RU2793123C2 - Hdm2-p53 inhibitor and bcl2 inhibitor interaction combinations and their use for cancer treatment - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: use of co-crystal succinic acid: (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 [HDM201] with a ratio of 1:1 (molar ratio), in the treatment of wild-type acute myeloid leukemia (AML) TP53, wherein the treatment further comprises administering a BCL2 inhibitor, which is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(oxan-4-yl)methyl]amino}phenyl)sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide [venetoclax], where a co-crystal with a succinic acid:HDM201 ratio of 1:1 (molar ratio) is administered on days 1-5 of a 28-day treatment cycle and where a co-crystal with a ratio of succinic acid:HDM201 of 1:1 (molar ratio) is administered at a dose of 20, 30 or 40 mg (expressed as HDM201 free base) on the days of administration, and where venetoclax is administered per daily dose from 300 mg to 600 mg.

EFFECT: treatment of wild-type acute myeloid leukemia (AML) TP53.

15 cl, 9 dwg, 3 tbl, 3 ex

Description

FIELD OF THE INVENTION

The present invention relates to a drug that is a combination inhibitor of the HDM2-p53 interaction, which is (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]imidazole-4- he [HDM201], and a BCL2 inhibitor, which is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N -[(3-nitro-4-{[(oxan-4-yl)methyl]amino}phenyl)sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide [venetoclax]. The present invention further relates to the use of said combination in the treatment of cancer, in particular hematological malignancies. The present invention also relates to the dose and dosing regimen related to this combination for the treatment of cancer.

BACKGROUND OF THE INVENTION

HDM201

p53 is induced and activated by a range of potentially oncogenic processes, including aberrant growth signals, DNA damage, ultraviolet radiation, and protein kinase inhibitors (Millard M, et al. Curr Pharm Design 2011;17:536-559), and regulates genes that control cell growth, DNA repair, apoptosis and angiogenesis (Bullock AN & Fersht AR. Nat Rev Cancer 2001;1:68-76; Vogelstein B, et al. Nature Education 2010;3(9):6).

Human Double Minute-2 (HDM2) is one of the most important p53 regulators. It binds directly to p53, inhibiting its transactivation and subsequently leading to its degradation in the cytoplasm (Zhang Y, et al. Nucleic Acids Res 2010;38:6544-6554).

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

In preclinical and in vivo cell models, potent and selective inhibitors of the HDM2-p53 interaction (also referred to as HDM2 inhibitors or MDM2 inhibitors), such as NVP-HDM201 (herein referred to as HDM201), have been shown to restore p53 function (Holzer P, et al . al Poster presented at AACR 2016, Abstract #4855, Holzer P, Chimia 2017, 71(10), 716-721). HDM201, which is an inhibitor of HDM2, i.e. (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2- (2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one and methods for its preparation have been disclosed, for example, in WO2013/ 111105.

Various dosing regimens have been described for HDM2 inhibitors and tested in clinical studies.

For example, US2013/0245089 discloses a method of treating a patient suffering from cancer by administering to the patient 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluorophenyl)-3-(3-chloro -2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino}-3-methoxybenzoic acid in an amount of from about 800 to about 3000 mg/day during an administration period of not more than about 7 days, days 1-7, of a 28 day treatment cycle followed by a rest period of about 21 to about 23 days.

B. Higgins et al. in Clinical Cancer Research in May 2014 (Higgins B. et al, Preclinical Optimization of MDM2 Antagonist Scheduling for Cancer Treatment by Using a Model-Based Approach. Clin Cancer Research 2014; 20:3742-3752 discloses a 28-day cycle schedule , in which RG7388 is administered once a week three times followed by 13 days of rest (28-day cycle schedule), or in which the drug is administered for 5 consecutive days of a 28-day schedule.

Additional dosing regimens for HDM2 inhibitors, such as intermittent high dose regimens and long-term low dose regimens, are described in WO 2015/198266, WO 2018/092020 and WO 2018/178925.

However, prolonged platelet depletion and/or disease resistance-limiting effect of drugs on bone marrow blasts in later treatment cycles is a common problem in HMD2 inhibitor therapies. Therefore, there remains a need to optimize the doses and schedules of these anti-cancer drugs to minimize side effects.

Venetoclax

Venetoclax is a highly active selective inhibitor of the anti-apoptotic protein of B-cell lymphoma (BCL)-2. Venetoclax directly binds to the BH3-binding groove of BCL-2, displacing pro-apoptotic BH3 motif-containing proteins like BIM to initiate mitochondrial outer membrane permeabilization (MOMP), caspase activation, and programmed cell death. Bcl-2 is an anti-apoptotic protein from the Bcl-2 protein family, which includes, in particular, Mcl-1 and Bcl-xL. Like Mcl-1 and Bcl-xL, Bcl-2 can bind pro-apoptotic effector molecules such as Bax/Bak and prevent their oligomerization and formation of transmembrane pores in the mitochondrial membrane. Due to this, Bcl-2 prevents the release of cytochrome C, thereby blocking the activation of caspases and, as a result, inhibits apoptosis. Apoptosis evasion is one of the key phenotypic hallmarks of cancer, so anti-apoptotic proteins such as Bcl-2, direct mediators of this evasion process, represent a potential therapeutic target (Certo et al. 2006). Venetoclax is a highly selective, orally bioavailable, small molecule Bcl-2 inhibitor that has been shown to be active 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 samples from a subject both in vitro and in xenograft mouse models (Pan et al. 2014).

Venetoclax-based monotherapy has been approved by the FDA for the treatment of CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma) with or without a 17p deletion that has or has not received at least one prior therapy [venetoclax US PI]. In Europe, venetoclax has been approved by the EMA for the treatment of CLL in the presence of a 17p deletion or TP53 mutation in adult subjects who have not received or are inappropriate B cell receptor pathway inhibitor therapy; for the treatment of CLL in the absence of a 17p deletion or TP53 mutation in adult subjects who have not been subjected to both chemoimmunotherapy and B-cell receptor pathway inhibitor therapy [venetoclax EU SmPC].

Venetoclax has been studied in AML/MDS, in phase I/II and in phase III clinical trials in both subjects with

AML unsuitable for standard induction chemotherapy and relapsed/refractory patients, and

for subjects with high-risk MDS, either alone or in combination with standard treatment and/or targeted therapies ([NCT01994837], [NCT02670044], [NCT03214562], [NCT02287233],

[NCT03069352], [NCT02993523], [NCT02966782], [NCT02942290], and [NCT03404193]).

