WO2020232214A1

WO2020232214A1 - Treating acute myeloid leukemia (aml) with mivebresib, a bromodomain inhibitor

Info

Publication number: WO2020232214A1
Application number: PCT/US2020/032825
Authority: WO
Inventors: Johannes Wolff; Kevin FREISE; Rujuta JOSHI; Mark Mckee
Original assignee: Abbvie Inc.
Priority date: 2019-05-14
Filing date: 2020-05-14
Publication date: 2020-11-19

Abstract

The present disclosure relates to methods of treating acute myeloid leukemia (AML) in a human subject in need thereof by administering an effective amount of mivebresib, optionally in combination with an effective amount of venetoclax, to the subject having AML.

Description

TREATING ACUTE MYELOID LEUKEMIA (AML)

WITH MIVEBRESIB, A BROMODOMAIN INHIBITOR

I. CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional Patent Application Serial No. 62/847,515, filed May 14, 2019, the disclosure of which is hereby incorporated by reference in its entirety.

II. FIELD OF THE INVENTION

The field of the invention relates to the use of mivebresib, optionally in combination with venetoclax, for the treatment of acute myeloid leukemia (AML) in a human subject in need thereof.

III. BACKGROUND OF THE INVENTION

The BET family proteins control diverse transcriptional programs that are important for cancer pathogenesis. In particular, the BET family protein BRD4 is highly enriched in regions known as“super enhancers,” which are very large enhancer regions that contain extensive binding sites for transcription factors. Genes associated with super enhancers are often highly expressed and very sensitive to BET inhibitors. In addition, BRD4 is associated with mitotic chromosomes and controls the post-mitotic transcription program that enables Gl/S transition during the cell cycle. Inhibition of BRD4 in vitro has been shown to result in pervasive G1 cell cycle arrest across almost a number of different cancer cell lines. Additionally, BRD4 physically interacts with the N-terminal domain of the androgen receptor (AR), and inhibition of BRD4 has been shown to disrupt AR signaling in vitro. Inhibition of BET bromodomains, e.g. BRD4, may impair the tumor microenvironment, thus inhibiting tumor growth. For example, inhibition of BRD4 has been shown to inhibit MYC expression, which may result in the collapse of the tumor microenvironment. BET family members have been established as being important for the maintenance of several cancer types, e.g. as in Zuber et al ., Nature 478: 524-528 (2011); Mertz et al. ; Proc. Nat’l. Acad. Sci. 108: 16669-16674 (2011); Delmore et al. , Cell 146: 1-14, (2011); and Dawson et al., Nature 478: 529-533 (2011); Prinjha, R.K., J. Witherington, and K. Lee, Trends Pharmacol Sci, 2012. 33(3): 146-53, each of the foregoing hereby incorporated by reference in their entireties.

The Bcl-2 family of proteins are the key regulators of mitochondria-dependent apoptosis in nucleated cells and consists of both anti-apoptotic (BC1-XL, Bcl-2, Bcl-W, Al, MCL-1) and pro-apoptotic (BAK, BAX, BID, BIM, BAD, BIK, BMF, NOXA, PUMA) members. Cellular expression of anti-apoptotic BCL-2 proteins is associated with inhibition of apoptosis and, in cases of overexpression, can result in aberrant proliferation. Involvement of Bcl-2 proteins in a number of cancers is described in both PCT Patent Application Publication WO 2005/049593 and PCT Patent Application Publication WO 2005/024636, both references are hereby incorporated by reference in their entireties. Bcl-2 has been implicated primarily in the survival of hematologic tumors.

Mivebresib is an oral small molecule inhibitor of the BET family of bromodomain- containing proteins. Mivebresib has been shown, in vitro , to bind to and inhibit BET proteins, e.g. BRD4, leading to G1 cell cycle arrest in some solid tumor cell lines, and down regulation of key cytokines and chemokines that are important in maintaining the tumor microenvironments of some malignancies. Mivebresib has been investigated preclinically in combination with venetoclax, see , . e.g ., Bui et al., Cancer Res. 2017 Jun 1;77(11):2976-2989; Fiskus W et al., Blood Cancer J. 2019 Jan 15;9(2):4; Kim SR et al., Oncotarget. 2018 Jun 26;9(49):29193-29207, all references hereby incorporated by reference in their entireties. Mivebresib has also been the subject of clinical trials for efficacy in treating solid tumors, for example, described in Piha-Paul et al. , Journal of Clinical Oncology 36, 2510-2510, hereby incorporated by reference in its entirety, where it showed a tolerable safety profile and led to stable disease in some subjects with malignant solid tumors.

Venetoclax is an orally available, selective small molecule inhibitor of the B-cell lymphoma-2 (Bcl-2) protein and is approved by the U.S. Food and Drug Administration

(“FDA”) for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy. Venetoclax is additionally approved, in combination with azacitidine or decitabine or low-dose cytarabine, for newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Furthermore, early signs of clinical activity have been observed with venetoclax in mantle cell lymphoma, Waldenstrom’s macroglobulinemia, follicular lymphoma, diffuse large B-cell lymphomas and multiple myeloma, both as a single agent or in combination with a number of other therapeutic agents; see Ashkenazi el al. Nature Reviews Drug Discovery 16, 273-284 (2017); and Leverson et al. Cancer Discovery 7, 1376-1393 (2017), both references hereby incorporated by reference in their entireties.

Although mivebresib has been shown to have encouraging preclinical efficacy in in vivo animal models and clinically in solid tumors, there remains an urgent need to identify a suitable therapeutic window for the administration of mivebresib, optionally in combination with venetoclax, for the treatment of hematological cancers, including acute myeloid leukemia (AML) in human subjects.

IV. SUMMARY OF THE IWI M ION

The present disclosure relates to methods for the treatment of acute myeloid leukemia (AML) in a human subject in need thereof comprising administering to the subject an effective amount of mivebresib, optionally in combination with venetoclax.

Accordingly, in one aspect, the present disclosure relates to method of treating acute myeloid leukemia (AML) in a human subject in need thereof. In some embodiments, the method comprises orally administering to said subject having AML an effective amount of mivebresib.

In some embodiments, the method comprises orally administering to said subject about 1.0 mg. to about 2.5 mg. mivebresib once daily. In some embodiments, the amount of mivebresib orally administered comprises about 1.0 mg. once daily. In some embodiments, the amount of mivebresib orally administered comprises about 1.5 mg. once daily. In some embodiments, the amount of mivebresib orally administered comprises about 2.0 mg. once daily. In some embodiments, the amount of mivebresib orally administered comprises about 2.5 mg. once daily. In some embodiments, the mivebresib is administered as a monotherapy. In some embodiments, the mivebresib is administered as a combination therapy. In some embodiments, the

combination therapy comprises mivebresib orally administered with venetoclax. In some embodiments, the amount of venetoclax orally administered comprises about 400 mg. to about 800 mg. venetoclax once daily. In some embodiments, the amount of venetoclax orally administered comprises about 400 mg. once daily. In some embodiments, the amount of venetoclax orally administered comprises about 800 mg. once daily. In some embodiments, the mivebresib is orally administered to the subject for a period of time sufficient to treat the AML.

In some embodiments, the AML is relapsed/refractory (R/R) AML. In some

embodiments, the mivebresib and the venetoclax is orally administered to the subject for a period of time sufficient to treat the AML. In some embodiments, the subject having AML achieves at least one of i) a complete remission (CR), ii) a complete remission with incomplete count recovery (CR), iii) a partial remission (PR) or iv) a morphologic leukemia free state (MLFS) as defined by International Working Group (IWG) Criteria. In some embodiments, the subject achieves a complete remission (CR). In some embodiments, the subject achieves a complete remission with incomplete count recovery (CR). In some embodiments, the subject achieves a partial remission (PR). In some embodiments, the subject achieves a morphologic leukemia free state (MLFS).

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof. In some embodiments, the method comprises orally administering to said subject having AML an effective amount of mivebresib.

In some embodiments, the method comprises orally administering to said subject 1.0 mg. to 2.5 mg. mivebresib once daily. In some embodiments, the amount of mivebresib orally administered comprises 1.0 mg. once daily. In some embodiments, the amount of mivebresib orally administered comprises 1.5 mg. once daily. In some embodiments, the amount of mivebresib orally administered comprises 2.0 mg. once daily. In some embodiments, the amount of mivebresib orally administered comprises 2.5 mg. once daily. In some embodiments, the mivebresib is administered as a monotherapy. In some embodiments, the mivebresib is administered as a combination therapy. In some embodiments, the combination therapy comprises mivebresib orally administered with venetoclax. In some embodiments, the amount of venetoclax orally administered comprises 400 mg. to 800 mg. venetoclax once daily. In some embodiments, the amount of venetoclax orally administered comprises 400 mg. once daily. In some embodiments, the amount of venetoclax orally administered comprises 800 mg. once daily. In some embodiments, the mivebresib is orally administered to the subject for a period of time sufficient to treat the AML.

In some embodiments, the AML comprises relapsed/refractory (R/R) AML. In some embodiments, the mivebresib and the venetoclax is orally administered to the subject for a period of time sufficient to treat the AML. In some embodiments, the subject having AML achieves at least one of i) a complete remission (CR), ii) a complete remission with incomplete count recovery (CRi), iii) a partial remission (PR) or iv) a morphologic leukemia free state (MLFS) as defined by International Working Group (IWG) Criteria. In some embodiments, the subject achieves a complete remission (CR). In some embodiments, the subject achieves a complete remission with incomplete count recovery (CRi). In some embodiments, the subject achieves a partial remission (PR). In some embodiments, the subject achieves a morphologic leukemia free state (MLFS).

