CA3097750A1 - Treating solid tumors with bromodomain inhibitors - Google Patents

Abstract

The present disclosure relates to methods of treating cancers characterized by the presence of a solid tumor in a human subject by administering an effective amount of mivebresib to the subject.

Description

TREATING SOLID TUMORS WITH BROMODOMAIN INHIBITORS
I. CROSS-REFERENCE TO RELATED APPLICATIONS
The present applications claims priority to U.S. Provisional Patent Application Serial No.
62/671,522, filed May 15, 2018, the disclosure of which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The field of the invention relates to the use of mivebresib for the treatment of cancers characterized by the presence of a solid tumor 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.
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. Although mivebresib has been shown to have encouraging preclinical efficacy in in vivo animal models, there remains an urgent need to identify a suitable therapeutic window for the administration of mivebresib for the treatment of cancers characterized by the presence of a solid tumor in human subjects.
IV. SUMMARY OF THE INVENTION
The present disclosure relates to methods for the treatment of cancers characterized by the presence of a solid tumor in a human subject in need thereof comprising administering to the subject an effective amount of mivebresib. The cancer may comprise, e.g., prostate cancer including but not limited to castration-resistant prostate cancer (CRPC), breast cancer, colorectal cancer, pancreatic cancer, head and neck cancer, and melanoma including but not limited to uveal melanoma.
Accordingly, in one aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor.
In some embodiments, the method comprises administering an effective amount of mivebresib to the patient. In some embodiments, the effective amount is about 1.5 to about 3.0 mg. of mivebresib .. once daily.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient about 1.5 mg. of mivebresib once daily.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient about 2.5 mg. of mivebresib once daily for about four days, discontinuing administration for about three days, and re-administering after about three days has ended.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient about 3.0 mg. of mivebresib once daily not more than three times in about one week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 1.5 mg. of mivebresib daily.

2 In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 2.5 mg. of mivebresib once daily for about four days, discontinuing administration for about three days, and re-administering after about three days has ended.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 3.0 mg. of mivebresib once daily not more than three times in about one week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 2.5 mg. of mivebresib once daily for four days, discontinuing administration for three days, and re-administering after three days has ended.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 3.0 mg. of mivebresib once daily not more than three times in one week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient an amount of mivebresib between about 9.0 mg. and about 10.5 mg.
per week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient about 9.0 mg. of mivebresib per week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient about 10.0 mg. of mivebresib per week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient about 10.5 mg. of mivebresib per week.

3 In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient an amount of mivebresib between 9.0 mg. and 10.5 mg. per week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 9.0 mg. of mivebresib per week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 10.0 mg. of mivebresib per week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 10.5 mg. of mivebresib per week.
In another aspect, the present disclosure is directed to a method of reducing the size of a solid tumor comprising contacting the solid tumor with an effective amount of mivebresib. In some embodiments, the effective amount of mivebresib corresponds to an amount of mivebresib administered according to any of the foregoing aspects. In some embodiments, the solid tumor is in a human subject.
In another aspect, the present disclosure is directed to a method of inhibiting cellular proliferation of a solid tumor comprising contacting the solid tumor with an effective amount of mivebresib. In some embodiments, the effective amount of mivebresib corresponds to an amount of mivebresib administered according to any of the foregoing aspects.
In some embodiments, the solid tumor is in a human subject.
In any of the foregoing aspects a method for treating a patient suffering from cancer characterized by the presence of a solid tumor, the cancer characterized by the presence of a solid tumor can comprise prostate cancer including but not limited to castration-resistant prostate cancer (CRPC), breast cancer, colorectal cancer, pancreatic cancer, head and neck cancer, and melanoma including but not limited to uveal melanoma. Additionally, in any of the foregoing aspects, the cancer characterized by the presence of a solid tumor can comprise ovarian cancer, leiomyosarcoma, mesenchymal chondrosarcoma, lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), endometrial adenocarcinoma, cholangiocarcinoma, pseudopapillary pancreatic carcinoma, small bowel cancer, salivary gland

