CDK inhibitors and their use as pharmaceuticals

Abstract

The present invention provides methods of treating cancer, for example, one or more hematological malignancies, in a subject in need thereof, by administering to the subject a therapeutically effective amount of a compound of Formula I either alone or in combination with a BTK inhibitor.

Description

105807.004018 CDK INHIBITORS AND THEIR USE AS PHARMACEUTICALS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 674,825, filed July 24, 2024; U.S. Provisional Application No.63 / 677,574, filed July 31, 2024; U.S. Provisional Application No.63 / 716,353, filed November 5, 2024; U.S. Provisional Application No.63 / 768,205, filed March 7, 2025; and U.S. Provisional Application No.63 / 816,058, filed June 2, 2025. The entirety of each aforementioned application is incorporated by reference herein. TECHNICAL FIELD

[0002] The present invention relates to the field of pharmaceutical compounds for the treatment of cancer including, for example, relapsed / refractory lymphoid malignancies. BACKGROUND

[0003] Cyclin‑dependent kinase 9 (CDK9) is a key regulator of transcription elongation and is a potential target in transcriptionally addicted cancers that are dependent on oncogenic drivers with short half‑lives, such as the oncogenes myelocytomatosis (MYC), myelobastosis (MYB), and myeloid leukemia cell differentiation protein (MCL1).

[0004] Selective CDK9 inhibition may be a promising approach to treat transcription-addicted cancers that are dependent on these oncogenic drivers. Accordingly, there is a need for improved therapies for treating hematological malignancies. The present disclosure addresses this need. SUMMARY

[0005] The disclosure provides methods of treating hematological malignancies in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of Formula (I):4898-9041-0326.1- 1 -105807.004018or a pharmaceutically acceptable salt thereof. Methods that further comprise administering to the subject a BTK inhibitor, and / or a BCL2 inhibitor are also provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] In the drawings, which are not necessarily drawn to scale, like numerals can describe similar components in different views. Like numerals having different letter suffixes can represent different instances of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various aspects discussed in the present document. In the drawings:

[0007] FIG.1 is a schematic of the study described in Example 1. DL refers to the dose level of the compound of Formula I.

[0008] FIG.2 is a graph showing the change in tumor burden with the compound of Formula I (i.e., Compound I) monotherapy and combination with zanubrutinib. Waterfall plot includes efficacy-evaluable patients who had baseline and ≥1 postbaseline tumor assessment of target lesions. Percent increase >100 is capped at 100%. Note: Best Overall Participant ID with (*) indicates participant is still on treatment. ALCL, anaplastic large cell lymphoma; CLL, chronic lymphocytic leukemia; combo, combination therapy; CR, complete response; DH, double hit; DL, dose level; DLBCL, diffuse large B-cell lymphoma; mono, monotherapy; MCL, mantle cell lymphoma; NA, not available; NOS, not otherwise specified; PD, progressive disease; PR, partial response; PTCL, peripheral T-cell lymphoma; RS, Richter syndrome; SLL, small lymphocytic lymphoma; SPD, sum of product diameters; TFH, follicular T-cell helper lymphoma.

[0009] FIGS.3A and 3B show duration of treatment with the compound of Formula I Monotherapy (FIG.3A) and in combination with zanubrutinib (FIG.3B) in patients with4898-9041-0326.1- 2 -105807.004018 R / R lymphoid malignancies. X denotes the end of treatment.aCensored at last assessment. ALCL, anaplastic large-cell lymphoma; CLL, chronic lymphocytic leukemia; CR, complete response; DH, double hit; DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma; NOS, not otherwise specified; PCPTCL, primary cutaneous peripheral T-cell lymphoma; PD, progressive disease; PR, partial response; PTCL, peripheral T-cell lymphoma; R / R, relapsed / refractory; RS, Richter syndrome; SD, stable disease ; TFH, follicular T-cell helper lymphoma.

[0010] FIGS.4A and 4B depict results from a patient case study for patients with R / R DLBCL with prior CAR-T therapy and mutated MYD88, CD79B, and CDKN2A. FIG. 4A shows scans from a 60‑year‑old female with R / R DLBCL (non‑GCB, double expressor) who received 4 lines of prior therapy, including CAR‑T therapy. The patient was enrolled to monotherapy dose level 1 (9 mg / m2) and achieved a CMR. FIG.4B shows results demonstrating that the patient’s PBMCs had a significant decrease in MCL1 (92%), MYC (97%), PCNA (82%), and pRNAP2 at end of infusion (2 hours), with prolonged transcriptional inhibition of MYC and PCNA for >6 hours. C6, cycle 6; CAR‑T, chimeric antigen receptor T‑cell; CMR, complete metabolic response; DLBCL, diffuse large B‑cell lymphoma; GBC, germinal center B‑cell; H, hour; PBMCs, peripheral blood mononuclear cells; PD, progressive disease; R / R, relapsed / refractory.