In monotherapy, venetoclax is moderately active with CR/CRi ratios of 19% (6/32 subjects) in subjects with

R/R or chemotherapy ineligible subjects with AML (Konopleva et al. 2016). For combination with a hypomethylating agent or low dose aracitin (LDAC) for AML subjects not eligible for chemotherapy, CR/CRi ratios of 59-62% are reported.

Combination

Cancer monotherapies are often affected by a lack of sustained efficacy and/or safety. Combination cancer therapies based on a combination of partners that exhibit a synergistic effect provide the advantage of a significant increase in long-term efficacy and an improved safety profile. For this reason, there remains a need for research into a combination of anticancer drugs.

BRIEF DESCRIPTION OF THE INVENTION

A new combination for the treatment of cancer has been created: the drug HDM201, which is an inhibitor of the HDM2-p53 interaction , and venetoclax, which is a BCL2 inhibitor.

One type of dosing regimen has been found to be particularly useful for the treatment of hematological malignancies with HDM201, an inhibitor of HDM2, in combination with venetoclax.

In particular, the present invention provides the following aspects, advantageous features, and specific embodiments, respectively, alone or in combination, as listed in the following embodiments.

1. The combination of a drug that is an inhibitor of the HDM2-p53 interaction, which is (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 [ HDM201] or a pharmaceutically acceptable non-covalent derivative thereof (including a salt, solvate, hydrate, complex, co-crystal), and a BCL2 inhibitor, which is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1- en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(oxan-4-yl)methyl]amino}phenyl)sulfonyl]-2-[(1H-pyrrolo [2,3-b]pyridin-5-yl)oxy]benzamide [venetoclax] or a pharmaceutically acceptable non-covalent derivative thereof (including salt, solvate, hydrate, complex, co-crystal).

2. Combination according to Embodiment 1 for use in the treatment of cancer.

3. A combination for use in the treatment of cancer according to Embodiment 2, wherein the cancer is hematoblastosis.

4. Combination for use in the treatment of cancer according to embodiment 3, wherein the hemoblastosis is acute myeloid leukemia (AML), preferably relapsed/refractory AML or first line (1L) AML (including both de novo and secondary AML).

5. Combination for use in the treatment of cancer according to embodiment 3, wherein the hemoblastosis is myelodysplastic syndrome (MDS), preferably high risk MDS (including high risk and very high risk MDS according to rIPSS (Revised International Predictive Scoring System)) .

6. A combination for use in the treatment of cancer according to any one of embodiments 2-5, wherein the cancer is a tumor expressing wild type TP53 .

7. Combination for use in the treatment of cancer according to any one of embodiments 3-6,

where HDM201 is administered on each of the first 3-7 days, preferably on each of the first 4-6 days, more preferably on each of the first 5 days of a 28 day treatment cycle;

where treatment with HDM201 consists of at least three 28 day treatment cycles,

where the daily dose of HDM201 drug for the first and second treatment cycles (i.e., induction cycles) is 50 mg to 100 mg, preferably 50 mg to 80 mg, more preferably 60 mg to 80 mg, even more preferably 60 mg , and the daily dose of HDM201 for the third and any of the subsequent treatment cycles (i.e., consolidation cycles) is 10 mg to 45 mg, preferably 20 mg to 40 mg, more preferably 30 mg to 40 mg, even more preferably 40 mg.

8. A combination for use in the treatment of cancer according to any one of embodiments 3-6,

where HDM201 is administered on each of the first 5 days of a 28 day treatment cycle,

where treatment with HDM201 consists of at least three 28 day treatment cycles, and

where the daily dose of HDM201 in induction cycles (cycles 1 and 2) is 60 mg to 80 mg, and where the daily dose of HDM201 in consolidation cycles (cycles 3 and subsequent) is 40 mg.

9. Combination for use in the treatment of cancer according to any one of embodiments 3-8,

where venetoclax is administered in a daily dose of 20 mg to 1000 mg, preferably 50 mg to 600 mg, more preferably 300 mg to 600 mg, even more preferably 400 mg to 600 mg, even more preferably 400 mg or 600 mg .

10. A combination for use in the treatment of cancer according to any one of embodiments 3-6,

where HDM201 is administered on each of the first 5 days of a 28-day treatment cycle, where treatment with HDM201 consists of at least three 28-day treatment cycles, where the daily dose of HDM201 in induction cycles (cycles 1 and 2) is from 60 mg to 80 mg, and where the daily dose of HDM201 in consolidation cycles (cycles 3 and thereafter) is 40 mg, and

where venetoclax is administered in a daily dose of 400 mg or 600 mg.

11. Combination or combination for use in the treatment of cancer in accordance with any of the previous embodiments, where HDM201 is present as a non-covalent derivative, while preferably said non-covalent derivative is selected from the group consisting of salt, solvate, hydrate, complex and co-crystal, more than preferably the non-covalent derivative is a co-crystal, even more preferably present as a co-crystal with succinic acid, even more preferably present as a co-crystal with a ratio of succinic acid: HDM201 of 1:1 (molar ratio).

12. Combination or combination for use in the treatment of cancer according to any of the previous embodiments, wherein the combination further provides for one or more other anti-cancer agents, wherein preferably said anti-cancer agent(s) is(are) selected from immuno-oncological drugs (eg, PD-1 [eg, PDR001(Novartis, INN spartalizumab)], PD-L1, LAG-3, TIM-3 [eg, MBG453(Novartis)], GTIR inhibitors, TGF-beta, IL15), FLT3 inhibitors (eg, gilterinib, quisartinib, midostaurin), BCL2 inhibitors (eg, navitoclax, venetoclax), other HDM2 inhibitors (eg, idasanutlin, AMG232, DS-3032B, ALRN6924/ATSP7041), hypomethylating agents (HMAs) (eg, Vidaza [azacytidine , 5-azacytidine], Dacogen [decitabine], guadecitabine), anthracyclines (eg, idarubicin, daunorubicin, doxorubicin, epirubicin, rubidomycin); anti-CD33 antibodies (eg, Mylotarg [gemtuzumab], vadastuximab) and others (eg, AraC [cytarabine, aracitin]).

13. A combination or combination for use in the treatment of cancer according to any of the previous embodiments, wherein the combination further comprises one or more other anticancer agents, preferably said anticancer agent(s) selected from cytarabine ( Ara-C), anthracycline, daunorubicin, idarubicin, rubidomycin, idamycin, midostaurin and azacitidine.

The combination therapy of the present invention provides the advantage of substantially increased long-term efficacy and an improved safety profile.

The dosing regimens of the present invention described above provide a very favorable therapeutic index, low incidence of grade 3/4 thrombocytopenia while achieving therapeutically relevant plasma levels, p53 pathway activation (upregulation of GDF-15) and clinical activity.