4 adenocarcinoma, stomach cancer, bile duct cancer, osteosarcoma, adenoid cystic carcinoma, cervical cancer, acinic cell carcinoma, duodenal cancer, nasopharyngeal cancer, merkel cell carcinoma, head and neck cancer, fallopian tube cancer, and endometrial cancer.
In any of the foregoing aspects, mivebresib can be administered to the patient for a period of time sufficient to treat the cancer. In any of the foregoing aspects, mivebresib can be administered as a monotherapy. In any of the foregoing aspects, the patient can achieve at least a stable disease (SD) response per RECIST 1.1 criteria. In any of the foregoing aspects, the patient can achieve at least a partial response (PR) per RECIST 1.1 criteria.
In any of the foregoing aspects, the patient can achieve a complete response (CR) per RECIST
1.1 criteria. In any of the foregoing aspects wherein the cancer comprises castration-resistant prostate cancer, the patient can achieve at least an absence of disease progression under PCWG3 consensus criteria.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from a cancer characterized by the presence of a solid tumor comprising administering to the patient an effective amount of mivebresib, the cancer comprising one of colorectal cancer, breast cancer, prostate cancer including but not limited to castration-resistant prostate cancer (CRPC), head and neck cancer, melanoma including but not limited to uveal melanoma, adenoid cystic carcinoma, duodenal cancer, ductal carcinoma, and desmoplastic small round cell cancer, and the patient achieving at least a stable disease (SD) response per RECIST
1.1 criteria. In some embodiments, the effective amount is about 1.5 to about 3.0 mg. of mivebresib once daily.
In some embodiments, the effective amount is about 1.5 mg. of mivebresib administered once daily. In some embodiments, the effective amount is about 2.5 mg. of mivebresib once daily for four days, followed by discontinuing administration for about three days, and re-administering after about three days has ended. In some embodiments, the effective amount is about 3.0 mg. of .. mivebresib once daily not more than three times in about one week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from a cancer characterized by the presence of a solid tumor comprising administering to the patient an effective amount of mivebresib, the cancer comprising one of colorectal cancer, breast cancer, prostate cancer including but not limited to castration-resistant prostate cancer (CRPC), head and neck cancer, melanoma including but not limited to uveal melanoma, adenoid cystic carcinoma, duodenal cancer, ductal carcinoma, and desmoplastic small round cell cancer,

5 and the patient achieving at least a stable disease (SD) response per RECIST
1.1 criteria. In some embodiments, the effective amount is 1.5 mg. of mivebresib orally administered once daily. In some embodiments, the effective amount is 2.5 mg. of mivebresib once daily for four days, followed by discontinuing administration for about three days, and re-administering after about three days has ended. In some embodiments, the effective amount is 3.0 mg. of mivebresib once daily not more than three times in about one week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from a cancer characterized by the presence of a solid tumor comprising administering to the patient an effective amount of mivebresib, the cancer comprising one of colorectal cancer, breast cancer, prostate cancer including but not limited to castration-resistant prostate cancer (CRPC), head and neck cancer, melanoma including but not limited to uveal melanoma, adenoid cystic carcinoma, duodenal cancer, ductal carcinoma, and desmoplastic small round cell cancer, and the patient achieving at least a stable disease (SD) response per RECIST
1.1 criteria. In some embodiments, the effective amount is between about 9.0 mg. and about 10.5 mg. per week.
In some embodiments, the effective amount is about 9.0 mg. of mivebresib per week. In some embodiments, the effective amount is about 10.0 mg. of mivebresib per week. In some embodiments, the effective amount is about 10.5 mg. of mivebresib per week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from prostate cancer. In some embodiments, the prostate cancer comprises castration-resistant prostate cancer (CRPC). In some embodiments, the method comprises orally administering to the patient between about 1.5 mg. to about 3.0 mg. of mivebresib. In some embodiments, the method comprises orally administering to the patient about 1.5 mg. of mivebresib daily. In some embodiments, the method comprises orally administering to the patient about 2.5 mg. of mivebresib once daily for about four days, discontinuing administration for about three days, and re-administering after about three days has ended.
In some embodiments, the method comprises orally administering to the patient about 3.0 mg. of mivebresib once daily not more than three times in about one week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from prostate cancer. In some embodiments, the prostate cancer comprises castration-resistant prostate cancer (CRPC). In some embodiments, the method comprises orally administering to the patient 1.5 mg. of mivebresib daily. In some embodiments, the method