[0011] FIGS.5A to 5C show the compound of Formula I pharmacokinetics and transcriptional inhibition of CDK9 Targets. In FIG.5A, the compound of Formula I shows rapid clearance after IV infusion with a half-life of approximately 1-2 hours administered as monotherapy or in combination with zanubrutinib. FIG.5B shows MYC in PBMCs. FIG. 5C shows MCL1 in PBMCs. The results indicate strong reductions in MYC and MCL1 transcripts at end of infusion for all dose levels; both MYC and MCL1 mRNA reduced for >6 hours with MYC recovering faster than MCL1. CDK9, cyclin‑dependent kinase 9; IQR, interquartile range; PBMCs, peripheral blood mononuclear cells; IV, intravenous; mRNA, messenger RNA. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0012] The present disclosure may be understood more readily by reference to the following detailed description of desired embodiments and the examples included therein.4898-9041-0326.1- 3 -105807.004018

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0014] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0015] As used in the specification and in the claims, the term "comprising" can include the embodiments "consisting of" and "consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or processes as "consisting of" and "consisting essentially of" the enumerated ingredients / steps, which allows the presence of only the named ingredients / steps, along with any impurities that might result therefrom, and excludes other ingredients / steps. Further, the term “comprising” should be understood as having its open-ended meaning of “including,” but the term also includes the closed meaning of the term “consisting.” For example, a composition that comprises components A and B can be a composition that includes A, B, and other components, but can also be a composition made of A and B only. Any documents cited herein are incorporated by reference in their entireties for any and all purposes.

[0016] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise. The modifier “about” should also be considered as disclosing the range4898-9041-0326.1- 4 -105807.004018 defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” can refer to plus or minus 10% of the indicated number. For example, “about 10%” can indicate a range of 9% to 11%, and “about 1” can mean from 0.9-1.1. Other meanings of “about” can be apparent from the context, such as rounding off, so, for example “about 1” can also mean from 0.5 to 1.4.

[0017] Unless indicated to the contrary, the numerical values should be understood to include numerical values which are the same when reduced to the same number of significant figures and numerical values which differ from the stated value by less than the experimental error of conventional measurement technique of the type described in the present application to determine the value.

[0018] All ranges disclosed herein are inclusive of the recited endpoint and independently of the endpoints. The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0019] As used herein, the term “effective amount” or “therapeutically effective amount” in the context of the administration of a substance to a subject refers to the amount of the substance that achieves a desired therapeutic effect.

[0020] The present invention provides compositions and methods for treating cancer in a subject in need thereof. In particular, the compounds and methods of the present disclosure include compositions and methods for treating transcriptionally addicted cancers that are dependent on oncogenic drivers with short half-lives such as MYC, MYB, and MCL1.

[0021] The terms “treatment,” “treating,” “treat” and the like shall be given its ordinary meaning and shall also include herein to generally refer to obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and / or adverse effect attributable to the disease. “Treatment” as used herein shall be given its ordinary meaning and shall also cover any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b)4898-9041-0326.1- 5 -105807.004018 inhibiting the disease symptom, e.g., arresting its development; and / or (c) relieving the disease symptom, e.g., causing regression of the disease or symptom.

[0022] As used herein, the term “treatment regimen” refers to coordinated dosages and administration timings of each of the compound Formula (I) (or pharmaceutically acceptable salt thereof) and a BTK and / or BCL2 inhibitor such that Formula (I) (or pharmaceutically acceptable salt thereof) and the BTK and / or BCL2 inhibitor are administered to the subject during an overlapping period of time. Thus, the “treatment regimen” of the disclosure encompasses both concurrent administration of the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) and the BTK and / or BCL2 inhibitor; and sequential administration of the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) and the BTK and / or BCL2 inhibitor. Moreover, the treatment regimen encompasses administration of the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) and the BTK and / or BCL2 inhibitor on the same day; on different days; and any permutation thereof.