In particular, the dosing regimens described above of the present invention provide an acceptable response of bone marrow (BM) blasts during the first two treatment cycles, while providing effective safety in subsequent treatment cycles (cycle 3 and subsequent), see figure 3, option 2 and figures 6-7.

BRIEF DESCRIPTION OF GRAPHICS

Hereinafter, the present invention is described in detail with reference to the accompanying figures, which depict the following.

Figure 1 shows an example of individual platelet (PLT) curves (Scheme 2C, i.e. d1-7q28d, 45 mg) from the CHDM201X2101 clinical study.

Figure 2 shows that the effect of the 2C dosing schedule (d1-d7q28d, daily dose of 45 mg HDM201) on the PLT curve is limited without recovery. Prolonged platelet depletion, PLT (G/L), versus time (d), median and interquartile range. Figure 2 also shows the effect of the dosing schedule on blast kinetics: Schedule 2C with a daily dose of 45 mg HDM201 provides good depletion of BM blasts. Early and maximum decrease in the level of neutrophils due to chemotherapy. (%) of BM blasts versus time (d).

The figure 3 shows the simulated curve for scheme 2C options 1, 2 and 3. Option 1: 60 mg (4 cycles); option 2: 60 mg (2 cycles) → 30 mg (2 cycles); option 3: 60 mg (2 cycles) → 0. Options 2-3 provide dose(s) to maximize BM blast response during the first 2 cycles with safety controls in subsequent cycles (cycles 3 and 4).

Figures 4-7 show modeling of platelet blast (PLT) and bone marrow (BM) scores from HDM201X2101 dose(s) to maximize BM blast response during the first 2 cycles with safety controls in subsequent cycles (cycles 3-5).

Figure 8 : Brief description of the anti-leukemic effect of the combination of HDM201 and venetoclax.

HDM201 enhances the antitumor activity of the selective Bcl-2 inhibitor venetoclax in an orthotopic AML patient model. NVP-HDM201 was administered po at 20 mg/kg 3 times a day of dosing, once a week either alone or in combination with venetoclax (ABT-199) po at 100 mg/kg once a day, 5 times a week, for 14 days. Initial group size: 5 animals.

(A) Mean leukemic load is plotted as a plot of peripheral blood CD45+ cells over time over a 14-day treatment period for each treatment group.

(B) Spleen weight and IHC staining of leukemic tissue density in the spleen. IHC analysis using a monoclonal primary mouse anti-human IDH1 antibody to the mutant IDH1R132H protein.

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

Figure 9 : Dosing of HDM201 in combination with venetoclax.

The effects of the combination on platelets can be mitigated by administering lower doses of HDM201 while maintaining antitumor activity. NVP-HDM201 was administered po at 5 mg/kg, 10 mg/kg, and 20 mg/kg 3 times a day of dosing, once a week, either alone or in combination with venetoclax (ABT-199) po at a dose of 100 mg/kg once a day, 5 times a week, for 3-6 weeks. Initial group size: 4 animals.

(A) Mean leukemia load is plotted as a plot of peripheral blood CD45+ cells over time.

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

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the present invention is described in more detail and illustrated in the examples.

Definitions

Additional terms are defined below and throughout this application.

As used herein, the singular forms refer to one or more (for example, to at least one) grammatical form objects.

The term "or" is used herein to mean the term "and/or" and is used interchangeably with it, unless the context clearly indicates otherwise.

The expressions "approximately" and "approximately" will generally mean an acceptable degree of error for the quantity being measured, taking into account the nature or accuracy of the measurements. Illustrative degrees of error are within 20 percent (%), typically within 10%, and in most cases within 5% of a given value or range of values.

The terms "combination" or "in combination with" are not intended to imply that the therapy or therapeutic agents must be administered at the same time and/or formulated for delivery together, although these delivery methods are within the scope described herein. document. Therapeutic agents in combination can be administered simultaneously with one or more additional therapies or therapeutic agents, before or after them. Therapeutic agents or therapeutic protocol can be applied in any order. Typically, each agent will be administered at a dose and/or time schedule that is determined for that agent. It should also be understood that the additional therapeutic agent used in this combination may be administered together in the same composition or administered separately in different compositions. In general, it is expected that additional therapeutic agents used in combination will be used at levels that do not exceed the levels at which they are used separately. In some embodiments, levels used in combination will be lower than levels when used alone.

HDM201 is defined by the following chemical names and structure.

HDM201:

Venetoclax is defined by the following chemical names and structure.

Venetoclax is available under the brand name Venclyxto in 10 mg, 50 mg and 100 mg film-coated tablets.

The term "HDM2-p53 interaction inhibitor" or "HDM2 inhibitor" for short, also referred to as "HDM2i", "Hdm2i", "MDM2 inhibitor", "MDM2i", "Mdm2i", means in this document any compound that inhibits HDM interaction -2/p53 or HDM-4/p53 with an IC ₅₀ of less than 10 μM, preferably less than 1 μM, preferably in the nM range as measured by time resolved fluorescence energy transfer (TR-FRET) analysis. Inhibition of p53-Hdm2 and p53-Hdm4 interactions is measured by time resolved fluorescence energy transfer (TR-FRET). Fluorescence energy transfer (or Förster resonant energy transfer) describes the energy transfer between donor and acceptor 5 fluorescent molecules. For this assay, an MDM2 protein (amino acids 2-188) and an MDM4 protein (amino acids 2-185) labeled with a C-terminal biotin fragment are used in combination with europium labeled streptavidin (Perkin Elmer, Inc., Waltham, Massachusetts, USA), which serves as a donor fluorophore. A Cy5 labeled peptide derived from p53, Cy5-TFSDLWKLL (aa 18-26 from p53), is an energy acceptor. Upon excitation of the donor molecule 10 at 340 nm, the binding interaction between MDM2 or MDM4 and the p53 peptide causes energy transfer and an enhanced response at the acceptor emission wavelength at 665 nm. Violation of the formation of the p53-MDM2 or p53-MDM4 complex due to the binding of the inhibitor molecule to the p53 binding site in MDM2 or MDM4 leads to increased donor radiation at 615 nm. FRET ratiometric readings are calculated from 15 raw data of two separate fluorescence signals measured in time-resolved mode (emission at 665 nm/emission at 615 nm x 1000). The analysis can be performed according to the following procedure. The assay is carried out in 1536w white microtiter plates (Greiner Bio-One GmbH, Frickenhausen, Germany) in a total volume of 3.1 µl by pooling 100 nl of compounds diluted in 90% DMSO/10% H2O (final DMSO concentration 3.2%), with 2 µl europium 20 labeled streptavidin (final concentration 2.5 nM) in reaction buffer (PBS, 125 mM NaCl, 0.001% Novexin (consists of carbohydrate polymers (Novexin polymers) designed to increase the solubility and stability of proteins; Novexin Ltd ., Cambridgeshire, UK), 0.01% gelatin, 0.2% pluronic (block copolymer of ethylene oxide and propylene oxide, BASF, Ludwigshafen, Germany), 1 mM DTT) followed by the addition of 0.5 µl of MDM2-Bio or MDM4- Bio diluted in assay buffer (final concentration 10 nM). The solution is left to pre-incubate for 15 minutes at room temperature followed by the addition of 0.5 μl of Cy5 p53 peptide in assay buffer (final concentration 20 nM). The plate is incubated at room temperature for 10 minutes before reading. Samples were measured using an Analyst GT multi-mode microplate reader (Molecular Devices) with the following settings of 30: dichroic mirror 380 nm, excitation at 330 nm, donor emission at 615 nm, and acceptor emission at 665 nm. IC50 values are calculated by curve fitting using XLfit. Unless otherwise noted, reagents were purchased from Sigma Chemical Co, St. Louis, MO, USA.