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising administering to said subject having AML an effective amount of mivebresib in combination with an effective amount of venetoclax. In some embodiments, the AML comprises relapsed/refractory (R/R) AML. In some embodiments, the effective amount of mivebresib is about 1.0 mg. to about 2.5 mg.

mivebresib administered orally once daily. In some embodiments, the effective amount of mivebresib is about 1.0 mg. mivebresib administered orally once daily. In some embodiments, the effective amount of mivebresib is about 1.5 mg. mivebresib administered orally once daily. In some embodiments, the effective amount of mivebresib is about 2.0 mg. mivebresib administered orally once daily. In some embodiments, the effective amount of mivebresib is about 2.5 mg. mivebresib administered orally once daily. In some embodiments, the effective amount of venetoclax is about 400 mg. to about 800 mg. venetoclax administered orally once daily. In some embodiments, the effective amount of venetoclax is about 400 mg. administered orally once daily. In some embodiments, the effective amount of venetoclax is about 800 mg. administered orally once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising administering to said subject having AML an effective amount of mivebresib in combination with an effective amount of venetoclax. In some embodiments, the AML comprises relapsed/refractory (R/R) AML. In some embodiments, the effective amount of mivebresib is 1.0 mg. to 2.5 mg. mivebresib administered orally once daily. In some embodiments, the effective amount of mivebresib is 1.0 mg. mivebresib administered orally once daily. In some embodiments, the effective amount of mivebresib is 1.5 mg. mivebresib administered orally once daily. In some embodiments, the effective amount of mivebresib is 2.0 mg. mivebresib administered orally once daily. In some embodiments, the effective amount of mivebresib is 2.5 mg. mivebresib orally once daily. In some embodiments, the effective amount of venetoclax is 400 mg. to 800 mg. venetoclax administered orally once daily. In some embodiments, the effective amount of venetoclax is 400 mg. administered orally once daily. In some embodiments, the effective amount of venetoclax is 800 mg. administered orally once daily.

In some embodiments, the AML comprises relapsed/refractory (R/R) AML. In some embodiments, the effective amount of mivebresib and the effective amount of venetoclax is orally administered to the subject for a period of time sufficient to treat the AML. In some embodiments, the subject having AML achieves at least one of i) a complete remission (CR), ii) a complete remission with incomplete count recovery (CR), iii) a partial remission (PR) or iv) a morphologic leukemia free state (MLFS) as defined by International Working Group (IWG) Criteria. In some embodiments, the subject achieves a complete remission (CR). In some embodiments, the subject achieves a complete remission with incomplete count recovery (CRi). In some embodiments, the subject achieves a partial remission (PR). In some embodiments, the subject achieves a morphologic leukemia free state (MLFS).

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.0 mg. to 2.5 mg. mivebresib once daily and 400 mg. to 800 mg.

venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.0 mg. to 1.5 mg. mivebresib once daily and 400 mg. to 800 mg.

venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.0 mg. to 2.0 mg. mivebresib once daily and 400 mg. to 800 mg.

venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.5 mg. to 2.5 mg. mivebresib once daily and 400 mg. to 800 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.5 mg. to 2.0 mg. mivebresib once daily and 400 mg. to 800 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 2.0 mg. to 2.5 mg. mivebresib once daily and 400 mg. to 800 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.0 mg. of mivebresib once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.5 mg. of mivebresib once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 2.0 mg. of mivebresib once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 2.5 mg. of mivebresib once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.0 mg. of mivebresib once daily and 400 mg. to 800 mg. of venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.5 mg. of mivebresib once daily and 400 mg. to 800 mg. of venetoclax once daily. In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 2.0 mg. of mivebresib once daily and 400 mg. to 800 mg. of venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 2.5 mg. of mivebresib once daily and 400 mg. to 800 mg. of venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.0 mg. to 2.5 mg. mivebresib once daily and 400 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.0 mg. to 1.5 mg. mivebresib once daily and 400 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.0 mg. to 2.0 mg. mivebresib once daily and 400 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.5 mg. to 2.5 mg. mivebresib once daily and 400 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.5 mg. to 2.0 mg. mivebresib once daily and 400 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 2.0 mg. to 2.5 mg. mivebresib once daily and 400 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.0 mg. to 2.5 mg. mivebresib once daily and 800 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.5 mg. to 2.5 mg. mivebresib once daily and 800 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.0 mg. to 1.5 mg. mivebresib once daily and 800 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.0 mg. to 2.0 mg. mivebresib once daily and 800 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.5 mg. to 2.0 mg. mivebresib once daily and 800 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 2.0 mg. to 2.5 mg. mivebresib once daily and 800 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.0 mg. of mivebresib once daily and 400 mg. venetoclax once daily. In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.5 mg. of mivebresib once daily and 400 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 2.0 mg. of mivebresib once daily and 400 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 2.5 mg. of mivebresib once daily and 400 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.0 mg. of mivebresib once daily and 800 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 1.5 mg. of mivebresib once daily and 800 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 2.0 mg. of mivebresib once daily and 800 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML 2.5 mg. of mivebresib once daily and 800 mg. venetoclax once daily.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce a Cmax of about 10 to about 20 ng/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some

embodiments, the effective amount of venetoclax is 400 mg. venetoclax. In some embodiments, the effective amount of venetoclax is 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is about 400 mg. venetoclax. In some embodiments, the effective amount of venetoclax is about 800 mg. venetoclax.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce a Cmax of about 10 to about 30 ng/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce a Cmax of about 15 to about 30 ng/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce a Cmax of about 5 to about 15 ng/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is 400 mg. venetoclax. In some embodiments, the effective amount of venetoclax is 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is about 400 mg. venetoclax. In some embodiments, the effective amount of venetoclax is about 800 mg. venetoclax.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce a Cmax of about 5 to about 20 ng/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is 400 mg. venetoclax. In some embodiments, the effective amount of venetoclax is 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is about 400 mg. venetoclax. In some embodiments, the effective amount of venetoclax is about 800 mg. venetoclax.

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce a Cmax of about 15 to about 25 ng/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce an AUCinf of about 100 to about 1000 ng *h/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce an AUCinf of about 200 to about 1000 ng *h/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce an AUCinf of about 100 to about 700 ng *h/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce an AUCinf of about 100 to about 400 ng *h/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce an AUCinf of about 200 to about 400 ng *h/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce an AUCinf of about 200 to about 600 ng *h/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some

embodiments, the effective amount of venetoclax is 400 mg. venetoclax. In some embodiments, the effective amount of venetoclax is 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is about 400 mg. venetoclax. In some embodiments, the effective amount of venetoclax is about 800 mg. venetoclax. In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce an AUCinf of about 300 to about 600 ng *h/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce an AUCinf of about 300 to about 1000 ng *h/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some

In another aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML an amount of mivebresib effective to produce an AUCinf of about 400 to about 1000 ng *h/mL. In some embodiments, the method further comprises orally administering to said subject an effective amount of venetoclax. In some embodiments, the effective amount of venetoclax is between about 400 mg. to about 800 mg. venetoclax. In some embodiments, the effective amount of venetoclax is between 400 mg. to 800 mg. venetoclax. In some

In another aspect, the present disclosure relates to mivebresib for use in treating a subject suffering from acute myeloid leukemia (AML), according to any aspect of the present disclosure.

In another aspect, the present disclosure relates to mivebresib and venetoclax for use in treating a subject suffering from acute myeloid leukemia (AML), according to any aspect of the present disclosure where mivebresib is administered in combination with venetoclax.

In another aspect, the present disclosure relates to use of mivebresib for the manufacture of a medicament for treating a subject suffering from acute myeloid leukemia (AML), according to any aspect of the present disclosure.

In another aspect, the present disclosure relates to use of mivebresib and venetoclax for the manufacture of a medicament for treating a subject suffering from acute myeloid leukemia (AML), according to any aspect of the present disclosure where mivebresib is administered in combination with venetoclax.

In any of the foregoing aspects where mivebresib is administered in combination with venetoclax, venetoclax may be administered according to a dosing schedule for ramp-up as disclosed herein. In some embodiments, the ramp-up is to 400 mg. or about 400 mg. venetoclax. In some embodiments, the ramp-up is to 800 mg. or about 800 mg. venetoclax.

In any of the foregoing aspects, mivebresib can be administered to the subject for a period of time sufficient to treat the AML.

In any of the foregoing aspects where mivebresib is administered in combination with venetoclax, any of mivebresib, venetoclax, and the combination of mivebresib and venetoclax can be administered to the subject for a period of time sufficient to treat the AML.

In any of the foregoing aspects, the AML can comprise relap sed/refractory (R/R) AML.

In any of the foregoing aspects, the subject having AML, including relapsed/refractory (R/R) AML, can achieve at least one of i) a complete remission (CR), ii) a complete remission with incomplete count recovery (CR), iii) a partial remission (PR) or iv) a morphologic leukemia free state (MLFS) as defined by International Working Group (IWG) Criteria. V. BRIEF DESCRIPTION OF THE DRAWINGS

Figure l is a waterfall plot describing best percentage change from baseline in bone marrow blasts. Black solid bars indicate subjects dosed with mivebresib as a monotherapy.