[0023] The term “administering,” when used in the context of administering a therapeutic agent to a subject, refers to introducing the therapeutic agent into the subject’s body. For example, therapeutic agents may be introduced into a subject’s body orally, nasally, subcutaneously, intravenously, intravesically, intramuscularly, transdermally, vaginally, rectally or in any combination thereof.

[0024] The compound of Formula I is a potent and highly selective CDK9 inhibitor that is being developed for select relapsed / refractory (R / R) hematologic malignancies as monotherapy and in combination with targeted agents. Zanubrutinib is a Bruton tyrosine kinase (BTK) inhibitor that upregulates BCL2 modifying factor (BMF), a proapoptotic molecule physiologically inhibited by BCL2, BCLXL, and BCLW (Kong, et al. ChemMedChem., 2018). The combination of CDK9 and BTK inhibition can lead to a synergistic effect by enhancing apoptotic priming and shifting dependency toward the CDK9 targets, MCL1 and BFL1.

[0025] The methods provided herein relate to methods of treating transcription- dependent cancer in a subject using specific inhibitors of CDK9. The cancer can include one or more hematological malignancies including, for example, one or more leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL),4898-9041-0326.1- 6 -105807.004018 and the like, one or more lymphomas including Hodgkin’s lymphomas, non-Hodgkin’s lymphoma, and the like, and / or one or more myelomas.

[0026] In some embodiments, the methods comprise administering to a subject the compound of Formula I as disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods comprise administering to a subject the compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with one or more other inhibitors such as, for example BTK inhibitors, BCL2 inhibitors, or combinations thereof. In some embodiments, the BCL2 inhibitor is venetoclax. In some embodiments, the BTK inhibitor is zanubrutinib.

[0027] The compound of Formula I (i.e., Compound I) is a CDK9 inhibitor having the structure shown below:Formula I

[0028] Methods of making the compound of Formula I are set forth in U.S. Patent No.11,673,893. Pharmaceutically acceptable salts of the compound of Formula I are set forth in US 2025 / 0011298. Pharmaceutically acceptable salts of the compound of Formula I include succinic acid, adipic acid, fumaric acid, glutaric acid, gentisic acid, hydrochloric acid, 1-hydroxy-2-naphthoic acid, salicylic acid, oxalic acid, and D-(−)-tartaric acid salts.

[0029] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In several embodiments, the pharmaceutically acceptable salt of the compound of Formula I is an acid addition salt of the compound. Such salts can be prepared by combining the compound of Formula I and an acid, such as a mineral acid, an organic acid, a sulfonic acids, or the like. Pharmaceutically4898-9041-0326.1- 7 -105807.004018 acceptable salts of the compound of Formula I include, for example, salts with succinic acid, adipic acid, fumaric acid, glutaric acid, gentisic acid, hydrochloric acid, 1-hydroxy-2- naphthoic acid, salicylic acid, oxalic acid, and D-(−)-tartaric acid. When the compound of Formula (I) is administered as a pharmaceutically acceptable salt, the amount of the salt that is administered is on the compound of Formula (I) basis. That is, the amount of salt that is administered is an amount that contains the specified amount of Formula (I) free base.

[0030] In some aspects, the disclosure provides methods of treating a hematological malignancy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of Formula (I):or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the methods comprising administering to the subject a therapeutically effective amount of the compound of Formula (I).

[0032] In other embodiments, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula I basis). In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I) is the succinate salt.

[0033] In some aspects of the disclosed methods, the subject is a mammalian subject, such as, for example, a human, canine, equine, bovine, murine, rattus, ovine, feline, non-human primate, and the like.

[0034] In some aspects of the disclosed methods, the subject is a human subject. In some embodiments, the human subject is younger than 18 years old. In some embodiments, the human subject is at least 18 years old.

[0035] In some aspects of the disclosed methods, the hematological malignancy is a relapsed / refractory lymphoid malignancy.4898-9041-0326.1- 8 -105807.004018

[0036] In some aspects of the disclosed methods, the hematological malignancy is leukemia, lymphoma, or myeloma.

[0037] In some aspects of the disclosed methods, the hematological malignancy is Aggressive B-Cell Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Mantle Cell Lymphoma (MCL), Richter's Syndrome (RS), T-cell Lymphoma (TCL), Diffuse Large B-cell Lymphoma (DLBCL), Diffuse Large B-cell Lymphoma – Double Hit (DLBCL-DH), Marginal Zone Lymphoma (MZL), Myeloid Malignancies, Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML), Myelodysplastic Syndrome (MDS), MDS / Myeloproliferative Neoplasm (MPN) Overlap Syndrome, Peripheral T-Cell Lymphoma (PTCL), or T follicular helper cell lymphoma (TFH).