6 comprises orally administering to the patient 2.5 mg. of mivebresib once daily for about four days, discontinuing administration for about three days, and re-administering after about three days has ended. In some embodiments, the method comprises orally administering to the patient 3.0 mg. of mivebresib once daily not more than three times in about one week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from prostate cancer. In some embodiments, the prostate cancer comprises castration-resistant prostate cancer (CRPC). In some embodiments, the method comprises orally administering to the patient 1.5 mg. of mivebresib daily. In some embodiments, the method comprises orally administering to the patient 2.5 mg. of mivebresib once daily for four days, discontinuing administration for about three days, and re-administering after three days has ended. In some embodiments, the method comprises orally administering to the patient 3.0 mg.
of mivebresib once daily not more than three times in about one week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from prostate cancer. In some embodiments, the prostate cancer comprises castration-resistant prostate cancer (CRPC). In some embodiments, the method comprises orally administering to the patient an amount of mivebresib between about 9.0 mg. and about 10.5 mg.
per week. In some embodiments, the method comprises orally administering to the patient about 9.0 mg. of mivebresib per week. In some embodiments, the method comprises orally administering to the patient about 10.0 mg. of mivebresib per week. In some embodiments, the method comprises orally administering to the patient about 10.5 mg. of mivebresib per week. In some embodiments, mivebresib is administered to the patient for a period of time sufficient to treat the cancer.
In any of the foregoing aspects directed to a method for treating a patient suffering from prostate cancer, mivebresib can be administered to the patient for a period of time sufficient to treat the prostate cancer. In any of the foregoing aspects, mivebresib can be administered as a monotherapy. In any of the foregoing aspects, the patient can achieve at least a stable disease (SD) response per RECIST 1.1 criteria. In any of the foregoing aspects, the patient can achieve at least a partial response (PR) per RECIST 1.1 criteria. In any of the foregoing aspects, the patient can achieve at least a partial response (PR) per RECIST 1.1 criteria.
In any of the foregoing aspects, the patient can achieve a complete response (CR) per RECIST
1.1 criteria. In any of the foregoing aspects wherein the cancer comprises castration-resistant prostate cancer,

