancer activity (92% T/C, p > 0.05). In contrast, HDM201 in combination with venetoclax induced complete tumor regression (-100% Reg), whereas only partial tumor regression was observed with venetoclax alone (-9% to -52% Reg). See Figures 1 and 2.

Consistent with the observations in peripheral blood, depletion of leukemic cells in the spleen was also observed by spleen weight and IHC staining of IDH1 ^R132H positive leukemic cells. HDM201 as a single agent resulted in modest reductions in spleen size and leukemic density. In contrast, HDM201 in combination with venetoclax resulted in almost complete depletion of leukemic cells in the spleen and significantly reduced spleen size (compared to naive animals), whereas venetoclax alone Only a partial reduction in spleen size and leukemic density was seen (see Figure 1).

In another study, HDM201 was tested in combination with venetoclax at three dose levels (5, 10, and 20 mg/kg HDM201). Administration of HDM201 at a 4-fold lower dose (5 mg/kg vs. 20 mg/kg) in the venetoclax combination increased platelet counts to levels comparable to untreated animals while still maintaining a high degree of tumor regression (- 75%Reg) (see Figure 2). These data suggest that the potential overlapping hematological toxicity of the combination can be mitigated by administering lower doses of HDM201 while maintaining antitumor activity. Example 2 CHDM201I12201 clinical research

Rationale and design for the study of HDM201 in combination with venetoclax and azacitidine:

The study will be a Phase Ib/II open-label, dose-confirming, proof-of-concept study of deceremarin (HDM201) in combination with venetoclax plus azacitidine in unfit adult AML participants. The primary objective of this study was to assess whether the combination of deceremarin and venetoclax plus azacitidine could enhance the clinical response in unsuitable AML patients without unacceptable levels of treatment toxicity.

Two subpopulations of adult participants with unsuitable AML will be assessed in separate groups. Group 1: Participants who responded poorly to first-line venetoclax plus azacitidine treatment, and Group 2: newly diagnosed untreated patients with adverse genetic risk stratification according to ELN 2017 (excluding mutant TP53) AML participants.

Study treatment (ceremarin in combination with venetoclax plus azacitidine) will be administered in cycles of a planned duration of 28 days and will continue until the participant experiences 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, the purpose of which is to determine the recommended extended dose (RDE) of desiremarin when administered in combination with venetoclax plus azacitidine.

Part 2 Line Extension to further evaluate the efficacy and safety of deceremarin RDE in combination with venetoclax plus azacitidine.

Study treatment will be administered in cycles of a planned duration of 28 days. Study treatment will be discontinued for any participant who does not achieve at least a partial response (PR) after a maximum of 4 cycles of taking ceremarin in combination with venetoclax plus azacitidine.

In each cycle, desiremarin will be administered orally once daily on Days 1 to 5, and venetoclax will be administered orally once daily at 400 mg starting on Day 1 (only after Cohort 2 is increased , as shown in the table below).

Azacitidine will be administered intravenously or subcutaneously at 75 mg/ ^m2 on Days 1 to 7 or Days 1 to 5, followed by administration on Days 8 and 9 (by the investigator according to local institutional guidelines). practice at its own discretion). In Arm 1, participants will continue to receive their doses of venetoclax and azacitidine, which were assessed as tolerable prior to study enrollment.

For both groups: Seremarin starting dose (dose level 1) was 20 mg QD, deseremarin was 10 mg QD at dose level -1, and 30 and 40 mg QD at dose levels +1 and + 2.

For each dose level, once the required number of evaluable participants has been determined, recruitment will be stopped to allow participants to complete the DLT observation period (1 cycle) and a safety review meeting. Participating investigators and the Novartis Team will make decisions on desiremarin doses guided by a Bayesian logistic regression model (BLRM). For dose levels to be considered for RDE, at least 6 evaluable participants are independently required for each arm. RDE will be determined individually based on data generated in each cohort of at least 9-15 evaluable participants (including safety data from another cohort, if available).

Following confirmation of applicable RDEs for each arm, Novartis will provide notification to the study site that Part 2 (Expansion) is open for recruitment. Recruitment for Part 2 will continue until a total of 25 evaluable participants (including participants in the safety run-in period) have been recruited with RDE in Arm 1. An additional 6 participants (approximately) will be recruited into the cohort 2 extension.