[0038] In some embodiments, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL), high-grade B-cell lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or Richter syndrome.

[0039] In some embodiments, the hematological malignancy is Diffuse Large B-cell Lymphoma – Double Hit (DLBCL-DH).

[0040] In some embodiments, the hematological malignancy is Peripheral T-Cell Lymphoma (PTCL).

[0041] In some embodiments, the hematological malignancy is Small Lymphocytic Lymphoma (SLL).

[0042] In some embodiments, the hematological malignancy is Mantle Cell Lymphoma (MCL).

[0043] In some embodiments, the hematological malignancy is Diffuse Large B-cell Lymphoma (DLBCL).

[0044] In some aspects of the disclosed methods, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered intravenously (IV). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered by intravenous infusion.

[0045] In other aspects of the disclosed methods, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at least once per week.

[0046] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered once per week.4898-9041-0326.1- 9 -105807.004018

[0047] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered twice per week.

[0048] In other aspects of the disclosed methods, the compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis), is administered in a dose of about 9 mg / m2– about 24 mg / m2, such as, for example, about 9 mg / m2, about 10 mg / m2, about 11 mg / m2, about 12 mg / m2, about 13 mg / m2, about 14 mg / m2, about 15 mg / m2, about 16 mg / m2, about 17 mg / m2, about 18 mg / m2, about 19 mg / m2, about 20 mg / m2, about 21 mg / m2, about 22 mg / m2, about 23 mg / m2, or about 24 mg / m2.

[0049] In other embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis), is administered in a dose of 9 mg / m2.

[0050] In other embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis), is administered in a dose of 15 mg / m2.

[0051] In other embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis), is administered in a dose of 18 mg / m2.

[0052] In other embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis), is administered in a dose of 24 mg / m2.

[0053] In some aspects, the disclosed methods further comprising administering a Bruton tyrosine kinase (BTK) inhibitor, such as, for example, ibrutinib, acalabrutinib, or zanubrutinib, to the subject. Thus, in these aspects, the subject is administered a treatment regimen comprising: (i) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and (ii) a Bruton tyrosine kinase (BTK) inhibitor.

[0054] In some embodiments, the BTK inhibitor is zanubrutinib.

[0055] In some embodiments, the zanubrutinib is administered orally.

[0056] In some embodiments, the zanubrutinib is administered daily.

[0057] In some embodiments, the zanubrutinib is administered in a dose of 320 mg once daily.

[0058] In other embodiments, the zanubrutinib is administered in a dose of 160 mg twice daily (BID).

[0059] In some embodiments, the zanubrutinib is administered as set forth in the June 2025 revision of the prescribing information for BRUKINSA® (zanubrutinib) capsules, for oral use / BRUKINSA® (zanubrutinib) tablets, for oral use.4898-9041-0326.1- 10 -105807.004018

[0060] In some aspects, the disclosed methods further comprising administering a BCL2 inhibitor, such as, for example, venetoclax, to the subject. Thus, in these aspects, the subject is administered a treatment regimen comprising: (i) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and (ii) a BCL2 inhibitor.

[0061] In some embodiments, the BCL2 inhibitor is venetoclax.

[0062] In some embodiments, the venetoclax is administered as set forth in the July 2024 revision of the prescribing information for VENCLEXTA® (venetoclax tablets), for oral use.

[0063] In some embodiments, the venetoclax is administered orally.

[0064] In some embodiments, the venetoclax is administered daily.

[0065] In some embodiments, the venetoclax is administered in a dose of 20 mg – 600 mg once daily.

[0066] In some aspects, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and (ii) a Bruton tyrosine kinase (BTK) inhibitor.

[0067] In some aspects, the disclosure provides a method of treating a cancer that is Aggressive B-Cell Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Mantle Cell Lymphoma (MCL), Richter's Syndrome (RS), T-cell Lymphoma (TCL), Diffuse Large B-cell Lymphoma (DLBCL), Diffuse Large B-cell Lymphoma – Double Hit (DLBCL-DH), Marginal Zone Lymphoma (MZL), Myeloid Malignancies, Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML), Myelodysplastic Syndrome (MDS), MDS / Myeloproliferative Neoplasm (MPN) Overlap Syndrome, Peripheral T-Cell Lymphoma (PTCL), or T follicular helper cell lymphoma (TFH) in a subject in need thereof, the method comprising administering to the subject a treatment regimen comprising: (i) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and (ii) zanubrutinib.