7 the patient can achieve at least an absence of disease progression under PCWG3 consensus criteria.
In another aspect, the present disclosure is directed to mivebresib for use in treating a patient suffering from cancer characterized by the presence of a solid tumor, according to any aspect of the present disclosure.
In another aspect, the present disclosure is directed to use of mivebresib for the manufacture of a medicament for treating a patient suffering from cancer characterized by the presence of a solid tumor, according to any aspect of the present disclosure.
.. IV. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 describes the organization of the dose escalation cohorts subjects were grouped into during the dose escalation study described in Example 1. The three main categories of cohorts included subjects taking mivebresib daily (left column), 4 days on/3 days off (middle column), and 3 times weekly (MWF, right column). Boxes which are shaded indicated cohorts which experienced evaluable dose-limiting toxicity (DLT) events. Boxes which are bolded indicated the cohorts with the optimal dose of mivebresib for each of the dosing schedules.
RECIST 1.1 scoring was utilized to evaluate patient response; SD = stable disease, PD =
progressive disease, per RECIST 1.1 guidelines. As shown, the optimal dose for daily administration of mivebresib was 1.5 mg, the optimal dose for 4 days on/3 days off was 2.5 mg.
and the optimal dose for 3 times weekly was 3.0 mg..
Figures 2A, 2B describe relevant pharmacokinetic (PK) data for the dose escalation study described in Example 1. Figure 2A shows a regression analysis of Cmax (ng/mL) v. dose (mg) of mivebresib for the daily (QD) cohorts (N), 4 days on/3 days off cohorts (1), and the 3 times weekly (MWF) cohorts (+). As shown, Cmax displayed a linear relationship to dose of mivebresib among the different dosing schedules; Cmax = -1.886124 +
9.3688543*dose (mg); R2 =0.92, p-value for slope < 0.0001. Figure 2B shows a regression analysis of AUC. (ng.hr/mL) v. dose (mg) of mivebresib for the daily (QD) cohorts (N), 4 days on/3 days off cohorts (1), and the 3 times weekly (MWF) cohorts (+). Tmax (not shown) was reported to be between about 2-4 hours. T1/2 was reported to be between about 13-32 hours. Slope for AUC. =
4.5417256 +
219.8727*dose (mg); R2 =0.75, p-value for Slope < 0.0003.

8 Figure 3 is a waterfall plot describing best percentage change in size of tumor/target lesion from baseline, stratified by dose per week. Black solid bars indicate <
7 mg. mivebresib per week, white bars with black outlines indicate 7 - < 10 mg. mivebresib per week, and hatched bars indicate > 10 mg. mivebresib per week. As shown, higher weekly doses of mivebresib, i.e.
at or above 7 - < 10 mg. per week and particularly > 10 mg., trended towards better efficacy as measured by reduction in tumor/target lesion from baseline.
VI. DETAILED DESCRIPTION OF THE INVENTION
The present disclosure includes a number of different dosing regimens and amounts for orally administering an effective amount of mivebresib to a patient.
Accordingly, in one aspect, the amount is between about 1.5 to about 3.0 mg.
of mivebresib. In this context, a range of about 1.5 mg. to about 3.0 mg. of mivebresib includes amounts ranging from, i.e. 1.425 mg. mivebresib up to 3.15 mg. mivebresib, and any intervening ranges therein. Accordingly, this aspect of the present disclosure is not limited by any particular dosing regimen and is only limited by the amount of mivebresib which is administered to the patient at once.
In another aspect, the amount is about 1.5 mg. of mivebresib given to the patient 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 is about 2.5 mg. of mivebresib given to the patient for four consecutive days, followed by discontinuing administration for three consecutive days, and then re-administering of mivebresib again (e.g., 2.5 mg. mivebresib PO 4 on/3 off).
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 is about 3.0 mg. of mivebresib given to the patient three times a week (e.g., 3.0 mg. mivebresib PO MWF). In this context, administering about 3.0 mg.
mivebresib includes administering about 3.15 mg., 3.12 mg., 3.09 mg., 3.06 mg., 3.03 mg., 3.0 mg., 2.97 mg., 2.94 mg., 2.91 mg., 2.88 mg., 2.85 mg., and any intervening ranges therein.