Assignment of participants to treatment groups and dose cohorts will be captured in the Interactive Response Technology (IRT) system and coordinated by Novartis AG.

For participants recruited into Arm 2, hospitalization was required from Cycle 1 Day 1 (C1D1) to Cycle 1 Day 3 (C1D3) (Day 3) to allow for close monitoring of chemical parameters, particularly detection of Tumor Lysis Syndrome ( TLS) and thereafter at the discretion of the investigator.

Participants who cannot tolerate one or both study drugs may continue to receive only one or more tolerated drugs at any time during the study, taking into account the benefit/risk balance of continuing to use one or more drugs at the discretion of the participant .

All participants will also have a 30-day safety follow-up after the last dose of study treatment.

All participants who discontinue study treatment will enter long-term follow-up (for efficacy and/or survival status), as described in the study flow diagram in Figure 3. Research Process

The study pipeline consisted of 3 periods: pre-treatment (screening), treatment and follow-up.

Participants will be assessed during screening and periodically during treatment and follow-up, as shown in the study flow diagram in Figure 4. Fundamental

Siremarin is a novel investigational agent with single-agent activity in AML participants. Studies have shown that it is reasonable to combine desiremarin with other agents, such as selective Bcl-2 inhibitors in AML, to enhance single-agent antileukemic activity.

The planned clinical trial will attempt to expand on these initial efficacy findings by evaluating desiremarin in combination with the Bcl-2 inhibitor venetoclax and the HMA (hypomethylating agent) azacitidine. The combination of venetoclax and azacitidine has demonstrated increased efficacy compared with azacitidine alone in an earlier phase 1b trial and has been fully approved by the FDA for the treatment of ineligible AML. Despite the improved efficacy of the venetoclax/HMA regimen, there remains a significant unmet medical need due to the large number of patients who do not achieve CR (complete remission) and the limited duration of observed CR. It is hypothesized that the addition of HDM201 to the combination of venetoclax and azacitidine could enhance the clinical response in unfit AML patients without unacceptable levels of treatment toxicity.

This is the first trial to evaluate the combination of ceremarin and venetoclax plus azacitidine. The combination of ceremarin and venetoclax is currently being evaluated in a Phase 1b, multi-arm, open-label study [CHDM201H12101C] in adult patients with AML or high-risk MDS.

In this study, the dose and regimen of desiremarin were selected based on the preclinical and clinical safety, efficacy and PK information of currently available single-agent first-in-human clinical trials [CHDM201X2101] and [CHDM201H12101C], while for venetoclax Grams, doses and regimens were selected from available clinical data from the venetoclax trial 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 [Efficacy and biological correlates of responses in a phase II study of venetoclax monotherapy in a patient model of acute myelogenous leukemia]. J Hematl Oncol [Journal of Hematology-Oncology] page 50 , and (ii) DiNardo CD, Jonas BA, Pullarkat V, et al (2020) Azacitidine and venetoclax in Previously Untreated Acute Myeloid Leukemia [Azacitidine and venetoclax in Previously Untreated Acute Myeloid Leukemia]. N Engl J Med [New England Journal of Medicine] pp. 617-29. In the ongoing [CHDM201H12101C] trial, after the first treatment cycle, dose escalation was performed in the desiremarin plus venetoclax arm based on safety data and supportive PK data for participants.

In study [CHDM201H12101C], the PK exposure and parameters of decitex in combination with venetoclax (400 mg QD) at doses of 20 mg and 30 mg on days 1 to 5 of each cycle were compared with historical decitex Marin single agent data [CHDM201X2101] are comparable. research group

The study population will include approximately 55 patients with chemotherapy-ineligible AML who do not respond well to first-line venetoclax plus azacitidine, or who have newly diagnosed untreated AML with high-risk clinical features. Inclusion criteria