[0068] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and (ii) zanubrutinib.

[0069] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound4898-9041-0326.1- 11 -105807.004018 of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis), and (ii) zanubrutinib.

[0070] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis), and (ii) 320 mg of zanubrutinib.

[0071] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis), and (ii) 320 mg of zanubrutinib.

[0072] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis) once weekly; and (ii) 320 mg of zanubrutinib once daily.

[0073] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis) once weekly; and (ii) 160 mg of zanubrutinib twice daily (BID).

[0074] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis) intravenously once weekly; and (ii) 320 mg of zanubrutinib orally once daily.

[0075] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis) intravenously once weekly; and (ii) 160 mg of zanubrutinib orally twice daily (BID).

[0076] In some aspects, the disclosure provides a method of treating Diffuse Large B-cell Lymphoma – Double Hit (DLBCL-DH) in a patient in need thereof, comprising administering to the patient a treatment regimen comprising 15 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis) intravenously once weekly; and (ii) 320 mg of zanubrutinib orally once daily.4898-9041-0326.1- 12 -105807.004018

[0077] In some aspects, the disclosure provides a method of treating Diffuse Large B-cell Lymphoma – Double Hit (DLBCL-DH) in a patient in need thereof, comprising administering to the patient a treatment regimen comprising 15 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis) intravenously once weekly; and (ii) 160 mg of zanubrutinib orally twice daily (BID).

[0078] In some aspects, the disclosure provides a method of treating Diffuse Large B-cell Lymphoma (DLBCL) in a patient in need thereof, comprising administering to the patient a treatment regimen comprising 15 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis) intravenously once weekly; and (ii) 320 mg of zanubrutinib orally once daily.

[0079] In some aspects, the disclosure provides a method of treating Diffuse Large B-cell Lymphoma (DLBCL) in a patient in need thereof, comprising administering to the patient a treatment regimen comprising 15 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis) intravenously once weekly; and (ii) 160 mg of zanubrutinib orally twice daily (BID).

[0080] In some aspects, the disclosure provides a method of treating Small Lymphocytic Lymphoma (SLL) in a patient in need thereof, comprising administering to the patient a treatment regimen comprising 18 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis) intravenously once weekly; and (ii) 320 mg of zanubrutinib orally once daily.

[0081] In some aspects, the disclosure provides a method of treating Small Lymphocytic Lymphoma (SLL) in a patient in need thereof, comprising administering to the patient a treatment regimen comprising 18 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis) intravenously once weekly; and (ii) 160 mg of zanubrutinib orally twice daily (BID).

[0082] In some aspects, the disclosure provides a method of treating Mantle Cell Lymphoma (MCL) in a patient in need thereof, comprising administering to the patient a treatment regimen comprising 18 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis) intravenously once weekly; and (ii) 320 mg of zanubrutinib orally once daily.

[0083] In some aspects, the disclosure provides a method of treating Mantle Cell Lymphoma (MCL) in a patient in need thereof, comprising administering to the patient a4898-9041-0326.1- 13 -105807.004018 treatment regimen comprising 18 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis) intravenously once weekly; and (ii) 160 mg of zanubrutinib orally twice daily (BID).

[0084] In some aspects, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and (ii) a BCL2 inhibitor.

[0085] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and (ii) venetoclax.

[0086] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis), and (ii) venetoclax.

[0087] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis), and (ii) about 20 mg – about 600 mg of venetoclax.

[0088] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (on a Formula I basis) once weekly; and (ii) about 20 mg – about 600 mg of venetoclax daily.

[0089] In some aspects, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (ii) a BTK inhibitor and (iii) a BCL2 inhibitor.

[0090] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (ii) zanubrutinib, and (iii) venetoclax.

[0091] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (ii) zanubrutinib, and (iii) venetoclax.4898-9041-0326.1- 14 -105807.004018

[0092] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (ii) 320 mg of zanubrutinib, and (iii) 20 mg –600 mg of venetoclax.

[0093] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (ii) 320 mg of zanubrutinib daily, and (iii) 20 mg –600 mg of venetoclax daily.