9 In another aspect, the effective amount is 1.5 mg. of mivebresib given to the patient once daily (e.g., 1.5 mg. mivebresib PO QD).
In another aspect, the amount is 2.5 mg. of mivebresib given to the patient for four consecutive days, followed by discontinuing administration for three consecutive days, and then re-administering of mivebresib again (e.g., 2.5 mg. mivebresib PO 4 on/3 off).
In another aspect, the amount is 3.0 mg. of mivebresib given to the patient three times a week (e.g., 3.0 mg. mivebresib PO MWF).
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 1.5 mg. of mivebresib daily.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 2.5 mg. of mivebresib once daily for about four days, discontinuing administration for about three days, and re-administering after about three days has ended.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 3.0 mg. of mivebresib once daily not more than three times in about one week.
In another aspect, the present disclosure is directed to a method for treating a patient __ suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 2.5 mg. of mivebresib once daily for four days, discontinuing administration for three days, and re-administering after three days has ended.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 3.0 mg. of mivebresib once daily not more than three times in one week.
These three distinct dosing regimens correspond to an amount of mivebresib administered to a patient ranging from about 9.0 mg. to about 10.5 mg. per week. See, e.g., Figure 3 for a representative waterfall plot. Accordingly, in yet another aspect, the effective amount of mivebresib administered to the patient is between about 9.0 mg. and about 10.5 mg.
per week. In this context, a range of about 9.0 mg. to about 10.5 mg. of mivebresib includes amounts ranging from, i.e. 8.55 mg. mivebresib up to 11.025 mg. mivebresib, and any intervening ranges therein. This aspect can include a dosing regimen of administering about 1.5 mg. of mivebresib once daily to the patient, a dosing regimen of administering about 2.5 mg. of mivebresib to the patient 4 days on/3 days off, as well as a dosing regimen of administering about 3.0 mg. of mivebresib to the patient 3x weekly, but any other dosing regimen which amounts to about 9.0 mg. to about 10.5 mg. of mivebresib being administered to the patient per week is considered embodied by this aspect of the present disclosure.
Accordingly, this aspect of the present disclosure is not limited by any particular dosing regimen, and is only limited by the amount of mivebresib which is administered to the patient per week.
In another aspect, the effective amount of mivebresib administered to the patient is about

10.5 mg. per week. In this context, administering about 10.5 mg. mivebresib includes administering about 11.025 mg., 10.92 mg., 10.815 mg., 10.71 mg., 10.605 mg., 10.5 mg., 10.395 mg., 10.29 mg., 10.185 mg., 10.08 mg., 9.975 mg., and any intervening ranges therein.
This aspect can include a dosing regimen of administering about 1.5 mg. of mivebresib daily to the patient, but any other dosing regimen which amounts to about 10.5 mg. per week is considered embodied by this aspect of the present disclosure. Accordingly, this aspect of the present disclosure is not limited by any particular dosing regimen, and is only limited by the amount of mivebresib which is administered to the patient per week.
In another aspect, the effective amount of mivebresib administered to the patient is about 10.0 mg. per week. In this context, administering about 10.0 mg. mivebresib includes administering 10.5 mg., 10.4 mg., 10.3 mg., 10.2 mg., 10.1 mg., 10.0 mg., 9.9 mg., 9.8 mg., 9.7 mg., 9.6 mg., 9.5 mg., and any intervening ranges therein. This aspect can include a dosing regimen of administering about 2.5 mg. of mivebresib to the patient 4 days on/3 days off, but any other dosing regimen which amounts to about 10.0 mg. per week is considered embodied by this aspect of the present disclosure. Accordingly, this aspect of the present disclosure is not limited by any particular dosing regimen, and is only limited by the amount of mivebresib which is administered to the patient per week.
In another aspect, the effective amount of mivebresib administered to the patient is about 9.0 mg. per week. In this context, administering about 9.0 mg. mivebresib includes administering 9.45 mg., 9.36 mg., 9.27 mg., 9.18 mg., 9.09 mg., 9.0 mg., 8.91 mg., 8.82 mg., 8.73 mg., 8.64 mg., 8.55 mg., and any intervening ranges therein. This aspect can include a