The HDM2 inhibitor according to the present invention is HDM201, i.e. (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl )-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one.

HDM201 may be present as a free molecule or as any other non-covalent derivative, including a salt, solvate, hydrate, complex, co-crystal, or mixtures thereof. HDM201 may be present as an acid derivative. The acid derivative may be a salt formed by HDM201 and an acid, or an acid complex of HDM201, or a co-crystal of an acid and HDM201. Preferably, HDM201 is present as a co-crystal. Preferably, the acid is succinic acid. Most preferably HDM201 is present as a co-crystal with succinic acid. Non-covalent derivatives of HDM201 are described in WO2013/111105.

In preferred embodiments, HDM201 is referred to as

succinic acid - (6S) -5- (5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl) -6- (4-chlorophenyl) -2- (2,4-dimethoxypyrimidine- 5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one (1:1).

When referring to a dose of HDM201 herein, for example, in mg (milligrams), the amount of HDM201 is in the form of a free base and not a salt, solvate, complex, or co-crystal.

The term "hematologic tumor" refers herein to cancer that begins in hematopoietic tissue, such as bone marrow, or cells of the immune system. Examples of 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 types of leukemia. More preferably, hematologic 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 hematologic tumors of the present invention are wild-type TP53 hematologic tumors. More preferably, the wild-type TP53 hematological tumors of the present invention are wild-type TP53 leukemia species. Even more preferably, wild-type TP53 hematologic tumors are selected from wild-type TP53 acute myeloid leukemia (AML), wild-type TP53 myelodysplastic syndrome (MDS), and wild-type TP53 acute lymphoblastic leukemia (ALL). Even more preferably, the wild-type TP53 hematologic tumor is AML with wild-type TP53 and/or MDS.

In accordance with the present invention, the HDM201 drug is administered on each of the first 3-7 days of a 28-day (4-week) treatment cycle, preferably the drug is administered on each of the first 4-6 days of a 28-day treatment cycle, more preferably on the first 5 days of a 28-day treatment cycle.

"On each of the first 5 days of a 28-day treatment cycle" means that HDM201 is administered to the patient on day 1 (d1), d2, d3, d4, and d5 followed by a drug-free period (also called a drug holiday or rest period) from day 6 to day 28. The next treatment cycle starts on day 29, which would be d1 of that next treatment cycle.

Preferably, the drug is administered at approximately the same time on each day of administration (ie, d1-d5 of a 28 day cycle). Preferably, the drug is administered once a day (qd) on each day of administration. More preferably, the drug is administered in the morning.

Preferably, the drug is administered on an empty stomach, i.e. at least 1 hour before or 2 hours after a meal.

Preferably, the drug is taken with a glass of water and without chewing the capsules or tablets.

If a patient is assigned a dose level at which multiple capsules/tablets are to be taken, the capsules/tablets should be taken sequentially within the shortest possible interval, eg within 5 minutes.

Preferably, the drug is administered by oral delivery, i.e. oral administration, orally (p. o.).

Preferably, the drug is presented as an oral dosage form, more preferably as a solid oral dosage form, for example, a capsule or tablet.

When dose ranges are given herein, e.g. "daily dose of the drug is from 50 mg to 100 mg", it should be understood that this discloses any whole number of mg endpoints and between these endpoints, for example, 50 mg , 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, ... 98 mg, 99 mg, 100 mg.

As a further aspect of the present invention, the following is provided.

The combination of HDM201 and venetoclax according to any of the embodiments described herein, wherein said combination is combined with one or more other/additional anti-cancer agents, preferably said anti-cancer agent(s) is(are) selected from immuno-oncological drugs agents (eg, PD-1 [eg, PDR001 (Novartis, INN spartalizumab)], PD-L1, LAG-3, TIM-3 [eg, MBG453 (Novartis)], GTIR inhibitors, TGF-beta, IL15), inhibitors FLT3 (eg, gilterinib, quisartinib, midostaurin), BCL2 inhibitors (eg, navitoclax, venetoclax), other HDM2 inhibitors (eg, idasanutlin, AMG232, DS-3032B, ALRN6924/ATSP7041), hypomethylating agents (HMA) (eg, Vidaza [ azacitidine, 5-azacytidine], Dacogen [decitabine], guadecitabine), anthracyclines (eg, idarubicin, daunorubicin, doxorubicin, epirubicin, rubidomycin); anti-CD33 antibodies (eg, Mylotarg [gemtuzumab], vadastuximab) and others (eg, AraC [cytarabine, aracitin]).

Preferably, the combination of HDM201 and venetoclax is combined with one or more therapeutically active agents selected from cytarabine (Ara-C), anthracycline, daunorubicin, idarubicin, rubidomycin, idamycin, midostaurin and aracitin.

In particular, in another preferred embodiment, the combination of HDM201 and venetoclax is combined with a TIM-3 inhibitor, preferably a TIM-3 inhibitor, which is MBG453 (Novartis). TIM-3 inhibitors, such as MBG453, are described in WO 2015/117002, the entire content of which is incorporated herein by reference.

Other/additional active agents may be dosed on the same day(s) as HDM201 or on days on which HDM201 is not dosed.

The secondary medical uses described in the embodiments of the present invention may be formulated in the following various alternative formats.

Combination of HDM201 and venetoclax for use in cancer treatment.

A method for treating cancer in human patients in need of such treatment, which comprises administering an effective amount of a combination of HDM201 and venetoclax.

The use of a combination of HDM201 and venetoclax for the manufacture/obtainment of a drug intended for the treatment of cancer.