[0094] In some embodiments, the disclosed methods comprise administering to the subject a treatment regimen comprising: (i) about 9 mg / m2– about 24 mg / m2of a compound of Formula (I), or a pharmaceutically acceptable salt thereof administered intravenously, (ii) 320 mg of zanubrutinib administered orally daily, and (iii) 20 mg –600 mg of venetoclax administered orally daily.

[0095] In some aspects of the disclosed methods, the method of treatment results in an overall objective response of complete response, partial response, or stable disease.

[0096] In some aspects of the disclosed methods, the method of treatment results in an overall objective response of complete response or partial response.

[0097] In some embodiments, the overall objective response is complete response.

[0098] In other embodiments, the overall objective response is partial response.

[0099] In other embodiments, the overall objective response is stable disease.

[0100] In some aspects of the disclosed methods, the duration of response at least 12 weeks.

[0101] In other embodiments, the duration of response at least 24 weeks.

[0102] In other embodiments, the duration of response at least 36 weeks.

[0103] In other embodiments, the duration of response at least 48 weeks.4898-9041-0326.1- 15 -105807.004018 Examples Example 1 – Dose Escalation (BOIN) Study

[0104] The compound of Formula I as monotherapy and in combination with standard-dose zanubrutinib in patients (pts) with select Relapsed / Refractory Lymphoid Malignancies.

[0105] The primary objectives of the study included determining safety, tolerability, and any dose‑limiting toxicities (DLTs), and determining a recommended phase 2 dose (RP2D) of the compound of Formula I monotherapy and in combination with Zanubrutinib. A secondary objection was to determine an overall response rate (ORR), and PD / PK.

[0106] To be eligible for the study, patients are required to have histologically or cytologically confirmed select hematological malignancies. The hematological malignancies must have met one of the following criteria: aggressive BCL subtypes, CLL / SLL (including Richter syndrome), MCL, MZL, TCL (monotherapy only). Furthermore patients were required the present as relapsed / refractory (R / R) to standard of care (SoC) or be ineligible for standard of care treatment. The patients were required to have relapsed / refractory disease following one of the following treatments: • >1 prior systemic therapy for aggressive BCL subtypes, MCL, MZL, TCL, SLL, and Richter syndrome; • At least two prior therapies for DLBCL; • at least two prior therapies including a Bruton tyrosine kinase inhibitor (BTKi) and venetoclax for chronic lymphocytic leukemia (CLL).

[0107] Exclusion Criteria: • Active central nervous system involvement by malignancy, uncontrolled intercurrent illnesses, and active infections requiring systemic therapy • Undergone HSCT within the last 90 days or have graft versus host disease (GvHD) Grade > 1 at study entry • Severe pulmonary disease with hypoxemia • History of another malignancy except for adequately treated non-melanoma skin cancer or lentigo maligna, superficial bladder cancer, and carcinoma in4898-9041-0326.1- 16 -105807.004018 situ of the cervix without evidence of disease, and asymptomatic prostate cancer without known metastatic disease and no requirement for therapy • Concurrent treatment or within 15 days of starting study treatment with strong CYP3A4 inhibitors • Prior exposure to a CDK9 inhibitor • Wait at least 5 half-lives of the agent or 14 days after their investigational or approved therapies before start of study treatment, whichever is shorter • Mean corrected QT interval of > 470 msec following triplicate ECG measurement or history of long QT syndrome • T-Cell leukemias.

[0108] Abbreviations: BCL, B-cell lymphoma; BOIN, Bayesian optimal interval design; BTKi, Bruton tyrosine kinase inhibitor; CLL, chronic lymphocytic leukemia; DL, dose level; DLTs, dose-limiting toxicities; MCL, mantle cell lymphoma; ORR, overall response rate; PD, pharmacodynamics; PK, pharmacokinetics; RP2D, recommended phase 2 dose; R / R, relapsed / refractory; SLL, small lymphocytic lymphoma; SoC, standard of care; TCL, T-cell lymphoma.

[0109] Methods- dosing and administration

[0110] The study treatment is given on a 21-day cycle. The compound of Formula I is administered intravenously (IV) weekly. Dose Levels of the compound of Formula I are 9 mg / m2, 15 mg / m2, 18 mg / m2, and 24 mg / m2. See FIG.1. Zanubrutinib is administered orally starting on cycle 1, day 1 (C1D1) at 320 mg daily or 160 mg twice daily (BID). The dose-limiting toxicity (DLT) observation period is 21 days. Patients who were at high risk for tumor lysis syndrome receive weekly ramp-up (DLT observation period of 35 days) or an accelerated ramp-up dosing of the compound of Formula I (DLT observation period of 28 days).