1. A signed informed consent form must be obtained before participating in the study

2. Age greater than or equal to 18 years old on the date of signing the Informed Consent Form (ICF)

3. AML participants based on WHO 2016 classification not eligible for chemotherapy and: a. Group 1 (suboptimal responders): have received at least 2 cycles and no more than 4 cycles of first-line venetoclax plus azacitidine treatment, and did not achieve CR, CRi, CRh, or MLFS (based on IWG; ELN 2017). Participants were enrolled into the study after two cycles only if they were not superior to SD at the end of the venetoclax plus azacitidine cycle. Otherwise, participants should be recruited after cycle 3 of venetoclax plus azacitidine. b. Group 2 (Newly diagnosed AML with high-risk clinical features: Newly diagnosed AML with poor genetic risk stratification (according to ELN 2017) (excluding TP53 mutation-positive participants).

4. Participants in both groups must be considered not eligible for standard of care standard of care (intensive) induction chemotherapy. Non-conformance was defined as follows: - Age 75 years or older OR - Age 18 to 74 years with at least one of the following comorbidities: i) Eastern Cooperative Oncology (ECOG) performance status 2 or 3; ii) treatment required Heart disease history of congestive heart failure, 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. Participation in therapy for myelometaplastic syndrome (MDS), myelofibrosis, essential thrombocythemia, polycythemia vera, or related AML if not previously treated, as specified in the exclusion criteria can be included in the study.

6. If the age is greater than or equal to 75 years old, the participant's ECOG physical status must be 0 to 2; or the participant's age is 18 to 74 years old and the status is 0 to 3.

7. AST and ALT ≤ 3 x upper limit of normal (ULN).

8. Total bilirubin ≤ 1.5 x ULN (except in cases of isolated Jabel syndrome, in which case higher total bilirubin is allowed if conjugated bilirubin ≤ 3.0 x ULN) .

9. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m ² (estimated based on the Modification of Diet in Renal Disease (MDRD) formula from a local laboratory).

10. WBC < 25 x 10 ⁹ /L (can be reduced with leukapheresis or hydroxyurea)

11. The participant is able to communicate with the investigator and has the ability to comply with the requirements of the research procedure. Main exclusion criteria:

Participants who met any of the following criteria were not eligible for inclusion in this study.

1. Has been exposed to MDM inhibitor therapy at any time.

2. Participants who were confirmed positive for TP53 mutation by local TP53 test.

3. Participants with del17p.

4. Previous treatment with any of the following approved or investigational antineoplastic agents at any time; checkpoint inhibitors, venetoclax, and hypomethylating agents (HMAs), such as decitabine or aza Cytidine. Prior treatment for AML, MDS, myelofibrosis, essential thrombocytopenia, or polycythemia vera except hydroxyurea, growth factors, ruxolitinib, and supportive care. In Arm 1, pre-treatment with venetoclax and azacitidine was allowed, as defined by the inclusion criteria, provided participants were recruited within 28 days of the last dose of venetoclax and/or azacitidine into research.

5. Participants with AML-M3/APL (acute promyelocytic leukemia) and PM-RARA (promyelocytic leukemia/retinoic acid receptor alpha) or AML secondary to Down 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 ruled out by at least one negative lumbar puncture prior to initiation of protocol therapy).

8. Participants with concomitant or previous malignancies, except - Participants with a history of MDS, myelofibrosis, essential thrombocythemia, polycythemia vera, aplastic anemia, or other prior blood disorders - The participant has a history of adequately treated malignancy, the participant is disease-free (no residual disease) for at least 1 year, and is not undergoing or requiring anti-cancer systemic therapy (i.e., chemotherapy, radiotherapy, or surgery) during the study period. Participants who were receiving adjuvant therapy (such as hormone therapy or long-term maintenance therapy) and had no residual disease for at least 1 year were eligible. duration of treatment

Participants may continue study treatment as planned unless: - They failed to achieve at least PR after taking deceramline in combination with venetoclax plus azacitidine for up to 4 cycles or until: - They experience progressive disease, or relapse from CR or CRi - They experience unacceptable toxicity - Start of treatment cycle delayed by more than 28 days due to toxicity (measured from the scheduled start date of the new cycle (i.e., measured from day 29 of the previous cycle)) - They plan to undergo hematopoietic stem cell transplantation (HSCT) or intensive chemotherapy at any time during the study - They did not abide by the agreement

