WO2023067483A1 - Combinaisons pharmaceutiques comprenant un inhibiteur de mdm2, un inhibiteur de bcl2 et un agent d'hypométhylation et leurs utilisations pour le traitement de malignités hématologiques - Google Patents

Combinaisons pharmaceutiques comprenant un inhibiteur de mdm2, un inhibiteur de bcl2 et un agent d'hypométhylation et leurs utilisations pour le traitement de malignités hématologiques Download PDF

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WO2023067483A1
WO2023067483A1 PCT/IB2022/059973 IB2022059973W WO2023067483A1 WO 2023067483 A1 WO2023067483 A1 WO 2023067483A1 IB 2022059973 W IB2022059973 W IB 2022059973W WO 2023067483 A1 WO2023067483 A1 WO 2023067483A1
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use according
inhibitor
hypomethylating agent
treatment
bcl2
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PCT/IB2022/059973
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Claire Fabre
Ensar HALILOVIC
Hans Dietrich Richard MENSSEN
Dhrubajyoti PATHAK
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Novartis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • 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 treating haematological malignancies involving said combination.
  • BACKGROUND 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.
  • p53 is one of the most frequently inactivated proteins in human cancer, either through direct mutation of the TP53 gene (found in approximately 50% of all human cancers) (Vogelstein, Bet al. Nature 2000;408:307-310) or via suppressive mechanisms such as overexpression of HDM2 (Zhao Y, et al. BioDiscovery 2013;8:4).
  • Potent and selective inhibitors of the HDM2-p53 interaction also referred to as HDM2 inhibitors or MDM2 inhibitors
  • e.g. NVP-HDM201 herein referred to as HDM201, and also known as siremadlin
  • the HDM2 inhibitor HDM201 i.e. (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro- pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H- pyrrolo[3,4-d]imidazol-4-one, and methods how to prepare it were disclosed in WO2013/111105 (Example 102).
  • Venetoclax is a potent, selective inhibitor of B-cell lymphoma (BCL)-2, an antiapoptotic protein. Venetoclax binds directly to the BH3-binding groove of BCL-2, displacing BH3 motif-containing pro-apoptotic proteins like BIM, to initiate mitochondrial outer membrane permeabilization (MOMP), caspase activation, and programmed cell death.
  • Bcl-2 is an antiapoptotic protein of the Bcl-2 family of proteins, which includes Mcl-1 and Bcl-xL, among others.
  • Bcl-2 can bind pro-apoptotic effector molecules such as Bax/Bak and prevent their oligomerization and formation of the transmembrane pores on the mitochondrial membrane. By doing so, Bcl-2 prevents release of cytochrome C, thereby blocking activation of caspases and subsequently inhibiting apoptosis. Evasion of apoptosis is one of the hallmarks of cancers, thus the anti-apoptotic proteins such as Bcl-2, facilitators of this evasion, represent a compelling therapeutic target (Certo et al.2006).
  • Venetoclax is a highly selective orally bioavailable small- molecule inhibitor of Bcl-2 that has shown 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 has been approved by the FDA for the treatment of CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma) with or without deletion 17p who have received at least one prior therapy [venetoclax US Pl].
  • CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
  • venetoclax has been approved by EMA for the treatment of CLL in the presence of 17p deletion or TP53 mutation in adult subjects who are unsuitable for or have failed a B-cell receptor pathway inhibitor; for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult subjects who have failed both chemo-immunotherapy and a B-cell receptor pathway inhibitor [venetoclax EU SmPC].
  • EMA EMA
  • CR/CRi rates 19% (6/32 subjects) in R/R or unfit for chemotherapy AML subjects
  • Hypomethylating agent in combination with venetoclax Hypomethylating agents (also known as demethylating agents) such as azacitidine and decitabine reduce the amount of cellular DNA methylation and increase the expression of tumor suppressor genes. Hypomethylating agents have been used in combination with venetoclax for the treatment of newly diagnosed unfit patients with AML, and this combination is increasingly being viewed as the standard of care in this patient group. Venetoclax 400 mg in combination with either azacitidine or decitabine demonstrated significant activity, with a CR/CRi rate of 71% and 74%, respectively (Jonas et al, Leukemia, 33, 2795-2804, 2019).
  • an MDM2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of a haematological malignancy, wherein the treatment further comprises administration of a BCL2 inhibitor or a pharmaceutically acceptable salt thereof and a hypomethylating agent or a pharmaceutically acceptable salt thereof.
  • a BCL2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of a haematological malignancy, wherein the treatment further comprises administration of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a hypomethylating agent or a pharmaceutically acceptable salt thereof.
  • a hypomethylating agent or a pharmaceutically acceptable salt thereof for use in the treatment of a haematological malignancy, wherein the treatment further comprises administration of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor or a pharmaceutically acceptable salt thereof.
  • a method of treating a haematological malignancy in a subject in need thereof comprises administering to the subject a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of a BCL2 inhibitor or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a hypomethylating agent or a pharmaceutically acceptable salt thereof.
  • 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.
  • HDM201 enhances antitumor activity of a selective Bcl-2 inhibitor venetoclax in AML patient derived orthotopic model.
  • NVP-HDM201 was administered po, at 20 mg/kg, 3 times on dosing day once weekly, either as a single agent or in combination with venetoclax (ABT-199) po at 100mg/kg, once daily 5 times a week, for 14 days.
  • Initial group size 5 animals.
  • Figure 2 Dose titration of HDM201 in combination with venetoclax: Effects of the combination on platelets could be mitigated with administration of lower doses of HDM201, while still maintaining the anti-tumor activity.
  • NVP-HDM201 was administered po, at 5 mg/kg, 10 mg/kg, and 20 mg/kg, 3 times on dosing day once weekly, either as a single agent or in combination with venetoclax (ABT-199) po at 100mg/kg, once daily 5 times a week, for 3-6 weeks.
  • Initial group size 4 animals.
  • the mean leukemic burden is represented as CD45+ cells in peripheral blood for each treatment group, plotted against time.
  • B Platelet count was measured in peripheral blood after 3 weeks of treatment and depicted in panel B.
  • Figure 3 Study flow diagram showing long-term follow-up (for efficacy and/or survival status) for all participants who discontinued study treatment in the planned CHDM201I2201 clinical trial.
  • FIG. 4 Study flow chart showing assessment of participants during screening and periodically during treatment and follow-up in the planned CHDM201I2201 clinical trial.
  • Embodiment 1 An MDM2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of a haematological malignancy, wherein the treatment further comprises administration of a BCL2 inhibitor or a pharmaceutically acceptable salt thereof and a hypomethylating agent or a pharmaceutically acceptable salt thereof.
  • a BCL2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of a haematological malignancy wherein the treatment further comprises administration of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a hypomethylating agent or a pharmaceutically acceptable salt thereof.