[0111] Results

[0112] Patient Demographics and Baseline Disease Characteristics

[0113] Fifty-six patients with relapsed / refractory (R / R) lymphoid malignancies were treated with the compound of Formula I. Thirty-five patients were treated with the compound of Formula I monotherapy and 21 with the compound of Formula I and zanubrutinib combination therapy (Table 1). The median duration of treatment was 6.0 weeks (range: 1‑51) for monotherapy and 15 weeks (range: 4‑57) for combination therapy.4898-9041-0326.1- 17 -105807.004018 The most common reason for discontinuation was disease progression (25 [71%] monotherapy; 14 [67%] combination therapy) and adverse events (5 [14%] monotherapy; 0 combination therapy).

[0114] Table 1: Patient Demographics and Baseline Disease Characteristicsa Includes 3 patients with HGBCL with BCL2 / MYC rearrangements and 1 patient with HGBCL NOS.bIncludes 12 patients with PTCL-NOS, 5 patients with Nodal TFH TCL, 2 patients with ALCL, and 1 patient with PCPTCL. ALCL, anaplastic large-cell lymphoma; CAR T, chimeric antigen receptor T cell; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; HGBCL, high-grade B-cell lymphoma; MCL, mantle cell lymphoma; NOS, not otherwise specified; PCPTCL, primary cutaneous peripheral T-cell lymphoma;4898-9041-0326.1- 18 -105807.004018 PTCL, peripheral T-cell lymphoma; SLL, small lymphocytic lymphoma; TCE, T-cell engager; TCL, T-cell lymphoma; TFH, follicular T-cell helper lymphoma.

[0115] The baseline disease characteristics observed in patients with aggressive BCL are shown in Table 2.

[0116] Table 2.a Includes DLBCL NOS, HGBCL, and patients with Richter syndrome. BCL, B-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; HGBCL, high-grade B-cell lymphoma; NOS, not otherwise specified.

[0117] Safety

[0118] The most frequent treatment-emergent adverse events (TEAEs) observed in ≥20% of patients were neutropenia (46%), nausea (38%), and anemia (21%), and the most frequent grade ≥3 TEAEs (≥10% of patients) were neutropenia (45%) and anemia (11%; Table 3)

[0119] Five patients discontinued treatment due to TEAEs in the monotherapy cohort; 3 TEAEs in 1 patient were treatment-related: grade 3 hypotension, grade 3 diarrhea,4898-9041-0326.1- 19 -105807.004018 and grade 4 neutropenia (n=1 each). No TEAEs led to treatment discontinuation in the combination therapy cohort.

[0120] The compound of Formula I dose interruptions due to TEAEs occurred in 27 patients (18 monotherapy; 9 combination therapy). Most of the interruptions were due to neutropenia and managed with growth factor support.

[0121] One DLT of grade 3 TLS occurred in a patient with primary cutaneous peripheral T-cell lymphoma who had extensive disease at the 24 mg / m2monotherapy dose level and did not receive ramp-up dosing. TLS was managed with rasburicase and IV fluids and resolved. The patient was able to resume study treatment as planned. No DLTs were observed in the combination therapy cohort.

[0122] Dose level 3 (18 mg / m2) was selected for dose confirmation for monotherapy and in combination with zanubrutinib due to higher rates of grade 3 / 4 neutropenia and of dose interruption and reductions in the 24 mg / m2dose level.

[0123] Table 3: TEAEs of ≥10% by Preferred TermTEAEs, treatment‑emergent adverse events.

[0124] Efficacy4898-9041-0326.1- 20 -105807.004018

[0125] See FIGs.2-5. Overall response rate (ORR) and best overall responses by disease are shown in Table 4. Table 4.CR, complete response; PR, partial response.

[0126] Conclusions

[0127] The compound of Formula I demonstrated activity and acceptable safety profile as monotherapy and in combination with zanubrutinib across a range of R / R lymphoid malignancies, including patients who received prior CAR T therapy.

[0128] The most common treatment-related adverse event was neutropenia, which was managed with growth factor support. Gastrointestinal side effects were managed with supportive care.

[0129] One DLT (grade 3 TLS) was observed in the monotherapy dose-escalation cohort at the 24 mg / m2dose. No other clinical TLS events were observed, including in patients who received ramp-up dosing of the compound of Formula I. No DLTs occurred in the combination therapy dose-escalation cohorts.