Participants who cannot tolerate one or both study drugs may continue to receive only one or more tolerated drugs at any time during the study, taking into account the benefit/risk balance of continuing to use one or more drugs at the discretion of the participant .

none

Hereinafter, the present invention is described in detail with reference to the accompanying drawings, in which:

[ Figure 1 ]: Summary of the anti-leukemia effect of HDM201 and venetoclax combination:

HDM201 enhances the antitumor activity of the selective Bcl-2 inhibitor venetoclax in an AML patient-derived orthotopic model. NVP-HDM201 was administered orally at 20 mg/kg once a week three times a week as a single agent or combined with venetoclax (ABT-199) (100 mg/kg once a day for 5 days a week). times) combined oral administration for 14 days. Initial group size: 5 animals.

(A) Mean leukemia burden is represented as CD45+ cells in peripheral blood for each treatment group, plotted against time of the 14-day treatment period.

(B) Spleen weight and IHC staining for leukemia density in the spleen. IHC analysis using anti-human IDH1 mouse monoclonal primary Ab directed against the IDH1R132H mutant protein.

In Figures (A) and (B), the order of lines and points follows the order in the legend (top to bottom, left to right).

[ Figure 2 ]: Dose titration of HDM201 in combination with venetoclax:

Administration of lower doses of HDM201 attenuated the effect of the combination on platelets while still maintaining antitumor activity. NVP-HDM201 was administered orally as a single agent at 5 mg/kg, 10 mg/kg, and 20 mg/kg three times a week on a weekly dosing day or in combination with venetoclax (ABT-199) (100 mg /kg, once a day, 5 times a week) combined oral administration for 3-6 weeks. Initial group size: 4 animals.

(A) Mean leukemia burden is expressed as CD45+ cells in peripheral blood for each treatment group, plotted against time.

(B) Platelet counts in peripheral blood were measured after 3 weeks of treatment and are depicted in panel B.

[ Fig. 3 ]: Study flowchart showing long-term follow-up (efficacy and/or survival status) of all participants who discontinued study treatment in the planned CHDM201I2201 clinical trial.

[ FIG. 4 ]: A study flow diagram showing the evaluation of participants during regular screening during treatment and follow-up in the planned CHDM201I2201 clinical trial.

none

Claims (32)