A drug intended for the treatment of cancer containing a combination of HDM201 and venetoclax.

EXAMPLES

Example 1 . Simulation of HDM201 dosing schedule

Platelet model

Based on PK/PD population modeling data from the CHDM201X2101 clinical study, a platelet model in patients with AML was developed, which confirms that the disease affects the regulation of platelet production. The model clarifies the following graph.

Bone marrow blast model

A PKPD model of bone marrow blasts has been developed that recognizes a delayed effect, loss of effect over time reproduced by the resistance component, and that concentrated administration reduces the effect of resistance. The model clarifies the following graph.

Derivation of key indicators from simulated curves of platelets and blasts

The population PK/PD models of Examples 1 and 2 were used to model PK, platelet and blast curves over time with inter-individual variability.

The effect of changing dosing schedules on these curves was studied.

The modeling took into account: cycle duration, dose level, number of injections, duration of treatment, induction/consolidation period.

The key indicators were: the proportion of patients with a platelet count below/above a given threshold depending on time, the proportion of patients above the PK threshold, the number of days with a number of blasts below the baseline.

The simulation was carried out using R (statistical software) with the Shiny software package.

The PK/PD data set from CHDM201X2101 was used to build the model and NLME evaluation was performed (Monolix 4.3.2). The model structure and parameter estimates are presented below. This provided downloadable information for R/shiny. The mlxR software package was used to model the longitudinal study data from the MLXTRAN model.

Model Structure

Parameter estimates

The following were found as the main results of PKPD modeling.

• Prolonged depletion of platelets and

• long-term treatment (> 6 months) is not possible without dose reduction or interruption:

- progressive decrease in the number of platelets with increasing treatment cycles,

- the effect of the disease resistance limiting drug on blasts after cycles 3 or 4.

Modeling supported dose and regimen selection for phase 2 studies in AML.

As the clinical trial CHDM201X2101 has shown, problems with HDM210 dosing in AML are:

• cumulative platelet toxicity,

• delay in hematopoietic recovery preventing dosage consolidation that could pose a risk for this indication.

The present simulation provides adequate control of these issues with respect to

dose reduction after 1 or 2, preferably 2 cycles of induction.

The simulation was used to support the dose escalation strategy in the HDM201A2101 clinical trial: a new D1-D5 (4-week cycle) regimen was defined instead of the D1-D7 (4-week cycle) regimen. The following table provides details of the new dose increase and new dosing schedules.

Table 1 . Modeling of platelet (PLT) and bone marrow (BM) metrics from HDM201X2101

Cohort Dosing schedule for HDM201 induction
Cycles 1+2 Dosing schedule for HDM201 consolidation
Cycles
3-5 Mean % of Subjects Above Target [C] from Cycle 1 ¹ Mean % of subjects with at least 1 PLT value above the 50 g/L threshold ² Number of days with BM blast value below baseline ^2.3 Mean % of subjects with a decrease in PLT from baseline ≥ 50% ² Mean % of subjects with PLT decrease from baseline ≥ 75% ² -1A 60 mg D1 60 mg D1 3 [2.8-3.4] 3.2 [2.4-3.4] 7.8 [7.1-8.3] 29 [27.8-29.8] 12.6 [12.4-13.2] -1B 45 mg, D1-D2 45 mg, D1-D2 15.2 [14-16.2] 7.8 [7.4-8.2] 12.1 [11.4-13] 39.8 [38.8-40.7] 20.8 [20.4-21.4] Starting from 1 40 mg, D1-D3 40 mg, D1-D3 35 [34-35.6] 12.2 [11.8-12.6] 16.8 [15.6-17.3] 48.6 [48-49.3] 29.2 [27.9-29.6] 2 40 mg, D1-D5 40 mg, D1-D5 69.4 [69-69.9] 19.4 [19-19.8] 38.2 [33.9-41.8] 63.2 [62.8-63.6] 41 [40.2-41.6] 3 60 mg, D1-D5 40 mg, D1-D5 89.6 [88.9-90] 25.2 [24.6-25.8] 63.1 [58.8-65.9] 69.9 [69.2-70.4] 48.4 [47.4-49.1] 4 80 mg, D1-D5 40 mg, D1-D5 96.8 [96.4-97.2] 29.4 [28.2-30] 82 [77.8-86.2] 76.4 [74.9-78.8] 57.4 [56.1-59.7] Note: Scores represent the median (2.5 to 97.5% percentiles) of 100 replicates performed on 500 subjects.
¹ is the mean concentration for tumor stasis from a tumor growth inhibition (PK/PD) simulation in a rat xenograft model.
² indicator value calculated from day 1 to day 140.
³ subjects who did not show a decrease in blast count from baseline were excluded from the metric inference.

Example 2: Pre-clinical study

Example 2 In Vivo Pharmacological Properties of the Combination of HDM201 and Venetoclax

HDM201 has been shown to enhance the antitumor activity of the selective Bcl-2 inhibitor venetoclax in vivo in many orthotopic models of AML patients. In mice carrying the IDH1/FLT3-ITDα mutant, treatment with HDM201 alone showed minimal anti-cancer activity (92%T/C, p>0.05). Conversely, HDM201 in combination with venetoclax induced complete tumor regression (-100% reg.), while only partial tumor regression was observed with venetoclax alone (-9 to -52% reg.). See figures 8 and 9.

As observed in peripheral blood, there was also a decrease in the number of leukemic cells in the spleen based on the weight of the spleen and the IHC stain of IDH1 ^R132H -positive leukemic cells. HDM201 alone resulted in a slight decrease in spleen size and leukemic cell density. Conversely, HDM201 in combination with venetoclax resulted in an almost complete removal of leukemia cells from the spleen and a significant reduction in spleen size compared to untreated animals, while venetoclax alone provided a partial reduction in spleen weight and leukemia cell density compared to control treated with medium- carrier (See figure 8).

In an additional study, HDM201 was tested at three dose levels (5, 10 and 20 mg/kg HDM201) in combination with venetoclax. HDM201, administered at a dose 4 times lower (5 mg/kg compared to 20 mg/kg), in combination with venetoclax, increased platelet counts to levels comparable to those in untreated animals while maintaining a high degree of tumor regression ( -75% reg.) (see figure 9). These data indicate that the possible overlap in hematological toxicities of the combination could be improved by administering a lower dose of HDM201 while maintaining antitumor activity.

Example 3 . Clinical Study

Rationale and Design for Dose/Mode and Duration of Treatment with HDM201 in Combination with Venetoclax

This is an open-label, multi-arm, phase 1b study of HDM201 in combination with venetoclax in subjects with high-risk AML or MDS.