  • Embodiment 3. A hypomethylating agent or a pharmaceutically acceptable salt thereof for use in the treatment of a haematological malignancy, wherein the treatment further comprises administration of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor or a pharmaceutically acceptable salt thereof.
  • a method of treating a haematological malignancy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an MDM2 inhibitor or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of a BCL2 inhibitor or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a hypomethylating agent or a pharmaceutically acceptable salt thereof.
  • 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 according to Embodiment 5 for use in the treatment of a haematological malignancy (e.g.
  • Embodiment 6 AML, e.g. unfit AML, e.g. TP53 wildtype unfit AML).
  • Embodiment 6 The MDM2 inhibitor for use according to Embodiment 1, the BCL2 inhibitor for use according to Embodiment 2, the hypomethylating agent for use according to Embodiment 3, the method according to Embodiment 4, or the combination according to Embodiment 5 or Embodiment 5a, wherein the MDM2 inhibitor is HDM201.
  • Embodiment 9 The MDM2 inhibitor for use according to any one of Embodiments 1 and 6 to 8, the BCL2 inhibitor for use according to any one of Embodiments 2 and 6 to 8, the hypomethylating agent for use according to any one of Embodiments 3 and 6 to 8 or the method according to any one of Embodiments 4 and 6 to 8, wherein the MDM2 inhibitor is administered orally.
  • Embodiment 12 The MDM2 inhibitor for use according to Embodiment 11, the BCL2 inhibitor for use according to Embodiment 11, the hypomethylating agent for use according to Embodiment 11 or the method according to Embodiment 11, wherein the daily dose of MDM2 inhibitor on each of the first 5 days of the 28 day treatment cycle is 20, 30 or 40 mg.
  • Embodiment 15 Embodiment 15.
  • Embodiment 19 The MDM2 inhibitor for use according to Embodiment 18, the BCL2 inhibitor for use according to Embodiment 18, the hypomethylating agent for use according to Embodiment 18 or the method according to Embodiment 18, wherein the haematological malignancy is AML.
  • the MDM2 inhibitor for use according to Embodiment 19 the BCL2 inhibitor for use according to Embodiment 19, the hypomethylating agent for use according to Embodiment 19 or the method according to Embodiment 19, wherein the AML is unfit (for standard induction chemotherapy) AML.
  • Embodiment 21 the MDM2 inhibitor for use according to Embodiment 19
  • the BCL2 inhibitor for use according to Embodiment 19 the hypomethylating agent for use according to Embodiment 19 or the method according to Embodiment 19, wherein the AML is unfit (for standard induction chemotherapy) AML.
  • the MDM2 inhibitor for use according to Embodiment 19 or Embodiment 20 the BCL2 inhibitor for use according to Embodiment 19 or Embodiment 20, the hypomethylating agent for use according to Embodiment 19 or Embodiment 20 or the method according to Embodiment 19 or Embodiment 20, wherein the treatment is administered to a subject who is: i) 75 years of age or older, or ii) from 18 to 74 years of age with at least one of the following co-morbidities: a) an ECOG performance Status 2 or 3; b) a cardiac history of congestive heart failure requiring treatment, or Ejection Fraction ⁇ 50%, or chronic stable Angina; c) pulmonary comorbidity (e.g.
  • Embodiment 22 The MDM2 inhibitor for use according to any one of Embodiments 19 to 21, the BCL2 inhibitor for use according to any one of Embodiments 19 to 21, the hypomethylating agent for use according to any one of Embodiments 19 to 21 or the method according to any one of Embodiments 19 to 21, wherein the AML is TP53 wild-type AML.
  • Embodiment 23 The MDM2 inhibitor for use according to any one of Embodiments 19 to 21, the BCL2 inhibitor for use according to any one of Embodiments 19 to 21, the hypomethylating agent for use according to any one of Embodiments 19 to 21 or the method according to any one of Embodiments 19 to 21, wherein the AML is TP53 wild-type AML.
  • the complete remission (CR) rate is ⁇ 30%
  • the posterior probability that the CR rate is ⁇ 15% is at least 97.5%
  • the posterior probability that CR rate is ⁇ 15%
  • Embodiment 24 The MDM2 inhibitor for use according to any one of Embodiments 19 to 23, the BCL2 inhibitor for use according to any one of Embodiments 19 to 23, the hypomethylating agent for use according to any one of Embodiments 19 to 23 or the method according to any one of Embodiments 19 to 23, wherein the treatment is administered to a subject who has previously received therapy with a combination of a BCL2 inhibitor (e.g. venetoclax) and a hypomethylating agent (e.g. azacitidine or decitabine, e.g. azacitidine), without further combination with an MDM2 inhibitor.
  • a BCL2 inhibitor e.g. venetoclax
  • a hypomethylating agent e.g. azacitidine or decitabine, e.g. azacitidine
  • CR Complete Remission
  • CRi Complete Remission with incomplete hematologic response
  • CRh CR with partial recovery of peripheral bloody counts
  • MLFS Morphologic Leukemia-Free State
  • day 1 of a first treatment cycle (e.g.28 day treatment cycle) with the MDM2 inhibitor, the BCL2 inhibitor and the hypomethylating agent is the day after a final day (e.g. day 28) of a final cycle of therapy with the BCL2 inhibitor and the hypomethylating agent).
  • a first treatment cycle e.g.28 day treatment cycle
  • the BCL2 inhibitor for use according to any one of Embodiments 19 to 23
  • Embodiment 26 is first line (1L) treatment (e.g. including both de novo and secondary AML).
  • Embodiment 28 is azacitidine and the azacitidine is administered on each of the first 7 days of a 28 day treatment cycle or on days 1 to 5, 8 and 9 of a 28 day treatment cycle, and wherein the treatment comprises at least two treatment cycles.
  • Embodiment 29 Embodiment 29.
  • Embodiment 30 Embodiment 30.
  • the MDM2 inhibitor for use according to Embodiment 30 the BCL2 inhibitor for use according to Embodiment 30, the hypomethylating agent for use according to Embodiment 30 or the method according to Embodiment 30, wherein the venetoclax is administered at 400mg daily (i.e. on all of days 1 to 28) of the second and any subsequent 28 day treatment cycles.
  • Embodiment 32 the MDM2 inhibitor for use according to Embodiment 30, the BCL2 inhibitor for use according to Embodiment 30, the hypomethylating agent for use according to Embodiment 30 or the method according to Embodiment 30, wherein the venetoclax is administered at 400mg daily (i.e. on all of days 1 to 28) of the second and any subsequent 28 day treatment cycles.
  • Embodiments 1 to 32 above, and Embodiments A to W below, are all directed to a combination of an MDM2 inhibitor, a BCL2 inhibitor and a hypomethylating agent or the use thereof in the treatment of a haematological malignancy, e.g. AML or MDS, e.g. AML, e.g. unfit AML.
  • a haematological malignancy e.g. AML or MDS
  • AML e.g. unfit AML.