White bars with a black outline indicate subjects dosed with mivebresib and venetoclax combination therapy. White bars with a black outline and black hatching indicates subjects who were initially dosed with mivebresib as a monotherapy and were switched to mivebresib and venetoclax combination therapy. As shown, subjects dosed with mivebresib as a monotherapy as well as subjects dosed with the mivebresib/venetoclax combination therapy both showed a decrease of close to -100% change in blast count, with 7 individuals receiving mivebresib monotherapy having a decrease in blast count and 12 individuals receiving combination therapy having a decrease in blast count.

Figures 2A, 2B, 2C represents blast percentage change over court of treatment for mivebresib as a monotherapy (n= 11) (Figure 2A), in combination with venetoclax (n= 14) (Figure 2B), and in those subjects switched from monotherapy to combination therapy (Figure 2C) (n = 5). As shown, a greater percentage of subjects receiving combination therapy (Figures 2B and 2C) exhibited a reduction in blast count over time compared to mivebresib monotherapy.

Figure 3 represents an analysis of overall survival for subjects with relapsed/refractory (R/R) acute myeloid leukemia (AML). Subjects receiving mivebresib as a monotherapy are represented by a dotted-dash line, subjects receiving mivebresib in combination with venetoclax are represented by a solid line, and subjects who were switched from monotherapy to

combination therapy are represented by a dashed line. As shown, median overall survival was 2.6 months (95% confidence interval, 1.8— 3.4 months).

Figure 4 represents mivebresib maximum serum concentration (Cmax, ng/mL)) vs dose (mg) for both monotherapy (A) and combination therapy (¨). As shown, there is a linear relationship between dose and maximum exposure for mivebresib that is consistent for both monotherapy and combination therapy cohorts (y = 6.8632x + 7.7895, R² = 0.8329).

Figure 5 represents mivebresib area under the curve at 24 hours (AUC24, ng * hr/mL)) vs dose (mg) for both monotherapy (A) and combination therapy (¨). As shown, there is a linear relationship between dose and exposure for mivebresib that is strongly consistent for both monotherapy and combination therapy cohorts (y = 73.053x + 165.82, R² = 0.9765). Figures 6A, 6C, 6C represent percentage change from baseline for PK markers in subjects with relapsed/refractory (R/R) acute myeloid leukemia (AML) treated with mivebresib. Figure 6A details DCXR, Figure 6B details CD93 and Figure 6C details HEXIM-1. As shown, percentage change from baseline for DCXR and HEXIM-1 increased linearly with increase in mivebresib exposure (Cmax) while CD93 decreased linearly.

VI. DETAILED DESCRIPTION OF THF INVENTION

The present disclosure includes a number of different dosing regimens and amounts for orally administering an effective amount of mivebresib, a pan-BET inhibitor, optionally in combination with venetoclax, a Bel -2 inhibitor, to a subject suffering from acute myeloid leukemia (AML), including relap sed/refractory (R/R) AML. These different dosing regimens and amounts represent an effective therapeutic window for mivebresib as a monotherapy and in combination with venetoclax for treatment of AML, with tolerable safety effects and significant improvements in observed efficacy over monotherapy as evidenced by human clinical data described herein. The duration of any of these dosing regimens and amounts may continue for as long as deemed necessarily by the prescribing physician. Dosing may be continued beyond the point at which the underlying cancer has begun to be treated and may be continued indefinitely. Mivebresib, optionally in combination with venetoclax, may or may not be combined with one or more additional therapeutics and still be considered within the scope of the present disclosure.

Accordingly, in one aspect, the present disclosure relates to a method of treating acute myeloid leukemia (AML), including relapsed/refractory (R/R) AML in a human subject in need thereof. The method generally comprises orally administering to said subject having AML an effective amount of mivebresib, optionally in combination with venetoclax. The amount of mivebresib orally administered can range from about 1.0 mg. to about 2.5 mg. mivebresib once daily, e.g. including about 1.0 mg., about 1.5 mg., about 2.0 mg., and about 2.5 mg. mivebresib. In this context, the range of about 1.0 mg. to about 2.5 mg. mivebresib includes amounts ranging from, i.e. 0.95 mg. mivebresib up to 2.625 mg. mivebresib. The mivebresib may or may not be administered as a monotherapy. The amount of venetoclax orally administered can range from about 400 mg. to about 800 mg., e.g. about 400 mg. and about 800 mg. In this context, the range of about 400 mg. to about 800 mg. venetoclax includes amounts ranging from, i.e. 380 mg. venetoclax up to 840 mg. venetoclax. The mivebresib and/or venetoclax is generally but not necessarily administered to the subject for a period of time sufficient to treat the AML.