For all subjects, TP53wt status should be characterized by at least the absence of mutations noted in exons 5, 6, 7 and 8.

Subjects will receive HDM201 in combination with venetoclax.

The dose of venetoclax will be gradually increased (increased) over a period of 4-5 days until the target daily dose to be tested (either 400 or 600 mg) is reached, as shown in the following graph:

dose escalation (RU) of venetoclax during cycle 1 (treatment group 2: HDM201+ venetoclax)

Once subjects have received their planned target daily dose, they will continue to take that dose of venetoclax.

Doses of HDM201 may be increased (see Table 3-1 for preliminary dose levels to be tested). Given the possible cumulative safety effects associated with HDM201, subjects did not receive a dose of HDM201 in excess of the planned maximum dose of 40 mg per day (>200 mg/cycle) from cycle 3 onwards on repeat dosing.

Upon completion of the dose escalation portion, the MTD and/or RD of HDM201 in combination with venetoclax will be administered to high risk subjects with AML and MDS.

Study treatments were administered as 28-day courses of treatment.

Each treatment cohort will include cohorts with 3-6 subjects treated with HDM201+venetoclax prior to MTD and/or RD, and a dosing regimen will be determined for future use.

Additional cohorts of 1-10 subjects may be included in the previously tested and declared safe dose level for one or both indications to better understand the safety, tolerability, PK and pre-potency of investigational treatments.

This is the first trial that will evaluate the combination of HDM201 with venetoclax. It is possible that pharmacokinetic drug-drug interactions and the combination of HDM201 with venetoclax may be characterized by overlapping toxic effects.

In this study, dose and regimen selection for HDM201 is based on currently available information on preclinical and clinical safety, efficacy, PK- and PKPD modeling from the first human clinical trial CHDM201X2101 of a single agent, with the dose and dosing regimen of venetoclax selected from clinical data available for venetoclax trials in AML (Konopleva et al. 2016 and DiNardo et al. 2018).

A dose escalation approach will be pursued to determine the appropriate dose of HDM201 in combination with venetoclax. The initial test dose of HDM201 in combination with venetoclax will be 20 mg. HDM201 will be administered orally once a day from day 1 to day 5 of a 28 day cycle. Based on PBPK SimCyp simulations at a baseline dose of HDM201 of 20 mg (daily from day 1 to 5 of a 28-day cycle), in combination with venetoclax (continuously every day), a minimal effect of DDI was predicted with a predicted increase in venetoclax exposure by ~1.20 times (AUC) during the initial dose escalation phase and at steady state. With planned combination doses for HDM201 (40 or 60 mg daily from days 1 to 5, 28 day cycle) and venetoclax (continuously every day), a 2-fold increase in exposure (AUC and Cmax) of venetoclax was expected. However, the PK of venetoclax was expected to gradually return to expected levels within 3-5 days after the fifth and final administration of HDM201. This anticipated and limited increase in venetoclax exposure is unlikely to require dose adjustment of venetoclax during co-management with HDM201. In addition, venetoclax was administered no more than 1200 mg each day without reaching the maximum tolerated dose. Thus, even if increased exposure to venetoclax is expected during co-management with HDM201, the estimated impact is low.

To reduce the risk of TLS and DDI effects, venetoclax will be administered orally once each day continuously and the dose will be gradually increased during the first treatment cycle with a 4-5 day dose escalation period (RU) until the target daily dose of venetoclax per cohort is reached. Subjects will then continue to take this target daily dose of venetoclax.

For the phase 1b venetoclax target dose ([NCT02203773]), more than 10 AML subjects were treated with venetoclax 400 mg daily in combination with hypomethylating agents with a tolerable safety profile, and subjects in the cohorts are already taking 400 mg (daily) and high dose (800 mg intermittent dosing schedule) combination (DiNardo et al. 2018). In addition, several ongoing Phase 2 and Phase 3 R/R studies in subjects not eligible for high-risk AML and MDS chemotherapy tested venetoclax in combination with standard care (low-dose chemotherapy or hypomethylating agents) with venetoclax in the target dose of either 400 mg or 600 mg ([NCT03404193], [NCT02993523], [NCT03069352]). Based on the above, the study chose a daily target dose of venetoclax of either 400 mg or 600 mg daily.

Very low (<5%) incidence of TLS ([NCT01994837], [NCT02670044], [NCT03214562], [NCT02287233], [NCT02993523]). The goal of dose escalation is to gradually reduce tumor burden to reduce the risk of TLS, especially in light of the expectation that combinations of investigational drugs have a synergistic effect.

Several studies testing venetoclax either alone or in combination for AML and MDS have reported varying initial doses of either 20 mg, 50 mg, or 100 mg daily. In a phase 2 study testing venetoclax as a standalone agent, the initial dose was 20 mg daily with dose increases after 5 days and no TLS was observed ([NCT01994837]). In a phase 1b study ([NCT02203773]) testing venetoclax with hypomethylating agents, of the 57 enrolled subjects, only 10 started at a dose of venetoclax 20 mg, while others started at a higher dose (50 mg or 100 mg daily) with an increase after 5 days, with no reported TLS (DiNardo CD, Pratz KW, Letai A, et al (2018) Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid

leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol; 19(2):216-228). Another phase 1b/2 study testing venetoclax in combination with LDAC ([NCT02287233]) used 50 mg as the starting dose, increased over 5 days, and no cases of clinically significant TLS were reported (Lin TL, Strickland SA, Fiedler W, et al (2016) Phase Ib/2 study of venetoclax with low-dose cytarabine in treatment-naive patients age ≥ 65 with acute myelogenous leukemia J Clin Oncol; 34(15): suppl 7007-7007). Based on the above, the initial dose of venetoclax will be 50 mg daily, and dose escalation, mainly to be studied, will be carried out after 4 days with a daily target dose of venetoclax of 400 mg. Alternatively, dose escalation after 5 days with a daily target dose of venetoclax of 600 mg may be studied based on observed clinical safety and PK data according to the BHLRM. In this group, the dose of both HDM201 and venetoclax may be increased; however, only one of the two study drugs (ie HDM201 or venetoclax) will be increased at a given time. An increase in each of the two investigational medicinal products can be tested in parallel in two different reduced cohort size cohorts, in both cases the increase is permitted by the BHLRM (i.e., appropriate dose combinations are allowed).

Based on these preliminary safety data and DDI assumptions, the starting dose for the combination satisfies the EWOC criteria within the BHLRM.

Rationale for choosing combination medicines

The rationale for combining HDM201 and venetoclax is based on the following evidence.