  • Embodiment A A method of treating TP53 wildtype unfit 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 in combination with a therapeutically effective amount of venetoclax or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of azacitidine or a pharmaceutically acceptable salt thereof.
  • Embodiment B A method of treating TP53 wildtype unfit 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 in combination with a therapeutically effective amount of venetoclax or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of azacitidine or a pharmaceutically acceptable salt thereof.
  • Embodiment B A method of treating TP53 wildtype unfit 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
  • Embodiment A wherein the subject is: i) 75 years of age or older, or ii) from 18 to 74 years of age with at least one of the following co-morbidities: a) an ECOG performance Status 2 or 3; b) a cardiac history of congestive heart failure requiring treatment, or Ejection Fraction ⁇ 50%, or chronic stable Angina; and c) DLCO ⁇ 65% or FEV1% ⁇ 65%.
  • Embodiment C The method according to Embodiment A or Embodiment B, wherein the treatment is administered to a subject who has previously received therapy with a combination of a BCL2 inhibitor (e.g. venetoclax) and a hypomethylating agent (e.g.
  • a BCL2 inhibitor e.g. venetoclax
  • a hypomethylating agent e.g.
  • Embodiment C1 The method according to Embodiment C, wherein the therapy with the combination of the BCL2 inhibitor and the hypomethylating agent comprises from two to four complete treatment cycles (e.g.28 day treatment cycles) of the BCL2 inhibitor and the hypomethylating agent.
  • Embodiment C2 The method according to Embodiment C or Embodiment C1, wherein treatment with the MDM2 inhibitor, the BCL2 inhibitor and the hypomethylating agent immediately follows the therapy with the combination of the BCL2 inhibitor and the hypomethylating agent (i.e. wherein day 1 of a first treatment cycle with the MDM2 inhibitor, the BCL2 inhibitor and the hypomethylating agent is the day after a final day (e.g. day 28) of a final cycle of therapy with the BCL2 inhibitor and the hypomethylating agent).
  • a final day e.g. day 28
  • Embodiment E The method according to Embodiment D, wherein the subject has adverse genetic risk stratification according to ELN 2017.
  • Embodiment F The method according to Embodiment E, wherein the AML has the genetic abnormality t(6;9)(p23;q34.1); DEK-NUP214.
  • Embodiment G The method according to Embodiment E, wherein the AML has the genetic abnormality t(v;11q23.3); KMT2A rearranged.
  • Embodiment H The method according to Embodiment H.
  • Embodiment E wherein the AML has the genetic abnormality t(9;22)(q34.1;q11.2); BCR-ABL1.
  • Embodiment I The method according to 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 according to Embodiment E, wherein the AML has the genetic abnormality ⁇ 5 or del(5q); ⁇ 7; ⁇ 17/abn(17p).
  • Embodiment K The method according to Embodiment E, wherein the AML has the genetic abnormality ⁇ 5 or del(5q); ⁇ 7; ⁇ 17/abn(17p).
  • Embodiment E wherein the AML has the genetic abnormality complex karyotype or monosomal karyotype.
  • Embodiment L The method according to Embodiment E, wherein the AML has the genetic abnormality Wild-type NPM1 and FLT3-ITDhigh.
  • Embodiment M The method according to Embodiment E, wherein the AML has the genetic abnormality Mutated RUNX1.
  • Embodiment N The method according to Embodiment E, wherein the AML has the genetic abnormality Mutated ASXL1.
  • Embodiment O The method according to any one of Embodiments A to N wherein the subject is 75 years of age or older.
  • Embodiment P The method according to any one of Embodiments A to N wherein the subject is 75 years of age or older.
  • Embodiment O wherein the subject has an ECOG performance status of from 0 to 2.
  • Embodiment Q The method according to any one of Embodiments A to N wherein the subject is from 18 to 74 years of age.
  • Embodiment R The method according to Embodiment Q wherein the subject has an ECOG performance status of from 0 to 3.
  • Embodiment S The method according to Embodiment Q or Embodiment R wherein the subject has chronic stable Angina.
  • Embodiment T The method according to Embodiment Q or Embodiment R wherein the subject has a cardiac history of congestive heart failure requiring treatment.
  • Embodiment U The method according to Embodiment U.
  • Embodiment Q or Embodiment R wherein the subject has a Left Ventricle Ejection Fraction of less than or equal to 50%.
  • Embodiment V The method according to Embodiment Q or Embodiment R wherein the subject has a DLCO of less than or equal to 65%.
  • Embodiment W The method according to Embodiment Q or Embodiment R wherein the subject has a FEV1% of less than or equal to 65%. It is thought that the combinations of the invention could be used to efficiently treat haematological malignancies such as MDS or AML, e.g. due to a synergistic effect in inhibition of cell proliferation and/or induction of apoptosis.
  • the MDM2 inhibitor is preferably administered on each of the first 5 days of a 28 day treatment cycle, wherein the treatment comprises at least two treatment cycles.
  • the treatment cycles are consecutive, i.e. follow directly on from one another, without a gap. In a scenario where there is only two treatment cycles this would correspond to: Days 1-5: MDM2 inhibitor administered (administration days) Days 6-28: MDM2 inhibitor not administered Days 29-33: MDM2 inhibitor administered (administration days) Days 34-56: MDM2 inhibitor not administered.
  • the treatment cycles are consecutive, i.e. follow directly on from one another, without an gap.
  • the MDM2 inhibitor is HDM201.
  • the daily dose of HDM201 on each administration day is from 10 to 50 mg, e.g. from 10 mg to 40 mg (expressed in terms of HDM201 free base).
  • the daily dose of HDM201 on each administration day is 20, 30 or 40 mg (expressed in terms of HDM201 free base).
  • the HDM201 is administered orally.
  • the HDM201 is HDM201 succinic acid co-crystal.
  • the BCL2 inhibitor is preferably administered orally.
  • the BCL2 inhibitor is venetoclax.
  • the BCL2 inhibitor is venetoclax and the venetoclax is administered at 100 mg on the first day of the first 28 day treatment cycle, 200 mg on the second day of the first 28 day treatment cycle, and 400 mg on each of the third to twenty-eighth days of the first 28 day treatment cycle.
  • venetoclax is administered at 400mg daily on each subsequent 28 day treatment cycle wherein there is at least one subsequent 28 day treatment cycle (i.e. at least two 28 day treatment cycles in total).
  • the treatment is administered to a subject who has previously undergone doublet combination therapy (e.g.
  • the daily dose of venetoclax on all administration days is 400 mg, from the first treatment cycle onwards, and there are at least two 28 day treatment cycles in total (of the MDM2 inhibitor, the venetoclax and the hypomethylating agent).
  • day 1 of a first 28 day treatment cycle e.g.