An MDM2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of hematological malignancies, wherein the treatment further comprises administering a BCL2 inhibitor or a pharmaceutically acceptable salt thereof and a hypomethylating agent or a pharmaceutical acceptable salt. A BCL2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of hematologic malignancies, wherein the treatment further comprises administering an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a hypomethylating agent or a pharmaceutical acceptable salt. A hypomethylating agent or a pharmaceutically acceptable salt thereof for use in the treatment of hematologic malignancies, wherein the treatment further comprises administering an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor or a pharmaceutically acceptable salt thereof acceptable salt. A method of treating a hematological 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 and a therapeutically effective amount of a BCL2 inhibitor or A combination of a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a hypomethylating agent or a pharmaceutically acceptable salt thereof. 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. The MDM2 inhibitor used as described in Claim 1, the BCL2 inhibitor used as described in Claim 2, the hypomethylation agent used as described in Claim 3, the method as described in Claim 4, or the The combination of Item 5, wherein the MDM2 inhibitor is HDM201. The MDM2 inhibitor used as described in Claim 1 or Claim 6, the BCL2 inhibitor used as described in Claim 2 or Claim 6, the hypomethylation agent used as described in 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. The MDM2 inhibitor used as described in claim 7, the BCL2 inhibitor used as described in claim 7, the hypomethylation agent used as described in claim 7, the method as described in claim 7, or the method described in claim 7 The combination according to Item 7, wherein the BCL2 inhibitor is venetoclax. The MDM2 inhibitor used as described in any one of claims 1 and 6 to 8, the BCL2 inhibitor used as described in any one of claims 2 and 6 to 8, any of claims 3 and 6 to 8 A hypomethylating agent for use, or the method of any one of claims 4 and 6 to 8, wherein the MDM2 inhibitor is administered orally. The MDM2 inhibitor used as described in any one of claims 1 and 6 to 9, the BCL2 inhibitor used as described in any one of claims 2 and 6 to 9, any of claims 3 and 6 to 9 A hypomethylating agent for use, or the method of 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. The MDM2 inhibitor used as described in claim 10, the BCL2 inhibitor used as described in claim 10, the hypomethylation agent used as described in claim 10, or the method as described in claim 10, wherein the The daily dose of MDM2 inhibitors ranges from 10 to 50 mg per day for the first 5 days of a 28-day treatment cycle. The MDM2 inhibitor used as described in claim 11, the BCL2 inhibitor used as described in claim 11, the hypomethylation agent used as described in claim 11, or the method as described in claim 11, wherein the The daily dose of the MDM2 inhibitor was 20, 30 or 40 mg for each of the first 5 days of the 28-day treatment cycle. The MDM2 inhibitor used as described in any one of claims 1 and 6 to 12, the BCL2 inhibitor used as described in any one of claims 2 and 6 to 12, any of claims 3 and 6 to 12 One of the hypomethylating agents used, the method as described in any one of claims 4 and 6 to 12, or the combination as described in any one of claims 5 to 7, wherein the low methyl The agent is azacitidine or decitabine. The MDM2 inhibitor used as described in any one of claims 1 and 6 to 13, the BCL2 inhibitor used as described in any one of claims 2 and 6 to 13, any of claims 3 and 6 to 13 A hypomethylating agent for use, or the method of any one of claims 4 and 6 to 13, wherein the hypomethylating agent is administered subcutaneously or intravenously. The MDM2 inhibitor used as described in any one of claims 1 and 6 to 14, the BCL2 inhibitor used as described in any one of claims 2 and 6 to 14, any of claims 3 and 6 to 14 A hypomethylating agent for use, or the method of any one of claims 4 and 6 to 14, wherein the BCL2 inhibitor is administered orally. The MDM2 inhibitor used as described in any one of claims 1 and 6 to 15, the BCL2 inhibitor used as described in any one of claims 2 and 6 to 15, any of claims 3 and 6 to 15 One of the hypomethylating agents used, the method as described in any one of claims 4 and 6 to 15, or the combination as described in any one of claims 5 to 7 and 13, wherein the MDM2 The inhibitor, the BCL2 inhibitor and the hypomethylating agent are in a non-fixed combination. The MDM2 inhibitor used as described in any one of claims 1 and 6 to 16, the BCL2 inhibitor used as described in any one of claims 2 and 6 to 16, any of claims 3 and 6 to 16 The hypomethylating agent used in one of the claims, 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 simultaneously or Use sequentially. The MDM2 inhibitor used as described in any one of claims 1 and 6 to 17, the BCL2 inhibitor used as described in any one of claims 2 and 6 to 17, any of claims 3 and 6 to 17 A hypomethylating agent for use, or a method as claimed in any one of claims 4 and 6 to 17, wherein the hematological malignancy is AML or MDS. The MDM2 inhibitor used as described in claim 18, the BCL2 inhibitor used as described in claim 18, the