• Preclinical evidence demonstrates that concurrent blocking of MDM2 and Bcl-2 has synergistic activity in samples from p53wt AML subjects and exhibits synergistic antitumor activity in various xenograft mouse models of AML (Example 2).

• Early clinical data from the MDM2 inhibitor, idasanutlin, in combination with venetoclax demonstrate preliminary activity in AML subjects (Daver N, Pollyea DA, Yee K, et al (2017) Preliminary Results from a Phase Ib Study Evaluating BCL-2 Inhibitor Venetoclax in Combination with MEK Inhibitor Cobimetinib or MDM2 Inhibitor Idasanutlin in Patients with Relapsed or Refractory (R/R) AML The American Society of Hematology -59th Annual Meeting and Exposition, Atlanta, Georgia).

population

The study was conducted on adult TP53wt patients with:

• R/R AML who did not have ≥ 1 previous regimen, or

• First-line AML ineligible for standard induction chemotherapy, or

• High-risk MDS not responding to treatment with a hypomethylating agent.

Only patients who met all of the following inclusion criteria and none of the exclusion criteria were treated in the study. National Cancer Institute version 5.0 CTCAE was used for all evaluations.

Inclusion Criteria

Patients eligible for inclusion in this study must meet all of the following criteria.

1. Male or female patients ≥ 18 years of age on the date of signing the informed consent form who had one of the following:

a. Patients with relapsed/refractory AML after ≥1 prior therapies (but ≤3 prior therapies) who relapse or present with symptoms of refractory disease (primary failure) and who are not considered candidates for standard therapy including cytarabine re-induction by the investigator or other prescribed chemotherapy regimens for patients with AML (excluded are patients who are eligible for standard chemotherapy with re-induction or hematopoietic stem cell transplantation and agree to receive them). In one embodiment, the AML is relapsed/refractory AML after one or more prior therapies in patients who relapse or show symptoms of a refractory disease (primary failure).

b. Patient with first-line AML not eligible for standard induction chemotherapy (including both de novo and secondary AML). Excluded are patients who are eligible for hematopoietic stem cell transplantation and agree to receive it. In another embodiment, the AML is first line AML, specifically in a patient(s) not eligible for standard induction chemotherapy (where AML includes both de novo and secondary AML).

c. High risk MDS in a patient (high and very high risk according to rIPSS) who has not been treated with a hypomethylating agent. In another embodiment, the MDS is the patient's high risk MDS (high and very high risk group according to rIPSS), specifically patients who have not been treated with a hypomethylating agent. ECOG) ≤ 1

3. The patient's tumor was TP53wt. At a minimum, exons 5, 6, 7, and 8 of the TP53 gene should be sequenced and determined to be mutation-free. TP53 status must be obtained from a bone marrow sample taken no more than 3 months prior to the signing of the main ICF.

4. Patients were candidates for serial bone marrow aspiration and/or biopsy according to departmental guidelines and underwent bone marrow aspiration and/or biopsy at screening, during and at the end of therapy in this study.

Main Exclusion Criteria

Patients eligible for inclusion in this study did not have to meet any of the following criteria.

• Prior combined treatment with compounds having the same mechanism of action:

- mdm2 or mdm4 inhibitors combined with Bcl-2 inhibitor

• History of severe hypersensitivity reactions to any ingredient of the investigational drug(s) and other monoclonal antibodies (mAbs) and/or their excipients.

• Patients with acute promyelocytic leukemia with PML-RARA.

• Allogeneic stem cell transplantation (HSCT) within the last 6 months and/or active GvHD requiring systemic immunosuppressive therapy.

• GI disorders that affect the absorption of orally taken HDM201 or venetoclax.

• Signs of active bleeding, or hemorrhagic diathesis, or primary coagulopathy (including familial).

Treatment and investigational medicinal products

For this study, the term "investigational drug" or "investigational treatment" refers to HDM201 or venetoclax. "Treatment group" or "study treatment" refers to a specific combination of treatments, ie, the combination of HDM201+venetoclax. The following investigational medicinal products were used in this study.

HDM201 capsules 10mg, 20mg, 40mg oral, 20mg (starting dose), day 1 to day 5 (28-day cycle), open-label study with patient-specific vials.

Venetoclax, 400 mg or 600 mg oral tablets, escalation from day 4 to day 5+daily (28-day cycle), open-label study with patient-specific vials; as far as available.

This study did not randomize.

HDM201 capsules were administered orally (p.o.) on an empty stomach at least 1 hour before or 2 hours after a meal. The subject was to take the capsules in the morning, at about the same time on each day of intake, with a glass of water and without chewing the capsules. If a subject was assigned a dose level at which multiple capsules were to be taken, then the capsules would be taken sequentially within as short an interval as possible. On visiting days, the subject will take HDM201 at the clinic under the supervision of the investigator or their designee, and on other days at home. If the subject has forgotten to take his/her daily dose, then he/she should resume taking the dose on the next scheduled day of dosing without making up for the missed doses. Any missed dose of investigational medicinal product must be reported to the investigator at the next study visit. HDM201 should be taken first.

Venetoclax film-coated tablets will be administered orally once a day according to local variations of label instructions. Subjects should be instructed to swallow the tablets whole with water at approximately the same time each day. Tablets should be taken with food (preferably during breakfast) to avoid the risk of insufficient effectiveness.

During the dose escalation period, venetoclax should be taken in the morning to facilitate laboratory monitoring.

If a subject misses a dose of venetoclax within 8 hours of their usual intake, the subject should take the missed dose as soon as possible on the same day. If the subject misses a dose of venetoclax within more than 8 hours, the subject should not take the missed dose and should continue on their usual dosing schedule at the usual time on the following days. However, if a missed dose occurs during the venetoclax escalation period, the subject should continue the missed dose the next day in order not to miss any venetoclax dose escalation during the escalation period.

On PK sampling days, the subject will be instructed to take his/her medication to the study site and dose at the clinic under the supervision of staff at the study site.

The subject could continue study treatment until the subject experienced unacceptable toxicity, disease progression (Cheson BD, Bennett JM, Kopecky K, et al (2003) Revised recommendations of the International Working Group (IWG) for diagnosis, standardization of response criteria , treatment outcomes, and reorting standards for therapeutic trials in acute myeloid leukemia J Clin Oncol 21(24):4642-9 and Cheson BD, Greenberg P, Bennett J, et al (2006) Clinical application and proposal for modification of the International Working Group (OWG) response criteria in myelodysplasia Blood 108:419-425). If more than 2 consecutive cycles of HDM201+venetoclax need to be missed due to study drug-related toxicity, then the drug combination should be completely discontinued.