  • the MDM2 inhibitor, the BCL2 inhibitor venetoclax, and the hypomethylating agent is the day after day 28 of a final 28 day doublet treatment cycle of treatment with the BCL2 inhibitor and the hypomethylating agent (preferably wherein there are from two to four 28 day doublet treatment cycles in total, more preferably wherein there are two or three 28 day doublet treatment cycles in total).
  • the patient has failed to achieve any of: a) Complete Remission (CR); b) Complete Remission with incomplete hematologic response (CRi); c) CR with partial recovery of peripheral bloody counts (CRh); and d) Morphologic Leukemia-Free State (MLFS).
  • the hypomethylating agent is azacitidine or decitabine, most preferably azacitidine.
  • the hypomethylating agent is preferably administered subcutaneously or intravenously, e.g. subcutaneously.
  • the hypomethylating agent is azacitidine and the azacitidine is administered on each of the first 7 days of a 28 day treatment cycle, and wherein the treatment comprises at least two treatment cycles, or wherein the azacitidine is administered on each of the first 5 days and days 8 and 9 of a 28 day treatment cycle, and wherein the treatment comprises at least two treatment cycles.
  • the azacitidine is administered at 20-200 mg/m 2 on administration days. More preferably, the azacitidine is administered at 50-100 mg/m 2 on administration days, most preferably about 75 mg/m 2 on administration days.
  • the 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.
  • the hypomethylating agent is decitabine
  • the decitabine is administered at 20 mg/m 2 on administration days.
  • the MDM2i e.g. HDM201
  • BCL2i e.g. venetoclax
  • hypomethylating agent e.g. azacitidine
  • the MDM2i, BCL2i and hypomethylating agent are preferably in the form of a non-fixed combination. However, in another (less preferred) aspect of the invention the MDM2i, BCL2i and hypomethylating agent are provided in the form of a fixed combination.
  • the MDM2i, BCL2i and hypomethylating agent may be for simultaneous or sequential use.
  • the term “hypomethylating agent” as used herein refers to a drug that inhibits DNA methylation, and includes azacitidine, decitabine and guadectabine.
  • the “hypomethylating agent” of the invention is azacitidine or decitabine, most preferably azacitidine.
  • MDM2i or “MDM2 inhibitor” as used herein refers to denotes herein any compound inhibiting the HDM-2/p53 or HDM-4/p53 interaction (preferably the HDM-2/p53 interaction) with an IC 50 of less than 10 ⁇ M, preferably less than 1 ⁇ M, preferably in the range of nM (e.g. less than 500 nM, e.g. less than 250 nM, e.g. less than 100 nM), measured by a Time Resolved Fluorescence Energy Transfer (TR-FRET) Assay.
  • TR-FRET Time Resolved Fluorescence Energy Transfer
  • the inhibition of p53-Hdm2 and p53-Hdm4 interactions is measured by time resolved fluorescence energy transfer (TR-FRET).
  • Fluorescence energy transfer (or Foerster resonance energy transfer) describes an energy transfer between donor and acceptor fluorescent molecules.
  • MDM2 protein amino acids 2-188
  • MDM4 protein amino acids 2-185
  • tagged with a C-terminal Biotin moiety are used in combination with a Europium labelled streptavidin (Perkin Elmer, Inc., Waltham, MA, USA) serving as the donor fluorophore.
  • the p53 derived, Cy5 labelled peptide Cy5- TFSDLWKLL (p53 aa18-26) is the energy acceptor.
  • the ratiometric FRET assay readout is calculated from the raw data of the two distinct fluorescence signals measured in time resolved mode (countrate 665nm / countrate 615nm x 1000).
  • the assay can be performed according to the following procedure: The test is performed in white 1536w microtiterplates (Greiner Bio-One GmbH, Frickenhausen, Germany) in a total volume of 3.1 ⁇ L by combining 100 nl of compounds diluted in 90% DMSO/10% H2O (3.2% final DMSO concentration) with 2 ⁇ L Europium labelled streptavidin (final concentration 2.5nM) in reaction buffer (PBS,125mM NaCl, 0.001% Novexin (consists of carbohydrate polymers (Novexin polymers), designed to increase the solubility and stability of proteins; Novexin Ltd., Cambridgeshire, United Kingdom), Gelatin 0.01 %, 0.2% Pluronic (block copolymer from ethylenoxide and propyleneoxide, BASF, Ludwigshafen, Germany), 1 mM OTT), followed by the addition of 0. ⁇ L MDM2-Bio or MDM4-Bio diluted in assay buffer (final concentration 10nM).
  • reaction buffer PBS,125m
  • a Bcl2 inhibitor or “BCL2i” or “a BCL2 inhibitor” or “BCL-2 inhibitor” or “Bcl-2 inhibitor” etc. is defined herein to refer to a compound which targets, decreases or inhibits anti- apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and/or Bcl-B).
  • haematological malignancy is used synonymously with “haematological tumor” and refers herein to a cancer that begins in blood-forming tissue, such as the bone marrow, or in the cells of the immune system.
  • hematological tumors are leukemia, lymphoma, and multiple myeloma. They are also often referred to as blood cancers.
  • Preferred hematological tumors of the present invention are leukemias. More preferably, the hematological tumors are selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL). Even more preferably, the hematological tumor is AML and/or MDS.
  • Particularly preferred hematological tumors of the present invention are TP53 wild-type hematological tumors. More preferably, the TP53 wild-type hematological tumors of the present invention are TP53 wild-type leukemias.
  • the TP53 wild-type hematological tumors are selected from TP53 wild-type acute myeloid leukemia (AML), TP53 wild-type myelodysplastic syndrome (MDS), and TP53 wild-type acute lymphoblastic leukemia (ALL).
  • AML TP53 wild-type acute myeloid leukemia
  • MDS TP53 wild-type myelodysplastic syndrome
  • ALL TP53 wild-type acute lymphoblastic leukemia
  • the TP53 wild-type hematological tumor is TP53 wild-type AML and/or MDS.
  • the TP53 wild-type hematological tumor is TP53 wild-type AML.
  • the AML e.g. TP53 wild-type AML
  • Unfit for standard induction chemotherapy
  • AML as used herein refers to AML based on WHO 2016 classification.
  • Unfit AML as used herein refers to AML based on WHO 2016 classification who are ineligible for (standard induction) chemotherapy.
  • De novo AML as used herein refers to AML in patients with no clinical history of prior myeloid malignancy (e.g. MDS or myeloproliferative disorder).
  • Secondary AML as used herein refers to AML in patients with a clinical history of prior myeloid malignancy (e.g. MDS or myeloproliferative disorder), which converts to AML.
  • the treatment is administered to a subject who is 18 years of age or older.
  • the treatment is administered to a subject who is, or has been determined to be, unfit, i.e. ineligible for standard induction chemotherapy, because they are either: i) 75 years of age or older, or ii) from 18 to 74 years of age with at least one of the following co-morbidities: a) an ECOG performance Status 2 (Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours) or 3 (Capable of only limited self-care; confined to bed or chair more than 50% of waking hours); b) a cardiac history of congestive heart failure requiring treatment or (ventricle, e.g.