11 dosing regimen of administering about 3.0 mg. of mivebresib to the patient 3x weekly, but any other dosing regimen which amounts to about 9.0 mg. per week is considered embodied by this aspect of the present disclosure. Accordingly, this aspect of the present disclosure is not limited by any particular dosing regimen, and is only limited by the amount of mivebresib which is administered to the patient per week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient an amount of mivebresib between 9.0 mg. and 10.5 mg. per week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 9.0 mg. of mivebresib per week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 10.0 mg. of mivebresib per week.
In another aspect, the present disclosure is directed to a method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient 10.5 mg. of mivebresib per week.
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 may or may not be administered as a monotherapy according to any aspect of the present disclosure.
The cancer to be treated as defined herein are cancers characterized by the presence of solid tumors. For example, the cancers may include prostate cancer including but not limited to castration-resistant prostate cancer (CRPC), breast cancer, colorectal cancer, pancreatic cancer, head and neck cancer, and melanoma including but not limited to uveal melanoma. Additional cancers characterized by the presence of solid tumors include those listed in TABLE 3 infra, which illustrate the diversity of solid tumors for which mivebresib has been tested and shown to be active.
In another aspect, the present disclosure is directed to a method of reducing the size of a solid tumor comprising contacting the solid tumor with an effective amount of mivebresib. In

12 some embodiments, the effective amount of mivebresib corresponds to an amount of mivebresib administered according to any aspect of the present disclosure, e.g. amounts corresponding to any of the dosing regimens or amounts described herein. In some embodiments, the solid tumor is in a human subject.
In another aspect, the present disclosure is directed to a method of inhibiting cellular proliferation of a solid tumor comprising contacting the solid tumor with an effective amount of mivebresib. In some embodiments, the effective amount of mivebresib corresponds to an amount of mivebresib administered according to any aspect of the present disclosure, e.g.
amounts corresponding to any of the dosing regimens or amounts described herein. In some embodiments, the solid tumor is in a human subject.
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.
"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 1.50 mg. mivebresib would include administering 1.575 mg., 1.56 mg., 1.545 mg., 1.53 mg., 1.515 mg., 1.5 mg., 1.485 mg., 1.47 mg., 1.455 mg., 1.440 mg., 1.425 mg., and any intervening ranges therein.

13 "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 II-dependent transcription elongation.
"Mivebresib" or "mivebresib" as used herein refers to N44-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-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 C22E119F2N304S and the molecular weight is 459.468 g/mol. Discovery and synthesis of mivebresib is described in, for example, McDaniel et at., 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

14 chemical structure of mivebresib is indicated below. In case of any conflict or ambiguity the following structure will control:

/

Mivebresib / ABBV-075 "PCWG3" or "PCWG3 consensus" as used herein refers to the "Prostate Cancer Working Group 3" consensus for trials involving castration-resistant prostate cancer (CRPC). PCWG3 evaluation criteria can include prostate-specific antigen (PSA) level progression as well as measurement of bone lesions. PSA level can be measured at a clinical baseline and is subsequently monitored. PSA progression does not necessarily indicate disease progression.
PSA progression can be defined as an increase that is about > 25% and > 2 ng/mL above the nadir and which is subsequently later confirmed. Bone lesions can be measured as either improved or stable, defined as having no new lesions, or worsening (new lesions present).
Changes in intensity alone may not constitute progression or regression.
Disease progression can be defined as the appearance of at least two new lesions on a first posttreatment scan, with at least two additional lesions on a next scan.
"RECIST" or "RECIST 1.1" as used herein refers to "Responsive Evaluation Criteria in Solid Tumors" and is a set of published rules/criteria that define patient progression during treatment. As described herein, RECIST 1.1 scoring recognizes four distinct categories;
"complete response" (CR), "partial response" (PR), "progressive disease" (PD), and "stable disease" (SD). "Complete response" as used herein requires disappearance of all target lesions, including any pathological lymph nodes having reduction in short axis to less than 10 mm.
"Partial response" as used herein requires at least a 30% decrease in the sum of diameters of target lesions using baseline sum diameters of the lesions as the reference point. "Stable disease"