[0130] The compound of Formula I showed fast clearance and had a short half-life of approximately 1 to 2 hours when given as monotherapy or in combination with Zanubrutinib.

[0131] Transcriptional inhibition of MYC and MCL1 demonstrated target engagement.

[0132] Data support use of the compound of Formula I (including at 18 mg / m2) as monotherapy in peripheral T-cell lymphoma and in combination with zanubrutinib in aggressive B-cell lymphomas.4898-9041-0326.1- 21 -

Claims

105807.004018 What is claimed:

1. A method of treating a hematological malignancy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of Formula (I):or a pharmaceutically acceptable salt thereof.

2. The method of any one of the preceding claims, wherein the compound of Formula (I) is administered intravenously (IV).

3. The method of any preceding claim, wherein the compound of Formula (I) is administered once per week.

4. The method of any preceding claim wherein the compound of Formula (I) is administered in a dose of about 9 mg / m2– about 24 mg / m2.

5. The method of claim 4 wherein the compound of Formula (I) is administered in a dose of 9 mg / m2.

6. The method of claim 4 wherein the compound of Formula (I) is administered in a dose of 15 mg / m2.

7. The method of claim 4 wherein the compound of Formula (I) is administered in a dose of 18 mg / m2.4898-9041-0326.1- 22 -105807.004018 8. The method of claim 4 wherein the compound of Formula (I) is administered in a dose of 24 mg / m2.

9. The method of any one of claims 1-8, wherein the method further comprises administering a Bruton tyrosine kinase (BTK) inhibitor to the subject.

10. The method of claim 9, wherein the BTK inhibitor is zanubrutinib.

11. The method of any one of claims 9-10, wherein the zanubrutinib is administered orally.

12. The method of any one of claims 9-11, wherein the zanubrutinib is administered daily.

13. The method of any one of claims 9-12, wherein the zanubrutinib is administered in a dose of 320 mg once daily.

14. The method of any one of claims 9-12, wherein the zanubrutinib is administered in a dose of 160 mg twice daily (BID).

15. The method of any one of the preceding claims, wherein the hematological malignancy is a relapsed / refractory lymphoid malignancy.

16. The method of any one of the preceding claims, wherein the hematological malignancy comprises a leukemia, lymphoma, or myeloma.

17. The method of any one of the preceding claims, wherein the hematological malignancy is diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL), high-grade B-cell lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or Richter syndrome.

18. The method of any one of the preceding claims, wherein the hematological malignancy is Aggressive B-Cell Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Mantle Cell Lymphoma (MCL),4898-9041-0326.1- 23 -105807.004018 Richter's Syndrome (RS), T-cell Lymphoma (TCL), Diffuse Large B-cell Lymphoma (DLBCL), Diffuse Large B-cell Lymphoma – Double Hit (DLBCL-DH), Marginal Zone Lymphoma (MZL), Myeloid Malignancies, Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML), Myelodysplastic Syndrome (MDS), MDS / Myeloproliferative Neoplasm (MPN) Overlap Syndrome, Peripheral T-Cell Lymphoma (PTCL), or T follicular helper cell lymphoma (TFH).

19. The method of claim 18, wherein the hematological malignancy is Diffuse Large B- cell Lymphoma – Double Hit (DLBCL-DH).

20. The method of claim 18, wherein the hematological malignancy is Peripheral T-Cell Lymphoma (PTCL).

21. The method of claim 18, wherein the hematological malignancy is Small Lymphocytic Lymphoma (SLL).

22. The method of claim 18, wherein the hematological malignancy is Mantle Cell Lymphoma (MCL).

23. The method of claim 18, wherein the hematological malignancy is Diffuse Large B- cell Lymphoma (DLBCL).

24. The method of any one of the preceding claims wherein the overall objective response is complete response or partial response.

25. The method of claim 24, wherein the overall objective response is complete response.

26. The method of claim 24, wherein the overall objective response is partial response.

27. The method of claim 25 or claim 26, wherein the duration of response at least 12 weeks.

28. The method of claim 25 or claim 26, wherein the duration of response at least 24 weeks.4898-9041-0326.1- 24 -105807.004018 29. The method of claim 25 or claim 26, wherein the duration of response at least 36 weeks.

30. The method of claim 25 or claim 26, wherein the duration of response at least 48 weeks.4898-9041-0326.1- 25 -

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