  • pulmonary comorbidity e.g. DLCO ⁇ 65% or FEV1% ⁇ 65%
  • the haematological malignancy to be treated is MDS
  • the MDS is intermediate risk, high risk, or very high risk according to the International Prognostic Scoring System of MDS (IWG-PM), more preferably high risk or very high risk.
  • IWG-PM International Prognostic Scoring System of MDS
  • Ventricle ejection fraction refers to the total amount of blood in the (left) ventricle pumped out with each heartbeat. A range of 55-70% is normal.
  • Ejection fraction can be measured using echocardiogram, an magnetic resonance imaging (MRI) scan of the heart, or a nuclear medicine scan (nuclear stress test) of the heart.
  • DLCO refers to the Diffusing capacity of the lungs for carbon monoxide, and is also known as transfer factor for carbon monoxide (TLCO), and is a test of lung function which measures the ability of the lungs to transfer inhaled gases to red blood cells in the pulmonary capillaries.
  • Standards for DLCO can be found in Am Rev Respir Dis.1987;136(5):1299., Eur Respir J. 2005;26(4):720, and Eur Respir J.2017;49(1) Epub 2017 Jan 3.
  • FEV1% also known as the FEV1/FVC ratio, and as the Tiffeneau-Pinelli index, is a ratio which refers to the percentage of a subjects vital capacity (maximum amount of air a person can expel from the lungs after a maximum inhalation) that they are able to release in the first second of a forced expiration.
  • FEV1% is used in the assessment of obstructive and restrictive lung conditions such as COPD. Normal FEV1% values are c.70-80%. Below 65% is indicative of reduced lung function.
  • the Tiffeneau-Pinelli index can be routinely calculated using a spirometer.
  • the treatment is administered to a subject who is 75 years of age or older with an ECOG performance status of from 0 to 2, or is from 18 to 74 years of age with an ECOG performance status of from 0 to 3.
  • the treatment is administered to a subject who is 75 years of age or older, or from 18 to 74 years of age with at least one of the following co-morbidities: a) an ECOG performance Status 2 or 3; b) a cardiac history of congestive heart failure requiring treatment or (ventricle, e.g. left ventricle) Ejection fraction) ⁇ 50% or chronic stable Angina; and c) pulmonary comorbidity (e.g. DLCO ⁇ 65% or FEV1% ⁇ 65%.
  • the treatment is administered to a subject who is from 18 to 74 years of age and has a cardiac history of congestive heart failure requiring treatment.
  • the treatment is administered to a subject who is from 18 to 74 years of age and has a left ventricle ejection fraction ⁇ 50%.
  • the treatment is administered to a subject who is from 18 to 74 years of age and has chronic stable Angina.
  • the treatment is administered to a subject who is from 18 to 74 years of age and has DLCO ⁇ 65%.
  • the treatment is administered to a subject who is from 18 to 74 years of age and has FEV1% ⁇ 65%.
  • the treatment is administered to a subject who has Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ⁇ 3 x upper limit of normal (ULN)
  • the treatment is administered to a subject who has total bilirubin ⁇ 1.5 x ULN.
  • the subject has isolated Gilbert syndrome, and the subject has ⁇ 3.0 x ULN.
  • the treatment is administered to a subject who has Estimated Glomerular Filtration Rate (eGFR) ⁇ 60 mL/min/1.73 m 2 based on Modification of Diet in Renal Disease (MDRD) formula.
  • eGFR Estimated Glomerular Filtration Rate
  • the treatment is administered to a subject who has white blood cells (WBC) ⁇ 25x10 9 /L. In an embodiment, the treatment is administered to a subject who does not have del17p.
  • the AML is not AML-M3 / APL / Acute promyelocytic leukemia with PM-RARA (promyelocytic leukemia / retinoic acid receptor alpha / PML-RARA t(15;17)(q22;q12)).
  • the AML is not AML secondary to Down’s syndrome.
  • the treatment is administered to a subject who is not (simultaneously) treated with an FLT3 inhibitor.
  • the treatment is administered to a subject who does not have active CNS leukemia.
  • the treatment is administered to a subject who does not have neurologic symptoms suggestive of CNS leukemia unless CNS leukemia has been excluded by at least one lumbar puncture showing negativity.
  • the complete remission (CR) rate is ⁇ 30% following from 2 to 6 complete (28 day) treatment cycles with the combination of MDM2i (e,g, HDM201), BCL2i (e.g. venetoclax) and hypomethylating agent (e.g. Azacitidine).
  • the treatment is administered to a subject who does not have an additional concurrent or prior malignancy, with the exception of prior MDS, myelofibrosis, essential thrombocythemia, polycythemia vera, aplastic anaemia, or other antecedent hematologic disorder.
  • the treatment is administered to a subject who has a history of an additional malignancy from which the subject has been disease free (absence of residual disease) for at least 1 year, and wherein no chemotherapy, radiotherapy or surgery is ongoing.
  • the subject with a history of an additional malignancy from which the subject has been disease free (absence of residual disease) for at least 1 year, and wherein no chemotherapy, radiotherapy or surgery is ongoing is receiving adjuvant therapy.
  • the adjuvant therapy is hormonal therapy or long-term maintenance therapy.
  • the treatment is administered to a subject who does not receive Hematopoietic Stem Cell Transplant (HSCT) or intensive chemotherapy during any of the 28 day treatment cycles (of combined MDM2i, BCL2i and hypomethylating agent therapy).
  • the posterior probability for a CR rate ⁇ 15% e.g. following from 2 to 6 complete treatment cycles with the combination of MDM2i (e.g. HDM201), BCL2i (e.g. venetoclax) and hypomethylating agent (e.g. azacitidine) is at least 90%, for example at least 92.5%, for example at least 95%, for example at least 97.5%.
  • the posterior probability for a CR rate ⁇ 15% following from 2 to 6 complete 28 day treatment cycles with the combination of MDM2i (e.g. HDM201), BCL2i (e.g. venetoclax) and hypomethylating agent (e.g. azacitidine) is at least 97.5%.
  • the CR rate is ⁇ 30% and the posterior probability that CR rate is ⁇ 15% is at least 97.5%.
  • the posterior median CR rate is ⁇ 30% and the posterior probability that CR rate is ⁇ 15% is at least 97.5%.
  • Posterior probability refers to Bayesian posterior probability.
  • Bayesian posterior probability the posterior probability of A occurring given that B occurred, can be expressed as: , wherein 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 given that A is true.
  • Standard induction chemotherapy as used herein is a term of art and refers to high dose chemotherapy typically used in the initial treatment of “fit” AML.