as used herein requires neither sufficient shrinking to qualify as a partial response nor sufficient increase to qualify as disease progression, using smallest sum diameters as a reference point.
"Progressive disease" as used herein requires at least a 20% increase in the sum of diameters of target lesions using the smallest sum on study as the baseline reference.
There must additionally be an absolute increase of at least 5.0 mm in lesion size. Finally, appearance of one or more new lesions is considered disease progression. Further RECIST 1.1 criteria is described in, for example, Eisenhauer et at. European Journal of Cancer 45 (2009) 228-247, hereby incorporated by reference in its entirety.
"Solid tumor" or "solid tumors" as used herein refer to abnormal masses or growths of tissue that are generally free of cysts or liquid, and as used herein excludes hematological malignancies, e.g. myeloid neoplasms and lymphoid neoplasms. Solid tumors may typically be benign or malignant, i.e. cancerous. Non-limiting examples of cancerous solid tumors include sarcomas and carcinomas. Non-limiting examples of cancers characterized by the presence of a solid tumor that are covered by the present disclosure include those listed in Table 3 infra, including colon cancer, including colorectal cancer, melanoma, including malignant melanoma and uveal melanoma, prostate cancer, pancreatic cancer, breast cancer, including ductal breast cancer, ovarian cancer, leiomyosarcoma, mesenchymal chondrosarcoma, lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), endometrial adenocarcinoma, cholangiocarcinoma, pseudopapillary pancreatic carcinoma, small bowel cancer, salivary gland adenocarcinoma, stomach cancer, bile duct cancer, osteosarcoma, adenoid cystic carcinoma, cervical cancer, acinic cell carcinoma, duodenal cancer, nasopharyngeal cancer, merkel cell carcinoma, head and neck cancer, fallopian tube cancer, and endometrial cancer.
"Subject" or "subjects" may be 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 patient suffering from cancer characterized by the presence of solid tumors, "treating" can include reducing, slowing, or halting tumor progression in the patient. More specifically, as used herein, "treatment" can also include a stable disease (SD) response in addition to partial response (PR) and complete response (CR) as defined by RECIST 1.1 scoring criteria. Thus, "treatment" of cancer as used herein explicitly does not require complete remission or even partial remission.
Specifically for castration-resistant prostate cancer (CRPC), "treatment" of cancer may additionally, but not necessarily, include an absence of disease progression as determined by PCWG3 consensus criteria.
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/definitions utilized in the Examples include the following:
ABBV-075 = Mivebresib AE = adverse event AUC = area under the curve, e.g. AUC.
ALT = alanine aminotransferase ANC = absolute neutrophil count AST = aspartate aminotransferase BP = blood pressure Cmax = maximum observed plasma concentration CR = complete response CRPC = castration-resistant prostate cancer CXDY = Cycle X, Day Y, e.g. C1D1 is Cycle 1, Day 1 CYP3A = cytochrome P4503A