hypomethylation agent used as described in claim 18, or the method as described in claim 18, wherein the The hematological malignancy is AML. The MDM2 inhibitor used as described in claim 19, the BCL2 inhibitor used as described in claim 19, the hypomethylation agent used as described in claim 19, or the method as described in claim 19, wherein the AML is not suitable for AML. The MDM2 inhibitor used as described in Claim 19 or Claim 20, the BCL2 inhibitor used as described in Claim 19 or Claim 20, the hypomethylating agent used as described in Claim 19 or Claim 20, Or the method as described in claim 19 or claim 20, wherein the treatment is administered to the following subjects: i) aged 75 years or over, or ii) Aged from 18 to 74 years old, with at least one of the following comorbidities: a) ECOG physical status is 2 or 3; b) Cardiac history of congestive heart failure requiring treatment, or ejection fraction ≤ 50%, or chronic stable angina; and c) DLCO ≤ 65% or FEV1% ≤ 65%. The MDM2 inhibitor used as described in any one of claims 19 to 21, the BCL2 inhibitor used as described in any one of claims 19 to 21, the used as described in any one of claims 19 to 21 A hypomethylating agent, or the method according to any one of claims 19 to 21, wherein the AML is TP53 wild-type AML. The MDM2 inhibitor used as described in any one of claims 19 to 22, the BCL2 inhibitor used as described in any one of claims 19 to 22, the used as described in any one of claims 19 to 22 Hypomethylating agent, or the method as claimed in any one of claims 19 to 22, wherein the treatment includes two to six complete treatments of the MDM2 inhibitor, the BCL2 inhibitor, and the hypomethylating agent cycles, and wherein after the two to six complete treatment cycles: i) Complete response (CR) rate ≥ 30%; and/or ii) The posterior probability of a CR rate ≥ 15% is at least 97.5%; and/or iii) CR rate ≥ 30%, the posterior probability of CR rate ≥ 15% is at least 97.5%. The MDM2 inhibitor used as described in any one of claims 19 to 23, the BCL2 inhibitor used as described in any one of claims 19 to 23, the used as described in any one of claims 19 to 23 A hypomethylating agent, or the method of 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 . The MDM2 inhibitor used as described in any one of claims 19 to 23, the BCL2 inhibitor used as described in any one of claims 19 to 23, the used as described in any one of claims 19 to 23 A hypomethylating agent, or the method of any one of claims 19 to 23, wherein the treatment is first-line (1L) treatment. The MDM2 inhibitor used as described in any one of claims 19 to 25, the BCL2 inhibitor used as described in any one of claims 19 to 25, the used as described in any one of claims 19 to 25 A hypomethylating agent, or the method according to any one of claims 19 to 25, wherein the AML is TP53 wild-type AML with poor genetic risk stratification according to ELN 2017. The MDM2 inhibitor used as described in any one of claims 1 and 6 to 26, the BCL2 inhibitor used as described in any one of claims 2 and 6 to 26, any of claims 3 and 6 to 26 One of the hypomethylating agents used, or the method as described in 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 includes at least two treatment cycles. The MDM2 inhibitor used as described in claim 27, the BCL2 inhibitor used as described in claim 27, the hypomethylation agent used as described in claim 27, or the method as described in claim 27, wherein the Azacitidine 20 to 200 mg/m ² on i) each day for the first 7 days of each 28-day cycle, or ii) each day for days 1 to 5, 8, and 9 of each 28-day treatment cycle One day cast. The MDM2 inhibitor used as described in claim 28, the BCL2 inhibitor used as described in claim 28, the hypomethylation agent used as described in claim 28, or the method as described in claim 28, wherein the Azacitidine at 75 mg/m ² administered i) on each of the first 7 days of each 28-day cycle, or ii) on each of days 1 through 5, 8, and 9 of each 28-day treatment cycle and. The MDM2 inhibitor used as described in any one of claims 1 and 6 to 29, the BCL2 inhibitor used as described in any one of claims 2 and 6 to 29, any of claims 3 and 6 to 29 The hypomethylating agent used in one of the claims, or the method as described in any one of claims 4 and 6 to 29, wherein the BCL2 inhibitor is venetoclax, and the venetoclax is used in the first 100 mg on Day 1 of each 28-day treatment cycle, 200 mg on Day 2 of the first 28-day treatment cycle, and on each of Days 3 through 28 of the first 28-day treatment cycle Administered at 400 mg. The MDM2 inhibitor used as described in claim 30, the BCL2 inhibitor used as described in claim 30, the hypomethylation agent used as described in claim 30, or the method as described in claim 30, wherein the Venetoclax was administered at 400 mg daily during the second and any subsequent 28-day treatment cycles. The MDM2 inhibitor used as described in any one of claims 1 and 6 to 29, the BCL2 inhibitor used as described in any one of claims 2 and 6 to 29, any of claims 3 and 6 to 29 The hypomethylating agent used in one of the claims, or the method as described in any one of claims 4 and 6 to 29, wherein the BCL2 inhibitor is venetoclax, and the venetoclax is 28 days 400 mg is administered each of days one through day twenty-eight of a treatment cycle, and wherein the treatment includes at least two treatment cycles.