  • Standard induction chemotherapy in AML is often a combination of cytarabine and an anthracycline drug such as daunorubicin or idarubicin. Induction tends to be short (typically around a week), but intensive and can cause serious side effects, so is not recommended in “unfit” AML patients who may not be able to cope with the resultant toxicity. Even in “fit” AML patients standard induction chemotherapy is typically given in the hospital in order that the patient can be monitored for serious side effects.
  • the treatment is administered to a subject who has previously received therapy with a combination of a BCL2 inhibitor (e.g. venetoclax) and a hypomethylating agent (e.g. azacitidine or decitabine, e.g. azacitidine), without further combination with an MDM2 inhibitor (referred to herein as the doublet treatment, the doublet combination etc.).
  • a BCL2 inhibitor e.g. venetoclax
  • a hypomethylating agent e.g. azacitidine or decitabine, e.g. azacitidine
  • MDM2 inhibitor MDM2 inhibitor
  • the therapy with the doublet combination of the BCL2 inhibitor and the hypomethylating agent comprises from two to four complete treatment cycles (e.g.28 day treatment cycles) of the BCL2 inhibitor and the hypomethylating agent, preferably two or three complete 28 day treatment cycles.
  • the 28 day treatment cycles of the BCL2 inhibitor and the hypomethylating agent in the doublet combination are aligned, i.e. day 1 of the BCL2 inhibitor treatment cycle is day 1 of the hypomethylating agent treatment cycle.
  • the treatment is administered to a subject who has previously received therapy with the doublet combination of the BCL2 inhibitor and the hypomethylating agent, and wherein treatment with the MDM2 inhibitor, the BCL2 inhibitor and the hypomethylating agent immediately follows the therapy with the doublet combination of the BCL2 inhibitor and the hypomethylating agent (i.e. wherein day 1 of a first treatment cycle of each of the MDM2 inhibitor, the BCL2 inhibitor and the hypomethylating agent is the day after a final day (e.g. day 28) of a final cycle of therapy with the doublet combination – i.e. the BCL2 inhibitor and the hypomethylating agent).
  • each doublet treatment cycle is 28 days. I.e. Day X – final day (e.g. day 28) of the final (preferably second, third or fourth, more preferably second or third) cycle of therapy with the doublet combination of the BCL2 inhibitor and the hypomethylating agent Day X+1 – first day (e.g. of a 28 day treatment cycle) of treatment with the MDM2 inhibitor, the BCL2i inhibitor and the hypomethylating agent.
  • the treatment is administered to a subject who, prior to treatment with the combination with an MDM2i (e.g. HDM201), a BCL2i (e.g. venetoclax) and a hypomethylating agent (e.g.
  • azacitidine has already undergone from two to four (preferably two or three) 28 day doublet treatment cycles of treatment of combined BCL2i (e.g. venetoclax) and hypomethylating agent (e.g. azacitidine or decitabine) therapy (without further combination with an MDM2i), yet has failed to achieve (based on IWG; ELN 2017): a) Complete Remission (CR); b) Complete Remission with Incomplete hematologic response (CRi); c) CR with partial recovery of peripheral bloody counts (CRh); or d) Morphologic Leukemia-Free state (MLFS).
  • the treatment is administered to a subject who has previously undergone two 28 day doublet treatment cycles of treatment of combined BCL2i (e.g.
  • the treatment is administered to a subject who has previously undergone three 28 day doublet treatment cycles of combined BCL2i (e.g. venetoclax) and hypomethylating agent therapy (e.g. azacitidine or decitabine, preferably azacitidine), and has achieved Partial Remission (PR).
  • BCL2i e.g. venetoclax
  • hypomethylating agent therapy e.g. azacitidine or decitabine, preferably azacitidine
  • PR Partial Remission
  • CRh complete remission with partial hematological recovery
  • ⁇ Bone marrow less than 5% blasts and no blasts with Auer rods
  • ⁇ Peripheral Blood Neutrophils greater than 0.5x10 9 /L and/or platelets > 50x10 9 /L
  • ⁇ No evidence of extramedullary disease such as CNS or soft tissue involvement
  • subject who is assessed as CRh would also fulfill the criteria of CRi. However, not all subjects who are assessed as CRi would automatically fulfill the criteria of CRh.
  • in each of the from two to four 28 day doublet treatment cycles of combined BCL2i e.g.
  • hypomethylating agent used in the doublet treatment cycles was either azacitidine or decitabine, for example wherein: i) Azacitidine was administered on each of the first 7 days of the 28 day doublet treatment cycle (e.g. subcutaneously or intravenously); or ii) Decitabine was administered on each of the first 5 days of the 28 day doublet treatment cycle (e.g. subcutaneously or intravenously).
  • the BCL2i in the doublet was venetoclax, and the venetoclax was administered in each of 28 days of the 28 day doublet treatment cycle (e.g. orally).
  • the venetoclax was administered at 100 mg on the first day of the first 28 day doublet treatment cycle, 200 mg on the second day of the first 28 day doublet treatment cycle, 300 mg on the third day of the first 28 day doublet treatment cycle and 400 mg on each of the fourth to twenty-eighth days of the first 28 day doublet treatment cycle.
  • the venetoclax was administered 400 mg daily on the second and any subsequent doublet treatment cycles.
  • the treatment is first line (1L) treatment (e.g. in newly diagnosed AML) (wherein the AML includes both de novo and secondary AML).
  • the AML is TP53 wildtype AML and has adverse genetic risk stratification according to ELN (European LeukemiaNet) 2017.
  • the AML has one or more of the genetic abnormalities: i) t(6;9)(p23;q34.1); DEK-NUP214; ii) t(v;11q23.3); KMT2A rearranged; iii) t(9;22)(q34.1;q11.2); BCR-ABL1; iv) inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1); v) ⁇ 5 or del(5q); ⁇ 7; ⁇ 17/abn(17p); vi) Complex karyotype, ⁇ monosomal karyotype
  • Favourable-risk AML subtypes include: a) t(8;21)(q22;q22.1); RUNX1-RUNX1T1; b) inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11; c) Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow ⁇ ; and d) Biallelic mutated CEBPA ⁇ Low, low allelic ratio ( ⁇ 0.5); high, high allelic ratio ( ⁇ 0.5); semiquantitative assessment of FLT3-ITD allelic ratio (using DNA fragment analysis) is determined as ratio of the area under the curve “FLT3-ITD” divided by area under the curve “FLT3-wild type”; As used herein, the term “first line treatment” simply means the first treatment for treating the disease from a temporal perspective.
  • the AML has the genetic abnormality t(6;9)(p23;q34.1); DEK-NUP214. In an embodiment, the AML has the genetic abnormality t(v;11q23.3); KMT2A rearranged. In an embodiment, the AML has the genetic abnormality t(9;22)(q34.1;q11.2); BCR-ABL1. In an embodiment, the AML has the genetic abnormality inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1). In an embodiment, the AML has the genetic abnormality ⁇ 5 or del(5q); ⁇ 7; ⁇ 17/abn(17p).