Dose escalation and dose modification

Initial dose

The choice of starting dose and dosing regimen for HDM201 at dose escalation is based on a previous phase I study of dose escalation and expansion of HDM201 as the only agent in subjects with AML/MDS (CHDM201X2101) in which the dose is 45 mg/day (days 1-7/28 -day cycle) was defined as RD. In this study, the starting dose and regimen of 20 mg/day HDM201 (days 1-5/28 days cycle) was chosen to increase the dose. The choice of dose and regimen was supported by translational preclinical modeling of monotherapy in rats with tumors and population-based PK/PD modeling of thrombocytopenia and bone marrow blasts from the CHDM201X2101 study in subjects with AML/MDS. The starting dose corresponded to approximately ~315% below the cumulative RD dose of a single HDM201 agent (estimated in CHDM201X2101 at 45 mg/day (days 1-7/28 days cycle) or 315 mg/cycle). At this dose level, ~15% of subjects are predicted to achieve preclinical mean target effective concentrations of HDM201 per cycle, with some likely clinical activity (decrease in bone marrow blasts) and limited target myelosuppression. In addition, simulations of PBPK SimCyp at a baseline HDM201 dose of 20 mg suggested a ~1.20-fold increase in venetoclax exposure during the baseline dose escalation and steady state phase.

In Group 2 treated with HDM201+venetoclax, the starting dose for HDM201 was 20 mg/day (days 1-5/28 day cycle). The initial dose of venetoclax of 50 mg will be gradually increased over a period of 4 days to reach the planned target dose of 400 mg/day of venetoclax. Once this target dose is reached, subjects will continue on that dose of venetoclax (28 day cycle). Only the dose of one of the two study drugs (ie HDM201 or venetoclax) can be increased at a given time. However, an increase in each of the two investigational medicinal products can be tested in parallel in two different cohorts with a reduced cohort size, in both cases the increase is permitted by the BHLRM (i.e., the appropriate dose combinations are allowed).

Preliminary dose levels

The following table 3-1 describes the initial dose and dose schedule of HDM201 that can be calculated during the HDM201+venetoclax combination. (1 cycle=28 days).

Dose level HDM201 Dose Cycles 1-2* HDM201 dose, cycles ≥ 3* -1** 10 mg, d1-5 10 mg, d1-5 1 (start) 20 mg, d1-5 20 mg, d1-5 2 30 mg, d1-5 30 mg, d1-5 3 40 mg, d1-5 40 mg, d1-5 4 50 mg, d1-5 40 mg, d1-5 5 60 mg, d1-5 40 mg, d1-5

*Additional and/or intermediate dose levels may be added during the course of the study. Cohorts could be replenished at any dose level below the MTD in order to better characterize safety, PK or PD.

**Dose level -1 was the dose for treatment if dose de-escalation from the baseline dose level is needed. No de-escalation of the initial dose below dose level -1 was allowed for this study.

The following table describes the starting dose and dose escalation of venetoclax that can be calculated during the HDM201+venetoclax combination (treatment group 2). Refer to the above sections for details regarding dosing during the dose escalation period.

Dose level Daily dose of venetoclax Dose frequency of venetoclax -1* 300 mg 1 (start) 400 mg Dose increase on day 4, then daily 2 600 mg Dose increase on day 5, then daily

*Dose level -1 represents the dose for treatment when dose de-escalation is required from the baseline dose level. No de-escalation of the initial dose below dose level -1 was allowed for this study.

Goals and Endpoints

Goals Endpoints Main purpose(s):
Describe safety and tolerability
each treatment group and identify
recommended doses and regimens for future
research End point(s) for primary goal(s)
Safety:
- Incidence of new cases and severity of AE and
SAE including laboratory changes
indicators, vital signs and ECG.
- Rate of new cases and DLT values.
Tolerability: Dose interruption, reduction
and dose intensity Secondary goal(s):
Characterization of the pharmacokinetic profile of the investigational medicinal products (HDM201 and venetoclax) administered as a combination.
Evaluate preliminary antitumor activity.
Assess pharmacodynamic (PD) effect. End point(s) for secondary goal(s)
PK parameters (e.g. AUC, Cmax, Tmax)
and concentration versus time profiles for each
study drug in combination
treatment regimens.
ORR, BOR and:
- EFS, RFS and DOR for AML
(Cheson 2003)
- PFS, TTR and DOR for MDS
(Cheson 2006)
Changes from baseline under GDF-15

List of abbreviations

AE Adverse event

SAE Serious Adverse Event

AUC Area under the curve

AML Acute myeloid leukemia

R/R Recurrent/refractory

BHLRM Bayesian Logistic Regression Model

BM Bone marrow

CR Complete remission

CTCAE Criteria for assessing the severity of the most common adverse events

MDS Myelodysplastic Syndrome

MTD Maximum Tolerated Dose

RD Recommended dose

FIH First human participation

EWOC Escalation with overdose control

Q4W Every 4 weeks

Q2W Every 2 weeks

TP53 Tumor protein 53

wt wild type

PML-RARA Promyelocytic leukemia/retinoic acid receptor alpha

GvHD Graft-versus-host disease

GI Gastrointestinal

ECG Electrocardiogram

DLT Dose limiting toxicity

ORR Total effectiveness of therapy

BOR Best Overall Response

PFS Progression-Free Survival

TTR Time to response development

DOR Response time

rIPSS Revised International Predictive Scoring System

DDI Drug-Drug Interaction

ICF informed consent form.

Claims (10)

1. Application of succinic acid co-crystal: (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 [HDM201] in 1:1 ratio (molar ratio), in the treatment of wild-type acute myeloid leukemia (AML) TP53, wherein the treatment further comprises administering a BCL2 inhibitor, which is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N- [(3-nitro-4-{[(oxan-4-yl)methyl]amino}phenyl)sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide [ venetoclax], where a co-crystal with a 1:1 ratio of succinic acid: HDM201 (molar ratio) is administered on days 1-5 of a 28-day treatment cycle, and wherein the co-crystal with a ratio of succinic acid: HDM201 of 1:1 (molar ratio) is administered at a dose of 20, 30 or 40 mg (expressed as HDM201 free base) on the days of administration, and where venetoclax is administered in a daily dose of 300 mg to 600 mg. 2. Use according to claim 1, wherein the AML is relapsing/refractory AML. 3. The use of claim 1 wherein the AML is first line (1L) AML (including both de novo and secondary AML). 4. Use according to any one of the preceding claims, wherein venetoclax is administered at a daily dose of 400 mg to 600 mg. 5. Use according to claim 4, where venetoclax is administered in a daily dose of 400 mg. 6. Use according to any one of the preceding claims, wherein the combination further comprises azacitidine.

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