In another aspect, the amount of mivebresib administered is about 1.0 mg. mivebresib given to the subject once daily ( e.g . 1.0 mg. mivebresib PO QD). In this context, administering about 1.0 mg. mivebresib includes administering 1.05 mg., 1.04 mg., 1.03 mg., 1.02 mg., 1.01 mg., 1.0 mg., 0.99 mg., 0.98 mg., 0.97 mg., 0.96 mg., 0.95 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 1.5 mg. of mivebresib given to the subject once daily (e.g., 1.5 mg. mivebresib PO QD). In this context, administering about 1.5 mg. mivebresib includes administering 1.575 mg., 1.560 mg., 1.545 mg., 1.53 mg., 1.515 mg., 1.5 mg., 1.485 mg., 1.47 mg., 1.455 mg., 1.44 mg., 1.425 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 2.0 mg. of mivebresib given to the subject once daily (e.g, 2.0 mg. mivebresib PO QD). In this context, administering about 2.0 mg. mivebresib includes administering 2.1 mg., 2.08 mg., 2.06 mg., 2.04 mg., 2.02 mg., 2.0 mg., 1.98 mg., 1.96 mg., 1.94 mg., 1.92 mg., 1.90 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 2.5 mg. of mivebresib given to the subject once daily (e.g, 2.5 mg. mivebresib PO QD). In this context, administering about 2.5 mg. mivebresib includes administering 2.625 mg., 2.60 mg., 2.575 mg., 2.55 mg., 2.525 mg., 2.5 mg., 2.475 mg., 2.45 mg., 2.425 mg., 2.4 mg., 2.375 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 1.0 mg. mivebresib given to the subject once daily in combination with about 400 mg. venetoclax once daily. In this context, administering about 1.0 mg. mivebresib includes administering 1.05 mg., 1.04 mg., 1.03 mg., 1.02 mg., 1.01 mg., 1.0 mg., 0.99 mg., 0.98 mg., 0.97 mg., 0.96 mg., 0.95 mg., and any intervening ranges therein, and administering about 400 mg. venetoclax once daily includes administering 420 mg., 416 mg., 412 mg., 408 mg., 404 mg., 400 mg., 396 mg., 392 mg., 388 mg., 384 mg., 380 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 1.5 mg. mivebresib given to the subject once daily in combination with about 400 mg. venetoclax once daily. In this context, administering about 1.5 mg. mivebresib includes administering 1.575 mg., 1.560 mg., 1.545 mg., 1.53 mg., 1.515 mg., 1.5 mg., 1.485 mg., 1.47 mg., 1.455 mg., 1.44 mg., 1.425 mg., and any intervening ranges therein, and administering about 400 mg. venetoclax once daily includes administering 420 mg., 416 mg., 412 mg., 408 mg., 404 mg., 400 mg., 396 mg., 392 mg., 388 mg., 384 mg., 380 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 2.0 mg. mivebresib given to the subject once daily in combination with about 400 mg. venetoclax once daily. In this context, administering about 2.0 mg. mivebresib includes administering 2.1 mg., 2.08 mg., 2.06 mg., 2.04 mg., 2.02 mg., 2.0 mg., 1.98 mg., 1.96 mg., 1.94 mg., 1.92 mg., 1.90 mg., and any intervening ranges therein, and administering about 400 mg. venetoclax once daily includes administering 420 mg., 416 mg., 412 mg., 408 mg., 404 mg., 400 mg., 396 mg., 392 mg., 388 mg., 384 mg., 380 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 2.5 mg. mivebresib given to the subject once daily in combination with about 400 mg. venetoclax once daily. In this context, administering about 2.5 mg. mivebresib includes administering 2.625 mg., 2.60 mg., 2.575 mg., 2.55 mg., 2.525 mg., 2.5 mg., 2.475 mg., 2.45 mg., 2.425 mg., 2.4 mg., 2.375 mg., and any intervening ranges therein, and administering about 400 mg. venetoclax once daily includes administering 420 mg., 416 mg., 412 mg., 408 mg., 404 mg., 400 mg., 396 mg., 392 mg., 388 mg., 384 mg., 380 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 1.0 mg. mivebresib given to the subject once daily in combination with about 800 mg. venetoclax once daily. In this context, administering about 1.0 mg. mivebresib includes administering 1.05 mg., 1.04 mg., 1.03 mg., 1.02 mg., 1.01 mg., 1.0 mg., 0.99 mg., 0.98 mg., 0.97 mg., 0.96 mg., 0.95 mg., and any intervening ranges therein, and administering about 800 mg. venetoclax once daily includes administering 840 mg., 832 mg., 824 mg., 816 mg., 808 mg., 800 mg., 792 mg., 784 mg., 776 mg., 768 mg., 760 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 1.5 mg. mivebresib given to the subject once daily in combination with about 800 mg. venetoclax once daily. In this context, administering about 1.5 mg. mivebresib includes administering 1.575 mg., 1.560 mg., 1.545 mg., 1.53 mg., 1.515 mg., 1.5 mg., 1.485 mg., 1.47 mg., 1.455 mg., 1.44 mg., 1.425 mg., and any intervening ranges therein, and administering about 800 mg. venetoclax once daily includes administering 840 mg., 832 mg., 824 mg., 816 mg., 808 mg., 800 mg., 792 mg., 784 mg., 776 mg., 768 mg., 760 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 2.0 mg. mivebresib given to the subject once daily in combination with about 800 mg. venetoclax once daily. In this context, administering about 2.0 mg. mivebresib includes administering 2.1 mg., 2.08 mg., 2.06 mg., 2.04 mg., 2.02 mg., 2.0 mg., 1.98 mg., 1.96 mg., 1.94 mg., 1.92 mg., 1.90 mg., and any intervening ranges therein, and administering about 800 mg. venetoclax once daily includes administering 840 mg., 832 mg., 824 mg., 816 mg., 808 mg., 800 mg., 792 mg., 784 mg., 776 mg., 768 mg., 760 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 2.5 mg. mivebresib given to the subject once daily in combination with about 800 mg. venetoclax once daily. In this context, administering about 2.5 mg. mivebresib includes administering 2.625 mg., 2.60 mg., 2.575 mg., 2.55 mg., 2.525 mg., 2.5 mg., 2.475 mg., 2.45 mg., 2.425 mg., 2.4 mg., 2.375 mg., and any intervening ranges therein, and administering about 800 mg. venetoclax once daily includes administering 840 mg., 832 mg., 824 mg., 816 mg., 808 mg., 800 mg., 792 mg., 784 mg., 776 mg., 768 mg., 760 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 1.0 mg. mivebresib given to the subject once daily in combination with about 400 mg. to about 800 mg. venetoclax once daily. In this context, administering about 1.0 mg. mivebresib includes administering 1.05 mg., 1.04 mg., 1.03 mg., 1.02 mg., 1.01 mg., 1.0 mg., 0.99 mg., 0.98 mg., 0.97 mg., 0.96 mg., 0.95 mg., and any intervening ranges therein, and administering about 400 mg. to about 800 mg. venetoclax once daily includes administering 380 mg. to 840 mg. venetoclax and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 1.5 mg. mivebresib given to the subject once daily in combination with about 400 mg. to about 800 mg. venetoclax once daily. In this context, administering about 1.5 mg. mivebresib includes administering 1.575 mg., 1.560 mg., 1.545 mg., 1.53 mg., 1.515 mg., 1.5 mg., 1.485 mg., 1.47 mg., 1.455 mg., 1.44 mg., 1.425 mg., and any intervening ranges therein, and administering about 800 mg. venetoclax once daily includes administering 840 mg., 832 mg., 824 mg., 816 mg., 808 mg., 800 mg., 792 mg., 784 mg., 776 mg., 768 mg., 760 mg., and any intervening ranges therein. In another aspect, the amount of mivebresib administered is about 2.0 mg. mivebresib given to the subject once daily in combination with about 400 mg. to about 800 mg. venetoclax once daily. In this context, administering about 2.0 mg. mivebresib includes administering 2.1 mg., 2.08 mg., 2.06 mg., 2.04 mg., 2.02 mg., 2.0 mg., 1.98 mg., 1.96 mg., 1.94 mg., 1.92 mg., 1.90 mg., and any intervening ranges therein, and administering about 400 mg. to about 800 mg. venetoclax once daily includes administering 380 mg. to 840 mg. venetoclax and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 2.5 mg. mivebresib given to the subject once daily in combination with about 400 mg. to about 800 mg. venetoclax once daily. In this context, administering about 2.5 mg. mivebresib includes administering 2.625 mg., 2.60 mg., 2.575 mg., 2.55 mg., 2.525 mg., 2.5 mg., 2.475 mg., 2.45 mg., 2.425 mg., 2.4 mg., 2.375 mg., and any intervening ranges therein, and administering about 400 mg. to about 800 mg. venetoclax once daily includes administering 380 mg. to 840 mg. venetoclax and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 1.0 to about 2.5 mg. mivebresib given to the subject once daily in combination with about 400 mg. venetoclax once daily. In this context, administering about 1.0 mg. to about 2.5 mg. mivebresib includes administering 0.95 mg. mivebresib to about 2.625 mg. mivebresib and any intervening ranges therein, and administering about 400 mg. venetoclax once daily includes administering 420 mg., 416 mg., 412 mg., 408 mg., 404 mg., 400 mg., 396 mg., 392 mg., 388 mg., 384 mg., 380 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is about 1.0 to about 2.5 mg. mivebresib given to the subject once daily in combination with about 800 mg. venetoclax once daily. In this context, administering about 1.0 mg. to about 2.5 mg. mivebresib includes administering 0.95 mg. mivebresib to about 2.625 mg. mivebresib and any intervening ranges therein, and administering about 800 mg. venetoclax once daily includes administering 840 mg., 832 mg., 824 mg., 816 mg., 808 mg., 800 mg., 792 mg., 784 mg., 776 mg., 768 mg., 760 mg., and any intervening ranges therein.

In another aspect, the amount of mivebresib administered is 1.0 mg. to 2.5 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. to 800 mg. of venetoclax once daily. In another aspect, the amount of mivebresib administered is 1.0 mg. to 1.5 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. to 800 mg. of venetoclax once daily.

In another aspect, the amount of mivebresib administered is 1.0 mg. to 2.0 mg. of mivebresib once daily and the amount of venetoclax administered 400 mg. to 800 mg. of venetoclax once daily.

In another aspect, the amount of mivebresib administered is 1.5 mg. to 2.5 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. to 800 mg. of venetoclax once daily.

In another aspect, the amount of mivebresib administered is 1.5 mg. to 2.0 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. to 800 mg. of venetoclax once daily.

In another aspect, the amount of mivebresib administered is 2.0 mg. to 2.5 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. to 800 mg. of venetoclax once daily.

In another aspect, the amount of mivebresib administered is 1.0 mg. of mivebresib once daily, optionally as a monotherapy.

In another aspect, the amount of mivebresib administered is 1.5 mg. of mivebresib once daily, optionally as a monotherapy.

In another aspect, the amount of mivebresib administered is 2.0 mg. of mivebresib once daily, optionally as a monotherapy.

In another aspect, the amount of mivebresib administered is 2.5 mg. of mivebresib once daily, optionally as a monotherapy.

In another aspect, the amount of mivebresib administered is 1.0 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. to 800 mg. of venetoclax once daily.

In another aspect, the amount of mivebresib administered is 1.5 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. to 800 mg. of venetoclax once daily.

In another aspect, the amount of mivebresib administered is 2.0 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. to 800 mg. of venetoclax once daily.

In another aspect, the amount of mivebresib administered is 2.5 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. to 800 mg. of venetoclax once daily. In another aspect, the amount of mivebresib administered is 1.0 mg. to 2.5 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. to 800 mg. of venetoclax once daily.

In another aspect, the amount of mivebresib administered is 1.0 mg. to 1.5 mg.

mivebresib once daily and the amount of venetoclax administered is 400 mg. of venetoclax once daily.

In another aspect, the amount of mivebresib administered is 1.0 mg. to 2.0 mg.

mivebresib once daily and the amount of venetoclax administered is 400 mg. venetoclax once daily.

In another aspect, the amount of mivebresib administered is 1.5 mg. to 2.5 mg.

In another aspect, the amount of mivebresib administered is 1.5 mg. to 2.0 mg.

In another aspect, the amount of mivebresib administered is 2.0 mg. to 2.5 mg.

In another aspect, the amount of mivebresib administered is 1.0 mg. to 2.5 mg.

mivebresib once daily and the amount of venetoclax administered is 800 mg. venetoclax once daily.

In another aspect, the amount of mivebresib administered is 1.5 mg. to 2.5 mg.

In another aspect, the amount of mivebresib administered is 1.0 mg. to 1.5 mg.

In another aspect, the amount of mivebresib administered is 1.0 mg. to 2.0 mg.

mivebresib once daily and the amount of venetoclax administered is 800 mg. venetoclax once daily. In another aspect, the amount of mivebresib administered is 1.5 mg. to 2.0 mg.

In another aspect, the amount of mivebresib administered is AML 2.0 mg. to 2.5 mg. mivebresib once daily and the amount of venetoclax administered is 800 mg. venetoclax once daily.

In another aspect, the amount of mivebresib administered is 1.0 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. venetoclax once daily.

In another aspect, the amount of mivebresib administered is 1.5 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. venetoclax once daily.

In another aspect, the amount of mivebresib administered is 2.0 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. venetoclax once daily.

In another aspect, the amount of mivebresib administered is 2.5 mg. of mivebresib once daily and the amount of venetoclax administered is 400 mg. venetoclax once daily.

In another aspect, the amount of mivebresib administered is 1.0 mg. of mivebresib once daily and the amount of venetoclax administered is 800 mg. venetoclax once daily.

In another aspect, the amount of mivebresib administered is 1.5 mg. of mivebresib once daily and the amount of venetoclax administered is 800 mg. venetoclax once daily.

In another aspect, the amount of mivebresib administered is 2.0 mg. of mivebresib once daily and the amount of venetoclax administered is 800 mg. venetoclax once daily.

In another aspect, the amount of mivebresib administered is 2.5 mg. of mivebresib once daily and the amount of venetoclax administered is 800 mg. venetoclax once daily.