  • the AML has the genetic abnormality Complex karyotype, ⁇ monosomal karyotype
  • synergistic effect refers to action of two or three therapeutic agents producing an effect, for example, slowing the progression of a proliferative disease, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compound and which typically are not biologically or otherwise undesirable.
  • the compound may be capable of forming acid addition salts by virtue of the presence of an amino group.
  • reference to therapeutic agents useful in the pharmaceutical combination of the present invention includes both the free base of the compounds, and all pharmaceutically acceptable salts of the compounds.
  • combination or “pharmaceutical combination” is defined herein to refer to either a fixed combination in one dosage unit form, a non-fixed combination or a kit of parts for the combined administration where the therapeutic agents may be administered together, independently at the same time or separately within time intervals, which preferably allows that the combination partners show a cooperative, e.g.
  • the single compounds of the pharmaceutical combination of the present invention could be administered simultaneously or sequentially.
  • the pharmaceutical combination of the present invention may be in the form of a fixed combination or in the form of a non-fixed combination.
  • the term “fixed combination” means that the therapeutic agents, e.g., the single compounds of the combination, are in the form of a single entity or dosage form.
  • the term “non-fixed combination” means that the therapeutic agents, e.g., the single compounds of the combination, are administered to a patient as separate entities or dosage forms either simultaneously or sequentially with no specific time limits, wherein preferably such administration provides therapeutically effective levels of the two therapeutic agents in the body of the subject, e.g., a mammal or human in need thereof.
  • the pharmaceutical combinations can further comprise at least one pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition comprising the pharmaceutical combination of the present invention and at least one pharmaceutically acceptable carrier.
  • carrier or “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
  • compositions are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutical composition is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human.
  • the present pharmaceutical combinations can be formulated in a suitable pharmaceutical composition for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulating, sugar-coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units.
  • the pharmaceutical composition may contain, from about 0.1 % to about 99.9%, preferably from about 1 % to about 60 %, of the therapeutic agent(s).
  • One of ordinary skill in the art may select one or more of the aforementioned carriers with respect to the particular desired properties of the dosage form by routine experimentation and without any undue burden.
  • the amount of each carriers used may vary within ranges conventional in the art.
  • the following references disclose techniques and excipients used to formulate oral dosage forms. See The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003).
  • These optional additional conventional carriers may be incorporated into the oral dosage form either by incorporating the one or more conventional carriers into the initial mixture before or during granulation or by combining the one or more conventional carriers with granules comprising the combination of agents or individual agents of the combination of agents in the oral dosage form.
  • the combined mixture may be further blended, e.g., through a V-blender, and subsequently compressed or molded into a tablet, for example a monolithic tablet, encapsulated by a capsule, or filled into a sachet.
  • the pharmaceutical combinations of the present invention can be used to manufacture a medicine.
  • the present invention relates to such pharmaceutical combinations or pharmaceutical compositions that are particularly useful as a medicine.
  • the combinations or compositions of the present invention can be applied in the treatment of haematological malignancies, e.g. AML or MDS, e.g. AML, e.g. unfit AML.
  • the present invention also relates to use of pharmaceutical combinations or pharmaceutical compositions of the present invention for the preparation of a medicament for the treatment of a haematological malignancies, e.g. AML or MDS, e.g. AML, e.g. unfit AML, and to a method for treating haematological malignancies, e.g. AML or MDS, e.g. AML, e.g.
  • treatment comprises a treatment relieving, reducing or alleviating at least one symptom in a subject, increasing progression-free survival, overall survival, extending duration of response or delaying progression of a disease.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer.
  • treatment also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease in a patient, e.g., a mammal, particularly the patient is a human.
  • treatment as used herein comprises an inhibition of the growth of a tumor incorporating a direct inhibition of a primary tumor growth and / or the systemic inhibition of metastatic cancer cells.
  • a "subject,” “individual” or “patient” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human.
  • a therapeutically effective amount of a compound (e.g. chemical entity or biologic agent) of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
  • the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the optimal dosage of each combination partner for treatment of a cancer can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known in the art.
  • each combination partner that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the particular mode of administration.
  • the unit dosage forms containing the combination of agents as described herein will contain the amounts of each agent of the combination that are typically administered when the agents are administered alone. Frequency of dosage may vary depending on the compound used and the particular condition to be treated or prevented. In general, the use of the minimum dosage that is sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art.
  • HDM201 as a single agent led to a modest reduction of spleen size and leukemic density.
  • HDM201 in combination with venetoclax resulted in a near complete depletion of the leukemic cells in spleen and significant reduction of spleen size comparable to na ⁇ ve animals, while venetoclax alone exhibited partial reduction of spleen size and leukemic density as compared to the vehicle control (See Figure 1).
  • HDM201 was tested at three dose levels (5, 10, and 20 mg/kg HDM201) in combination with venetoclax.
  • -75%Reg high degree of tumor regression
  • Example 2 CHDM201I12201 Clinical Study Rationale and design for study investigating HDM201 in combination with venetoclax and azacitidine:
  • the study will be a phase Ib/II open label dose confirmation, proof of concept study of siremadlin (HDM201) in combination with venetoclax plus azacitidine in Unfit Adult AML participants.
  • the primary purpose of this study is to assess whether siremadlin in combination with venetoclax plus azacitidine can enhance the clinical response in unfit AML patients without unacceptable levels of treatment-emergent toxicities. Two subpopulations of adult participants with unfit AML will be evaluated in separate arms.
  • Arm 1 participants who responded sub-optimally to first-line venetoclax plus azacitidine treatment
  • Arm 2 participants with newly diagnosed untreated AML with adverse genetic risk stratification according to ELN 2017 (excluding mutant TP53).
  • the study treatment (siremadlin in combination with venetoclax plus azacitidine) will be administered in cycles with a planned duration of 28 days and will continue until the participants experience disease progression/relapse or unacceptable toxicity.
  • the study will enroll approximately 55 participants and will be conducted in two parts: Part 1 is the safety run in part with the objective to determine the recommended dose for expansion (RDE) of siremadlin when administered in combination with venetoclax plus azacitidine.
  • RDE recommended dose for expansion
  • Part 2 is the Expansion part to further asses the efficacy and safety of siremadlin RDE in combination with venetoclax plus azacitidine.
  • Study treatment will be administered in cycles with a planned duration of 28 days. Any participant who does not achieve at least Partial Response (PR) after taking siremadlin in combination with venetoclax plus azacitidine for a maximum of 4 cycles will discontinue study treatment.
  • PR Partial Response
  • siremadlin will be administered orally once daily from Day 1 to Day 5
  • venetoclax will be administered orally once daily at 400mg starting on Day 1 (following a ramp-up in Arm 2 only, as per the following table)
  • Azacitidine will be administered intravenously or subcutaneously at 75 mg/m 2 either from Days 1 to 7 or from Days 1 to 5, followed by administration Days 8 and 9 (at the discretion of the investigator following local institutional practice).