In another aspect, the amount of mivebresib administered is an amount effective to produce a Cmax of about 10 to about 20 ng/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce a Cmax of about 10 to about 30 ng/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce a Cmax of about 15 to about 30 ng/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax. In another aspect, the amount of mivebresib administered is an amount effective to produce a Cmax of about 5 to about 15 ng/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce a Cmax of about 5 to about 20 ng/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce a Cmax of about 15 to about 25 ng/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof about 100 to about 1000 ng * h/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof about 200 to about 1000 ng * h/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof about 100 to about 400 ng * h/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof about 100 to about 700 ng * h/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof about 200 to about 400 ng * h/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof about 200 to about 600 ng * h/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof about 300 to about 600 ng * h/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax. In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof about 300 to about 1000 ng * h/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof about 400 to about 1000 ng * h/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce a Cmax of 10 to 20 ng/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce a Cmax of 10 to 30 ng/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce a Cmax of 15 to 30 ng/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce a Cmax of 5 to 15 ng/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce a Cmax of 5 to 20 ng/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce a Cmax of 15 to 25 ng/mL. In some embodiments, the mivebresib is co-administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof 100 to 1000 ng * h/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof 200 to 1000 ng * h/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax. In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof 100 to 400 ng * h/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof 100 to 700 ng * h/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof 200 to 400 ng * h/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof 200 to 600 ng * h/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof 300 to 600 ng * h/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof 300 to 1000 ng * h/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax.

In another aspect, the amount of mivebresib administered is an amount effective to produce an AUCinfof 400 to 1000 ng * h/mL. In some embodiments, the mivebresib is co administered with an effective amount of venetoclax.

In any of the aspects of the present disclosure where mivebresib is administered in combination with venetoclax, venetoclax may be administered according to a dosing schedule for ramp-up, e.g. for-ramp up to an about 400 mg. once daily dose or for an about 800 mg. once daily dose. In some embodiments, the dosing schedule for ramp-up can comprise administering 20 mg. venetoclax once daily for about one week, followed by administering 50 mg. venetoclax once daily for about one week, followed by administering 100 mg. venetoclax once daily for about one week, followed by administering 200 mg. venetoclax once daily for about one week, followed by administering 400 mg. venetoclax once daily. In some embodiments, the dosing schedule for ramp-up can comprise administering 20 mg. venetoclax once daily for about one week, followed by administering 50 mg. venetoclax once daily for about one week, followed by administering 100 mg. venetoclax once daily for about one week, followed by administering 200 mg. venetoclax once daily for about one week, followed by administering 400 mg. venetoclax once daily for about one week, followed by administering 800 mg. venetoclax once daily. In some embodiments, the dosing schedule for ramp-up can comprise administering 100 mg.

venetoclax on day 1, administering 200 mg. venetoclax on day 2, and 400 mg. venetoclax on day 3 and beyond. In some embodiments, the dosing schedule for ramp-up can comprise

administering 100 mg. venetoclax on day 1, administering 200 mg. venetoclax on day 2, 400 mg. venetoclax on day 3, and 800 mg. venetoclax on day 4 and beyond.

In another aspect, the present invention is directed to a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprising orally administering 2.5 mg. mivebresib and 400 mg. venetoclax once daily to the subject, wherein the venetoclax is administered according to a dosing schedule for ramp-up, the dosing schedule for ramp-up comprising administering 100 mg. venetoclax on day 1, administering 200 mg. venetoclax on day 2, and 400 mg. venetoclax on day 3 and beyond.

In another aspect, the present invention is directed to a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprising orally administering 2.5 mg. mivebresib and 400 mg. venetoclax once daily to the subject, wherein the venetoclax is administered according to a dosing schedule for ramp-up, the dosing schedule for ramp-up comprising administering 100 mg. venetoclax on day 1, administering 200 mg. venetoclax on day 2, and 400 mg. venetoclax on day 3, and 800 mg. venetoclax on day 4 and beyond.

In another aspect, the present invention is directed to a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprising orally administering 2.5 mg. mivebresib and 400 mg. venetoclax once daily to the subject, wherein the venetoclax is administered according to a dosing schedule for ramp-up, the dosing schedule for ramp-up comprising 20 mg. venetoclax once daily for about one week, followed by administering 50 mg. venetoclax once daily for about one week, followed by administering 100 mg. venetoclax once daily for about one week, followed by administering 200 mg. venetoclax once daily for about one week, followed by administering 400 mg. venetoclax once daily.

In another aspect, the present invention is directed to a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprising orally administering 2.5 mg. mivebresib and 400 mg. venetoclax once daily to the subject, wherein the venetoclax is administered according to a dosing schedule for ramp-up, the dosing schedule for ramp-up comprising administering 20 mg. venetoclax once daily for about one week, followed by administering 50 mg. venetoclax once daily for about one week, followed by administering 100 mg. venetoclax once daily for about one week, followed by administering 200 mg. venetoclax once daily for about one week, followed by administering 400 mg. venetoclax once daily for about one week, followed by administering 800 mg. venetoclax once daily.

In any of the aspects of the present disclosure, the subject having AML can achieve at least one of i) a complete remission (CR), ii) a complete remission with incomplete count recovery (CRi), iii) a partial remission (PR) or iv) a morphologic leukemia free state (MLFS) as defined by International Working Group (IWG) Criteria. Thus, in some embodiments, the subject can achieve a complete remission (CR). In some embodiments, the subject can achieve a complete remission with incomplete count recovery (CRi). In some embodiments, the subject can achieve a partial remission (PR). In some embodiments, the subject can achieve a morphologic leukemia free state (MLFS).

“About” as used herein generally refers to amounts that are within ± 10% from the reported value, e.g. ± 10%, ± 9% ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, < ± 1%, and any intervening ranges therein. In context of dosing, the term“about” includes values of ± 5% from the reported value, e.g. ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, < ± 1%, and any intervening ranges therein. For example, administering an amount of about 2.5 mg. mivebresib would include administering 2.625 mg., 2.6 mg., 2.575 mg., 2.55 mg., 2.525 mg., 2.5 mg. 2.475 mg., 2.45 mg., 2.425 mg., 2.4, 2.375 mg., and any intervening ranges therein.

“Administering”,“administer”, or“administration” as used herein refers to oral administration and explicitly includes self-administration, i.e. by the subject in need thereof, or administration by another individual to the subject in need thereof.

“BET”,“BET protein”, or“BET proteins” as used herein refers to the Bromodomain and Extra Terminal family of proteins. BET proteins function as transcription regulators and control many transcriptional programs that are required for cancer pathogenesis. There are 46 known bromodomain (BRD)-containing proteins in the human genome and 4 of them (BRD2, BRD3, BRD4, and BRDT) comprise the BET family. BRDT is exclusively expressed in testis and ovary, whereas BRD2, BRD3, and BRD4 are ubiquitously expressed. Each member of the BET family contains 2 bromodomains which recognize acetylated lysine residues on histone proteins. Once bound to the acetylated histone markers, BET family proteins often activate transcription through recruiting the positive transcription elongation factor complex (pTEFb) that is essential for ribonucleic acid (RNA) polymerase Il-dependent transcription elongation.

“IWG” or“IWG criteria” or as used herein refers to the“International Working Group Uniform Response Criteria” and is a set of published criteria for evaluating patient progression during treatment, e.g. for acute myeloid leukemia (AML). As described herein, IWG scoring for AML recognizes the following distinct assessment categories;“complete remission” (CR), “complete remission with incomplete count recovery (CRi),“partial remission” (PR), “morphologic leukemia free state” (MLFS),“resistant disease” (RD),“aplasia”, and

“morphologic relapse” (MR).“Complete remission” or“CR” as used herein refers to an absolute neutrophil count > 1000 pL, platelets > 100,000 pL, red cell transfusion independent, and bone marrow with < 5% blasts and additionally includes absence of extramedullary disease. “Complete remission with incomplete count recovery” or“CRi” as used herein includes all of the criteria for“complete remission” except the absolute neutrophil count > 1000 pL and the platelet count above > 100,000 pL.“Partial remission” or“PR” as used herein includes the criteria for a “complete response” but with a decrease of at least 50% in the percentage of blasts to 5 to 25% in the bone marrow aspirate. “Morphologic leukemia free state” or“MLFS” as used herein includes less than 5% blasts in an aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. “Resistant disease” or“RD” as used herein refers to the failure to achieve CR, CRi, PR, and only for subjects surviving at least seven (7) days following completion of initial treatment, with evidence of persistent leukemia by blood and/or bone marrow examination. “Aplasia” as used herein refers to the subject surviving > seven (7) days after initial treatment, with death while cytopenic, and with aplastic bone marrow. “Morphologic relapse” or“MR” as used herein refers to having bone marrow blasts > 5%, or reappearance of blasts in the blood, or development of extramedullary disease.

“Mivebresib” or“mivebresib” as used herein refers to N-[4-(2,4-difluorophenoxy)-3-(6- methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide or a pharmaceutically acceptable salt thereof and may interchangeably be used with the term “ABBV-075”. Mivebresib is assigned CAS No. 1445993-26-9. The molecular formula is C22H19F2N3O4S and the molecular weight is 459.468 g/mol. Discovery and synthesis of mivebresib is described in, for example, McDaniel et al, J. Med. Chem. 2017, 60, 8369-8384, the disclosure of which is hereby incorporated by reference in its entirety, and U.S. Patent No. 9,296,741, (see, e.g. , Example 36), the disclosure of which is hereby incorporated by reference in its entirety. Mivebresib has been tested in a number of solid tumor flank xenograft mouse models including but not limited to NSCLC, pancreatic cancer, breast cancer, head-and-neck cancer, and prostate cancer, particularly castration-resistant prostate cancer (CRPC); see, e.g., Faivre et al., Mol Cancer Res. 2017, 15(1), 35-44, hereby incorporated by reference in its entirety. Models from each of these tumor types have shown > 70% tumor growth inhibition with mivebresib as a monotherapy. In the majority of these in vivo models, mivebresib exhibited efficacy that was comparable or superior to standard-of-care agents. Mivebresib is known to exist in at least two crystalline polymorphic forms, described in, for example, U.S. Patent No. 9,321,765, the disclosure of which is hereby incorporated by reference in its entirety. The chemical structure of mivebresib is indicated below. In case of any conflict or ambiguity the following structure will control:

Mivebresib / ABB V-075

“Subject” or“subjects” as used herein is used interchangeably with“patient” or “patients”. “Subject” or“subjects” means a human subject or subjects.

“Treatment”,“treat”, or“treating” refer to a method of alleviating or abrogating a disease and/or its underlying symptoms. “Treating” or“treatment” does not require complete alleviation of signs or symptoms and does not require a cure. In the context of“treating” a subject suffering from acute myeloid leukemia (AML), e.g ., relap sed/refractory (R/R) AML,“treating” can include reducing, slowing, or halting disease progression in the subject. More specifically, as used herein,“treatment” can also, but not necessarily, include achieving a complete remission (CR), complete remission with incomplete count recovery (CRi), partial remission (PR), and morphologic leukemia free state (MLFS) as defined by IWG criteria.

“Venetoclax” or“venetoclax” as used herein refers to 4-(4-{[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]phenyl}sulfonyl)-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide or a pharmaceutically acceptable salt thereof, and may be used interchangeably with, for example, the terms“ABT-199”, Venclexta®, and Venclyxto. Venetoclax is assigned CAS No. 1257044-40-8. The molecular formula is C45H50CIN7O7S, having a molecular weight of 868.447 g/mol. The molecular formula of venetoclax is C45H50CIN7O7S, having a molecular weight of 868.447 g/mol. Venetoclax has been previously administered to subjects suffering from hematologic malignancies in monotherapy and combination dosing. Doses administered in venetoclax clinical studies have ranged from 20 mg. to 1,200 mg., administered once daily (QD) by mouth (PO). Synthesis of venetoclax is described in U.S. Patent Nos. 8,546,399 and 9,174,982 (see, e.g, Example 5), and WO 2010/138588, the disclosures of which are hereby incorporated by reference in their entireties. The chemical structure of venetoclax is indicated below. In case of any conflict or ambiguity the following structure will control:

Venetoclax / Venclexta® / Venclyxto / ABT-199

Unless otherwise defined herein, scientific and technical terms used herein have the meanings that are commonly understood by those of ordinary skill in the art. In the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Unless otherwise required by context, singular terms, e.g.“a”,“an”, and“the”, shall include pluralities and plural terms shall include the singular. The use of“and” and“or” means “and/or” unless stated otherwise. The use of the term“including”, as well as other forms, such as“includes” and“included”, is not limiting. Any range described here will be understood to include the endpoints and all values between the endpoints, i.e. the recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

Each of the applications and patents cited in this text, as well as each document or reference, patent or non-patent literature, cited in each of the applications and patents (including during the prosecution of each issued patent;“application cited documents”), and each of the PCT and foreign applications or patents corresponding to and/or claiming priority from any of these applications and patents, and each of the documents cited or referenced in each of the application cited documents, are hereby expressly incorporated herein by reference in their entirety. Publications disclosed herein are provided solely for their disclosure prior to the filing date of the present disclosure and are not an admission of materiality or that such publications constitute prior art to the present disclosure.

VII. EXAMPLES

The following non-limiting Examples serve to further illustrate the present disclosure. Abbreviations/defmitions utilized in the Examples include the following:

ABBV-075 = mivebresib

ABT-199 = venetoclax

AE = adverse event

ALT = alanine aminotransferase

AML = acute myeloid leukemia

AP = aplasia

AST = aspartate aminotransferase

AUC = area under the curve

AUC24 = = area under the curve at 24 hours

AUCinf = area under the curve extrapolated to infinite time

AUC24/D = dose-normalized AUC24

AUCinf/D = dose-normalized AUCinf

BP = blood pressure

Cmax = maximum serum concentration

Cmax/D = dose-normalized Cmax

CLss/F = apparent oral clearance

CR = complete remission

CRi = complete remission with incomplete count recovery

CTCAE = Common Terminology Criteria for Adverse Events

CXDY = Cycle X, Day Y, e.g. C1D1 is Cycle 1, Day 1 CYP3 A = cytochrome P4503 A

DLT = dose-limiting toxicity

ECG = electrocardiogram

ECOG = Eastern Cooperative Oncology Group

ELN = European LeukemiaNet

GVHD = graft-versus-host-disease

IWG = International Working Group

LC-MS/MS = liquid chromatography-tandem mass spectrometry

Mivebresib = N- [4-(2,4-difluorophenoxy)-3 -(6-methyl-7-oxo-6, 7-dihydro- 1 H- pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide or a pharmaceutically acceptable salt thereof.

MLFS = morphologic leukemia free state

MTD = maximum tolerated dose

NCI = National Cancer Institute

ORR = objective response rate

PD = pharmacodynamics

PK = pharmacokinetics

PO = orally administered, e.g. administered“by mouth”

aPPT = activated partial thromboplastin time

PR = partial remission

PS = performance status

PT = prothrombin time

QD = once daily, e.g. administered once daily

Rac = accumulation ratio

RBC = red blood cell

RD = resistant disease

R/R or RR = relapsed/refractory, e.g. relap sed/refractory AML

SCLC = small cell lung cancer

SOC = standard of care

T 1/2 = biological half-life

Tmax = time to reach maximum serum concentration TEAE = treatment-emergent adverse event

TGI = tumor growth inhibition

TLS = tumor lysis syndrome

ULN = upper limit of normal

Venetoclax = 4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 - yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]phenyl}sulfonyl)-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide or a pharmaceutically acceptable salt thereof.

1. Preclinical Efficacy of Mivebresib and Venetoclax Combination Therapy

Combination treatment with mivebresib and venetoclax has been conducted in preclinical models using AML and SCLC xenografts. Mice bearing NCI-H1963 tumors received modest benefit from treatment with mivebresib monotherapy with 1 mg/kg PO QD (56% tumor growth inhibition (TGI)) compared to tumors treated with inactive vehicle. Monotherapy venetoclax 50 mg/kg PO QD also had modest efficacy (57% TGI). Combination therapy with mivebresib and venetoclax at previously described doses resulted in marked efficacy (96% TGI), and re treatment of growing tumors after cessation of initial therapy resulted in tumor size stabilization.

2. Phase I Dose Expansion Cohort Study— Acute Myeloid Leukemia (AML)

Study Design

This dose expansion study (NCT02391480) was designed to assess the safety and pharmacokinetics (PK) of mivebresib (ABBV-075) in order to determine a therapeutic window for the treatment of acute myeloid leukemia (AML) as a monotherapy or in combination with venetoclax (ABT-199). Individuals in the combination therapy cohorts received 50% or 100% of the highest dose of mivebresib cleared in the monotherapy cohorts, combined with either 400 mg. or 800 mg. venetoclax. Venetoclax dosing started with a ramp-up phase of 4 days (starting at Cycle 1) to mitigate the risk of tumor lysis syndrome (TLS); mivebresib was added to venetoclax once the target dose for venetoclax was reached. Tumor lysis syndrome (TLS) is an important identified risk of venetoclax; see TABLE 1 below for an overview of venetoclax ramp- up phase, and TABLE 14 infra for TLS diagnostic criteria utilized in this study. All subjects were hospitalized and closely monitored the day prior to the start of combination therapy and for the first 48 hours after mivebresib was added to venetoclax; mivebresib was added to the daily regimen once the ramp-up phase for venetoclax was completed, i.e. on C1D4 and onward for 400 mg. venetoclax and C1D5 for 800 mg. venetoclax and onward. Venetoclax was provided as one of 10 mg., 50 mg., or 100 mg. film-coated tablets.

TABLE 1. Venetoclax Dose Ramp-Up (400 mg. and 800 mg. dosing cohorts)

CXDY

Cycle 1, Day 1; PO = oral administration; QD = once daily

Study drugs were administered orally once daily (PO QD) until progressive disease (PD) or unacceptable toxicity was reached. All subjects were hospitalized and closely monitored the day prior to start of combination and for the first 48 hours after mivebresib was added to venetoclax. Gene expression analysis was performed on RNA extracted from whole blood samples collected at multiple time points (pre-treatment and after mivebresib administration). ds-cDNA was prepared using the SeqPlex RNA Amplification Kit (Sigma) per manufacturer’s protocol. Illumina sequencing was used to perform the analysis. All subjects had PK and serial BP monitoring for Cycle 1 Day 1 (C1D1) and on Cycle 1 Day 8 (C1D8) and Cycle 2 Day 1 (C2D1). Plasma samples were analyzed for mivebresib using validated liquid chromatography- tandem mass spectrometry (LC-MS/MS) method and assessed by non-compartmental analysis methods. All subjects received TLS prophylaxis prior to and during treatment.