  • the participants will continue receiving their venetoclax and azacitidine doses that were evaluated as tolerable prior to study enrollment.
  • the siremadlin starting dose (dose level 1) will be 20 mg QD with dose level -1 at siremadlin 10 mg QD and dose level +1 and +2 respectively 30 and 40 mg QD.
  • dose level 1 For each dose level, once the required number of evaluable participants has been confirmed, enrollment will be halted in order to allow the participants to have completed the DLT observation period (1 cycle) and a Safety Review Meeting has been conducted.
  • the participating investigators and the Novartis Team will make decisions regarding siremadlin dose as guided by a Bayesian Logistic Regression model (BLRM).
  • BLRM Bayesian Logistic Regression model
  • the RDE will be determined separately (including safety data from the other arm, if available).
  • Novartis Upon confirmation of the applicable RDE in each arm, Novartis will provide notification to the investigational sites indicating that Part 2 (expansion) is open to enrollment. Enrollment to Part 2 will continue until a total of 25 evaluable participants (including those in the safety run-in) are enrolled at the RDE in Arm 1. An additional 6 participants (approximately) will be enrolled in the expansion part of Arm 2.
  • the assignment of a participant to a treatment arm and dose cohort will be captured in the interactive response technology (IRT) system and coordinated by Novartis.
  • IRT interactive response technology
  • C1D1 Cycle 1 Day 1
  • C1D3 Cycle 1 Day 3
  • TLS tumor lysis syndrome
  • participants unable to tolerate one or two of the study drugs may continue to receive only the tolerated drug(s) considering the participants benefits/risk balance of continuing the drug(s) as per the investigator’s judgement.
  • All participants will also be followed for safety for 30 days after the last dose of study treatment. All participants who discontinued study treatment will enter a long-term follow-up (for efficacy and/or survival status) as described in the study flow diagram of Figure 3.
  • Study Flow The study flow is comprised of 3 periods: Pre-treatment (screening), treatment and follow-up. Participants will undergo assessments during screening and periodically during treatment and follow-up as shown in the study flow chart of Figure 4.
  • Rationale Siremadlin is a novel investigational agent with single-agent activity in AML participants. Studies have shown that there is rationale to combine siremadlin with other agents such as selective Bcl- 2 inhibitors in AML to improve single agent anti-leukemic activity. The planned clinical trial will seek to extend these preliminary findings of efficacy by evaluating siremadlin in combination with the Bcl-2 inhibitor venetoclax and the HMA (hypomethylating agent) azacitidine.
  • Bcl-2 inhibitor venetoclax and the HMA (hypomethylating agent) azacitidine.
  • siremadlin and venetoclax are currently being evaluated in a Phase 1b, multi-arm, open level study [CHDM201H12101C] in adult patients with AML or high risk MDS.
  • the selection of the dose and regimen for siremadlin is based on the currently available preclinical and clinical safety, efficacy, and PK information from the single agent first-in- human clinical trial [CHDM201X2101] and [CHDM201H12101C], while for venetoclax, the dose and regimen are selected from clinical data available for venetoclax trials in AML (i) Konopleva M, Pollyea DA, Potluri, J, et al (2016) Efficacy and Biological Correlates of Response in a Phase II study of venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia models.
  • study [CHDM201H12101C] the PK exposures and parameters of siremadlin at doses of 20 mg and 30 mg on days 1 to 5 of each cycle in combination with venetoclax (400 mg QD) were comparable to historical siremadlin single agent data [CHDM201X2101].
  • Study Population The study population will include approximately 55 patients with AML who are ineligible for chemotherapy, and who either responded sub-optimally to first line venetoclax plus azacitidine treatment or have newly diagnosed untreated AML presenting with high-risk clinical features.
  • Inclusion Criteria 1 Signed Informed consent must be obtained prior to participation in the study 2. Age greater than or equal to 18 years at the date of signing the informed consent form (ICF) 3.
  • Arm 2 newly diagnosed AML presenting with high-risk clinical features: newly diagnosed AML with adverse genetic risk stratification (according to ELN 2017) (except TP53 mutation positive participants). 4. Participants in both arms must be considered ineligible for standard of care standard (intensive) induction chemotherapy.
  • Ineligibility is defined by the following: - 75 years of age or greater OR - from 18 to 74 years of age with at least one of the following co-morbidities: i) Eastern Cooperative Oncology (ECOG) Performance Status of 2 or 3; ii) Cardiac History of congestive heart failure requiring treatment or Ejection Fraction less than or equal to 50%, or chronic stable angina; iii) DLCO less than or equal to 65% or FEV1 less than or equal to 65% 5.
  • Participants with antecedent of myelodysplastic syndromes (MDS), myelofibrosis, essential thrombocythemia, polycythemia vera or therapy related AML may be included in the study, provided no prior therapy, as specified in the exclusion criteria.
  • WBC ⁇ 25x10 9 /L may be reduced with leukopheresis or hyroxyurea.
  • Participant is able to communicate with the investigator, and has the ability to comply with the requirements of the study procedures. Key Exclusion Criteria Participants meeting any of the following criteria are not eligible for inclusion in this study. 1. Prior exposure to MDM-inhibitor therapy at any time. 2. Participants with TP53 mutation positive, as defined by local TP53 testing. 3. Participants with del17p. 4. Previous treatment at any time, with any of the following antineoplastic agents, approved or investigational; checkpoint inhibitors, venetoclax and hypomethylating agents (HMAs) such as decitabine or azacitidine.
  • HMAs hypomethylating agents
  • CNS central nervous system
  • Participants who are receiving adjuvant therapy such as hormonal therapy or long-term maintenance therapy who have no residual disease for at least 1 year are eligible.
  • Treatment Duration A participant may continue study treatment as scheduled unless: - They fail to achieve at least PR after taking siremadlin in combination with venetoclax plus azacitidine for a maximum of 4 cycles Or until: - They experience progressive disease, or relapse from CR or CRi - They experience unacceptable toxicity -
  • the initiation of a treatment cycle is delayed due to toxicities by more than 28 days (measured from the intended start date of the new cycle (i.e.
  • HSCT Hematopoietic Stem Cell Transplant

Abstract

L'invention concerne une combinaison pharmaceutique comprenant un inhibiteur de MDM2, un inhibiteur de BCL2 et un agent d'hypométhylation. La présente invention concerne également des méthodes de traitement de malignités hématologiques impliquant ladite combinaison.
PCT/IB2022/059973 2021-10-19 2022-10-18 Combinaisons pharmaceutiques comprenant un inhibiteur de mdm2, un inhibiteur de bcl2 et un agent d'hypométhylation et leurs utilisations pour le traitement de malignités hématologiques WO2023067483A1 (fr)

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