The dose limiting toxicity (DLT) period was 28 days for monotherapy starting from the first day of therapy, and 21 days for combination starting after the first day of both drugs in target dose. DLT events were defined as clinically significant adverse events (AE) or abnormal laboratory values assessed as unrelated to disease progression, intercurrent illness, or

concomitant medications and occurring during the first 4 weeks after administration of the first dose that meets any of the below criteria. Notably, neutropenia and thrombocytopenia were not considered a DLT.

DLT Definitions for this study included:

1. Any grade > 2 neurotoxicity.

2. Unexpected grade 2 toxicity which requires dose reduction or dose delay lasting greater than 1 week.

3. Grade > 3 nausea or vomiting for > 48 hours or diarrhea for > 72 hours despite maximum supportive care. Grade > 3 hypertension despite anti-hypertensive treatment.

4. All other grade > 3 adverse events, unless an alternative etiology has been identified, were considered a DLT.

5. Prolonged myelosuppression, as defined by the NCI criteria specific for leukemia, /. e. , marrow cellularity < 5% on Day 42 or later (6 weeks) from start of therapy without evidence of leukemia.

6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) Grade 4 elevation or Grade 3 elevation lasting for more than 7 days.

7. Treatment delay of 14 days or greater due to unresolved toxicity.

For those subjects who received the combination therapy of mivebresib and venetoclax, the following additional DLTs were included:

1. Clinical TLS, however a change in Cr must have been greater than 0.5 mg./dL.

2. Laboratory TLS in instances where the metabolic abnormalities did not resolve themselves within 72 hours despite appropriate clinical management.

Grade 3 or 4 hyperuricemia or hypocalcemia or Grade 3 hyperkalemia, if transient (z.e., lasting < 48 hours) and without manifestations of clinical TLS, was not considered a DLT.

Furthermore, subjects in this study were selected to have the following procedures:

1. Triplicate electrocardiogram (ECG) at screening.

2. PK and serial blood pressure (BP) monitoring for 8 hours on C1D1.

3. PK, serial BP, and triplicate ECG through 8 hours after dosing on C2D1. Subject Inclusion Criteria

For this study, the following inclusion criteria was utilized.

1. Subjects must have been > 18 years of age at time of enrollment.

2. Subjects must have had histological confirmation of AML, not amenable to curative therapy, that is refractory after standard of care (SOC) or for which SOC therapy does not exist.

3. Subjects with a history of autologous or allogenic stem cell transplantation must have recovered from any transplant-related toxi cities and be 100 days post-autologous transplant prior to first dose of study drug, or > 6 months post-allogenic transplant, prior to first dose of study drug, and without graft-versus-host disease (GVHD).

4. Subjects must have had an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0— 2.

5. Subjects must have had adequate renal function as demonstrated by a calculated creatinine clearance value of > 50 mL/min by the Cockcroft-Gault formula or a creatinine clearance value of > 50 mL/min based on a 24-hour urine collection.

6. Subjects must have had adequate hepatic function as demonstrated by aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN unless liver metastases were present, then AST and ALT < 5.0 c ULN; bilirubin < 1.5 c ULN unless Gilbert's Syndrome was present, then bilirubin may be > 1.5 ^c ULN. Activated partial thromboplastin time (aPPT) and prothrombin time (PT) were not to exceed 1.5 x ULN.

7. Subjects must have had QT interval corrected for heart rate (QTc) interval < 480 milliseconds (msec) on the baseline electrocardiogram.

Subject Exclusion Criteria

For this study, the following exclusion criteria was utilized.

1. Subjects that had untreated brain or meningeal metastases.

2. Subjects that had received anti-cancer therapy including chemotherapy, immunotherapy, biologic or any investigational therapy within a period of 21 days prior to the start of the study.

3. Subj ects with unresolved toxi cities from most recent prior anti-cancer therapy. 4. Subjects that received within a period of 7 days prior to the start of the study, any of steroid therapy for anti -neoplastic intent, strong/moderate CYP3 A inhibitors, and/or strong/moderate CYP3 A inducers, except as pre-approved.

5. Subjects that consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit within 3 days prior to start of the study.

6. Subjects that had major surgery within 28 days prior to Study Day 1.

7. Subjects that had psychiatric illness/social situation that would limit compliance with study requirements.

8. Subjects that were unable to swallow or absorb oral tablets normally.

9. Subjects that had known infection with hepatitis B or hepatitis C.

10. Subjects that had active peptic ulcer disease or other hemorrhagic

esophagiti s/ gastriti s .

11. Subjects that had symptoms of gross hematuria or gross hemoptysis.

12. Subjects with a history of long QT syndrome.

13. Subjects with peripheral neuropathy > grade 2.

14. Subjects that were currently exhibiting symptomatic or persistent, uncontrolled hypertension defined as a systolic blood pressure > 140 and/or diastolic blood pressure > 90 mmHg.

Criteria for Evaluation

Subjects were evaluated based on response criteria for acute myeloid leukemia (AML) from the revised guidelines by the International Working Group (IWG). Assessments were performed at cycle 2 day 1 (C2D1), cycle 3 day 1 (C3D1), and every 2 cycles thereafter for response assessment until two successive bone marrow samples documented a complete remission (CR). Transfusion independence information were collected on all subjects, defined as absence of any red blood cell (RBC) transfusion during any consecutive eight (8) weeks during the treatment period. Adverse event (AE) severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Efficacy was evaluated among all subjects who received at least one week of therapy at the prescribed target dose. Disease was assessed with bone marrow aspirate and/or biopsy at screening, C2D1, and as clinically indicated. Subjects could also consent to optional bone marrow biopsy collection at the final visit.

Dosing Cohorts

A total of 44 subjects with relap sed/refractory (R/R) acute myeloid leukemia (AML) were enrolled in this study. 19 subjects were dosed with mivebresib as a monotherapy, 25 subjects were dosed with mivebresib/venetoclax combination therapy, and 5 subjects were switched from mivebresib monotherapy to mivebresib/venetoclax combination therapy. A total of 18 subjects discontinued the study. Reasons for discontinuation included adverse event (AE) related to progression (14.3%, n=7) and AE not related to progression (22.4%, n=l 1). A summary of subject demographics is shown in TABLE 2 below. A breakdown of subject doing cohorts is shown in TABLE 3 below. Briefly, there were a total of seven (7) distinct dosing cohorts. Dosing cohort 1 had 7 subjects enrolled, received 2.5 mg. per day mivebresib as a monotherapy. Dosing cohort 2 had 4 subjects enrolled and received 2.0 mg. per day mivebresib as a monotherapy. Dosing cohort 3 had 8 subjects enrolled and received 1.5 mg. per day mivebresib as a monotherapy. Dosing cohort 4 had 6 subjects enrolled and received 1.0 mg. per day mivebresib and 400 mg. per day venetoclax. Dosing cohort 5 had 8 subjects enrolled and received 1.0 mg./day mivebresib and 800 mg. per day venetoclax. Dosing cohort 6 had 16 subjects enrolled and received 2.5 mg. per day mivebresib and 800 mg. per day venetoclax.

TABLE 2. Subject Demographics

ECOG = Eastern Cooperative Oncology Group; PS = performance status.

TABLE 3. Subject Dosing Cohorts

¹ Includes 1 subject who moved from monotherapy

2 Includes 4 subjects who moved from monotherapy

DLT = dose-limiting toxicity; PO = oral administration; QD = once daily Safety

Overall mivebresib as a monotherapy and as a combination therapy with venetoclax was well tolerated in subjects with relapsed/refractory (R/R) acute myeloid leukemia (AML) with few DLTs. Treatment-emergent adverse events (TEAEs) in > 30% of all subjects are summarized in TABLE 4 below. TEAEs for those individuals who switched from mivebresib monotherapy to mivebresib/venetoclax combination therapy is reflected in the“monotherapy” column when the individuals were in the mivebresib monotherapy cohort, and in the

“combination” column when switched to their respective mivebresib/venetoclax combination cohort. 23 (100%) of subjects reported grade 3 or 4 TEAEs. The most common grade 3 or 4 TEAEs were anemia in 12 (52.2%) subjects, thrombocytopenia in 10 (43.5%) subjects, and febrile neutropenia in 6 (26.1%) subjects. 19 (82.6%) subjects experienced serious adverse events (AEs) which included febrile neutropenia (4 subjects, 17.4%) and pneumonia (3 subjects, 13.0%). 13 subjects died of causes which were assessed as unrelated to mivebresib, including 5 subjects due to AML progression.

TABLE 4. Summary of Treatment-Emergent Adverse Events in >30% of Subjects

¹ n = 8 for 1.5 mg. mivebresib; n = 4 for 2.0 mg. mivebresib; n = 7 for 2.5 mg. mivebresib

² n = 6 for 1.0 mg. mivebresib + 400 mg. venetoclax; n = 8 for 1.0 mg. mivebresib + 800 mg. venetoclax; n = 16 for 2.5 mg. mivebresib + 800 mg. venetoclax

3 Taken from TABLE 3 supra

TEAE = treatment-emergent adverse event

Efficacy

Both mivebresib monotherapy and mivebresib with venetoclax showed antileukemic effects in subjects with relapsed/refractory (R/R) acute myeloid leukemia (AML). In addition, for both mivebresib monotherapy and mivebresib with venetoclax, the observed antileukemic effects occurred at doses lower than the maximum tolerated dose (MTD). A summary of IWG responses is provided in TABLE 5 below. The objective response rate (ORR) was 75.5% (37/49) in subjects evaluable for efficacy. A total of 2 subjects achieved complete remission (CR), both receiving mivebresib/venetoclax combination therapy. 1 subject achieved complete remission with incomplete hematologic recovery (CRi), receiving mivebresib monotherapy. 2 subjects achieved partial remission (PR), both receiving mivebresib/venetoclax combination therapy. 1 subject achieved a morphologic leukemia-free state (MLFS), receiving mivebresib/venetoclax combination therapy. 1 subject had aplasia and 1 subject had morphological relapse (MR), both receiving mivebresib/venetoclax combination therapy. 29 subjects had resistant disease (RD). The remaining 12 subjects were not evaluable.

Best percentage change from baseline in bone marrow blasts is shown in Figure 1. Blast percentage change over court of treatment for mivebresib as a monotherapy, in combination with venetoclax, and in subjects who were switched from monotherapy to combination therapy is shown in Figures 2A, 2B, and 2C respectively. An analysis of overall survival for subjects with R/R AML is shown in Figure 3. The median time to progression was 2.4 months (95% confidence interval, 1.7— 4 months, and median overall survival was 2.6 months (95% confidence interval, 1.8— 3.4 months).

TABLE 5. Summary of IWG responses in evaluable subjects with R/R AML

Pharmacokinetics (PK)

Mivebresib has a high plasma protein binding and is mainly metabolized by CYP3 As. Mivebresib is a low clearance compound and has high potential for cytochrome-P450-mediated drug-drug interaction. It has a high oral bioavailability of approximately 60%, with plasma terminal half-life around 20 hours. Significant correlation with drug exposure (Cmax) was observed in peripheral blood samples after 6 hours of mivebresib treatment. A summary of observed pharmacokinetics of mivebresib as a monotherapy is provided in TABLES 6, 7, 8 and the pharmacokinetics of mivebresib in combination with venetoclax is provided in TABLES 9, 10, and 11 below. Values are presented as a geometric mean (mean, %CV). Maximum serum concentration (Cmax) vs. dose for mivebresib in both monotherapy and combination therapy is displayed in Figure . AUC24 vs. dose for mivebresib in both monotherapy and combination therapy is displayed in Figure 5.

TABLE 6. Pharmacokinetic parameters for 1.5 mg QD Mivebresib monotherapy

a R_ac: Accumulation Ratio calculated as AUC Day 8/Day 1

b Median (minimum - maximum)

c Harmonic mean

d CLss/F AUC24 = area under the curve at 24 hours; AUCinf = area under the curve extrapolated to infinite time; AUC24/D = dose-normalized AUC24; AUCinf/D = dose-normalized AUCinf; Cmax = maximum serum concentration; Cmax/D = dose-normalized Cmax; CLss/F = apparent oral clearance; QD = once daily; Rac = accumulation ratio, i.e. calculated as AUC Day 8/Day 1 ; T 1/2 = biological half-life; Tmax = time to reach maximum serum concentration;

TABLE 7. Pharmacokinetic parameters for 2.0 mg QD Mivebresib monotherapy

a Rac: Accumulation Ratio calculated as AUC Day 8/Day 1

b Median (minimum - maximum)

c Harmonic mean

d CLss/F

AUC24 = area under the curve at 24 hours; AUCinf = area under the curve extrapolated to infinite time; AUC24/D = dose-normalized AUC24; AUCinf/D = dose-normalized AUCinf; Cmax = maximum serum concentration; Cmax/D = dose-normalized Cmax; CLss/F = apparent oral clearance; QD = once daily; Rac = accumulation ratio, i.e. calculated as AUC Day 8/Day 1; T1/2 = biological half-life; Tmax = time to reach maximum serum concentration; TABLE 8. Pharmacokinetic parameters for 2.5 mg QD Mivebresib monotherapy

a Rac: Accumulation Ratio calculated as AUC Day 8/Day 1

b Median (minimum - maximum)

c Harmonic mean

d CLss/F

AUC24 = area under the curve at 24 hours; AUCinf = area under the curve extrapolated to infinite time; AUC24/D = dose-normalized AUC24; AUCinf/D = dose-normalized AUCinf; Cmax = maximum serum concentration; Cmax/D = dose-normalized Cmax; CLss/F = apparent oral clearance; QD = once daily; Rac = accumulation ratio, i.e. calculated as AUC Day 8/Day 1 ; T 1/2 = biological half-life; Tmax = time to reach maximum serum concentration;

TABLE 9. Pharmacokinetic parameters for 1.0 mg Mivebresib + 400 mg Venetoclax

QD combination therapy

a Rac: Accumulation Ratio calculated as AUC Day 8/Day 1

b Median (minimum - maximum)

c Harmonic mean

d CLss/F

AUC24 = area under the curve at 24 hours; AUCinf = area under the curve extrapolated to infinite time; AUC24/D = dose-normalized AUC24; AUCinf/D = dose-normalized AUCinf; Cmax = maximum serum concentration; Cmax/D = dose-normalized Cmax; CLss/F = apparent oral clearance; QD = once daily; Rac = accumulation ratio, i.e. calculated as AUC Day 8/Day 1; T1/2 = biological half-life; Tmax = time to reach maximum serum concentration;

TABLE 10. Pharmacokinetic parameters for 1.0 mg Mivebresib + 800 mg Venetoclax

QD combination therapy

a Rac: Accumulation Ratio calculated as AUC Day 8/Day 1

b Median (minimum - maximum)

c Harmonic mean

d CLss/F

TABLE 11. Pharmacokinetic parameters for 2.5 mg Mivebresib + 800 mg Venetoclax

QD combination therapy

a Rac: Accumulation Ratio calculated as AUC Day 8/Day 1

b Median (minimum - maximum)

c Harmonic mean

d CLss/F

Pharmacodynamics (PD)

Dose-dependent pharmacodynamic effect (gene modulation: HEXIM1, MYC, DCXR, CD93) was observed in peripheral blood samples after 6hrs of mivebresib treatment. A cytogenetic analysis was performed using standard institutional guidelines and is summarized in TABLE 12 below. Molecular profiling mostly utilized myeloid-specific Next Gen Sequencing targeted panels. A summary of the pharmacodynamic (PD) molecular profile of subjects with relapsed/refractory (R/R) acute myeloid leukemia (AML) treatment with mivebresib

monotherapy and those with mivebresib/venetoclax combination therapy is presented in TABLE 13 below. Percentage change from baseline for PK markers in RR AML subjects treated with mivebresib is shown in Figures 6 A, 6B, and 6C.

TABLE 12. Summary of Subject Cytogenetic Risk Category

1 Cytogenetic risk groups defined as per 2017 European LeukemiaNet (ELN) risk stratification

TABLE 13. Summary of Subject PD Molecular Profiles

TABLE 14. Diagnosis of Tumor Lysis Syndrome (TLS)

24-hour period within 3 days before the start of therapy or up to 7 days afterward.

² Clinical TLS requires the presence of Laboratory TLS plus one or more findings from the Clinical TLS column.

3 Corrected calcium = measured calcium level in mg/dL + 0.8 ^c (4 - albumin in gm/dL).

⁴ Acute kidney injury, unless attributable to another cause, represents clinical TLS even if criteria for laboratory TLS are not satisfied.

It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the scope and spirit of the present disclosure. Therefore, it should be understood that various embodiments of the disclosure described herein are illustrative only and not intended to limit the scope of the disclosure. All references cited herein are hereby incorporated by reference in their entirety.

Claims

CLAIMS What is claimed is:

1. A method of treating acute myeloid leukemia (AML) in a human subject in need thereof comprising orally administering to said subject having AML about 1.0 mg. to about 2.5 mg. mivebresib once daily.

2. The method of claim 1, wherein the amount of mivebresib orally administered comprises about 1.0 mg. once daily.

3. The method of claim 1, wherein the amount of mivebresib orally administered comprises about 1.5 mg. once daily.

4. The method of claim 1, wherein the amount of mivebresib orally administered comprises about 2.0 mg. once daily.

5. The method of claim 1, wherein the amount of mivebresib orally administered comprises about 2.5 mg. once daily.

6. The method of any of claims 1-5, wherein the AML comprises relapsed/refractory (R/R) AML.

7. The method of any of claims 1-6, wherein the mivebresib is administered as a monotherapy.

8. The method of any of claims 1-6, wherein the mivebresib is administered as a combination therapy.

9. The method of any of claims 1-6, 8, further comprising administering to said subject about 400 mg. to about 800 mg. venetoclax once daily.

10. The method of claim 9, wherein the amount of venetoclax orally administered comprises about 400 mg. once daily.

11. The method of claim 9, wherein the amount of venetoclax orally administered comprises about 800 mg. once daily.

12. The method of any of claims 1-7, wherein the mivebresib is orally administered to the subject for a period of time sufficient to treat the AML.

13. The method of any of claims 9-12, wherein the mivebresib and venetoclax are orally administered to the subject for a period of time sufficient to treat the AML.

14. The method of any of claims 8-13, wherein the AML comprises relapsed/refractory (R/R) AML.

15. The method of any of claims 1-14, wherein the subject achieves at least one of i) a complete remission (CR), ii) a complete remission with incomplete count recovery (CRi), iii) a partial remission (PR) or iv) a morphologic leukemia free state (MLFS) as defined by

International Working Group (IWG) Criteria.