DLT = dose-limiting toxicity ECG = electrocardiogram ECOG = Eastern Cooperative Oncology Group GI = gastrointestinal Mivebresib = N44-(2,4-difluorophenoxy)-3-(6-methy1-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide or a pharmaceutically acceptable salt thereof.
MWF = Monday, Wednesday, Friday, e.g. administered Monday, Wednesday, and Friday MTD = maximum tolerated dose NSCLC = non-small cell lung cancer ORR = objective response rate PCWG3 = Prostate Cancer Working Group 3 PD = progressive disease PFS = progression-free survival PK = pharmacokinetics PO = orally administered, e.g. administered "by mouth"
PSA = prostate-specific antigen aPPT = activated partial thromboplastin time PR = partial response PS = performance status PT = prothrombin time SCLC = small cell lung cancer SD = stable disease Tmax = time to maximum observed plasma concentration, e.g. time to Cmax QD = once daily, e.g. administered once daily RECIST = Response Evaluation Criteria in Solid Tumors, e.g. RECIST 1.1 ULN = upper limit of normal 1. Phase I Dose Escalation Study¨Solid Tumors Study Design This dose escalation 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 cancers characterized by the presence of solid tumors.
The dose escalation cohort determined dose-limiting toxicities (DLT), maximum tolerated dose (MTD) and the therapeutic dosing window of orally administered mivebresib at different monotherapy dosing schedules in subjects with advanced solid tumors. The first dosing schedule included continuous daily dosing of mivebresib. In additional dosing schedules subjects were administered .. mivebresib with breaks between some treatment days as selected based on PK
and safety data from prior subjects treated on the protocol. Other dosing schedules for mivebresib included dosing 4 days followed by 3 days off drug or dosing three times weekly (administered Monday/Wednesday/Friday). See Figure 1 for a breakdown of the different dosing cohorts.
In this study, mivebresib was given daily for 28-day cycles, beginning with a dose of 1.0 mg. mivebresib. The starting clinical dose of 1.0 mg./day was arrived at based on pre-clinical modeling of 1 mg/kg/day in rats. Calculations for the starting dose included a 10-fold safety factor included; thus, 1 mg/60 kg/day was approximated as the starting point.
Dose escalation followed a traditional 3 + 3 design. Dose levels doubled for each new cohort until grade 2 or greater toxicity, but no DLT, was seen in 2/3 subjects within a cohort. Doses for the next 3 cohorts after grade 2 or greater toxicity escalated by decreasing incremental dose ratios of 0.67, 0.5, and 0.33. Doses for remaining cohorts escalated by incremental dose ratios of 0.33.
Additional schedules that were explored began with a dose of mivebresib that was at or below the MTD of daily dosing. Subjects with controlled disease, who had not experienced a DLT and who had tolerable side effects, continued to receive treatment until disease progression or unacceptable toxicity occurred. The therapeutic dosing window of orally administered mivebresib for each schedule (daily, 4 days on/3 days off, and 3 times weekly) was determined.
Tumor assessments were performed within 28 days prior to the beginning of the cycle, ever 8 weeks from the beginning of the cycle, and at the termination of the study.
Dose-limiting toxicity (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 following criteria:
DLT Definitions for this study included:
1. Grade > 4 absolute neutrophil count (ANC) decrease lasting > 7 days, grade > 4 platelet count decrease, or grade > 3 ANC decrease with fever.
2. Any grade > 2 neurotoxicity.
3. Unexpected grade 2 toxicity which requires dose reduction or dose delay lasting greater than 1 week.
4. Grade > 3 nausea or vomiting for > 48 hours or diarrhea for > 72 hours despite maximum supportive care. Grade > 3 hypertension despite anti-hypertensive treatment.
5. All other grade > 3 adverse events, unless an alternative etiology has been identified, were considered a DLT.
Furthermore, subjects in this study were selected to have the following procedures:
1. Pre-treatment tumor biopsy.
2. Pharmacokinetic (PK) draws and serial blood pressure (BP) monitoring through 24 hours after dosing on C1D1, with a single electrocardiogram (ECG) at each draw;
3. PK draws and serial BP monitoring through 8 hours after dosing on C1D8, with single ECG at each draw; and 4. PK at 14 h, 17 h, and 20 h after dosing and serial BP monitoring on C1D15, with single ECG at each draw.
Subject Inclusion Criteria For the solid tumor dose escalation cohort, the following inclusion criteria was utilized.
After meeting the selection criteria, enrolled subjects were assigned a subject number and dose level. A minimum of 3 subjects were enrolled at each dose level in this study.
1. Subjects must have been > 18 years of age at time of enrollment.
2. Subjects must have had cancer not amenable to curative therapy; must have histological confirmation of locally advanced or metastatic solid tumor that is either refractory after standard of care therapy for the disease or for which standard of care therapy did not exist.
3. Subjects must have consented to provide archived tissue sample of tumor lesion for biomarker analysis.

4. Subjects must have had an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
5. Subjects must have had a serum albumin level during screening of > 3.2 g/dL.
6. Subjects must have had absolute neutrophil count (ANC) > 1,500/mm3 and platelets > 100,000/mm3; and hemoglobin > 9.0 g/dL.
7. 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.
8. 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 x ULN; bilirubin < 1.5 x ULN
unless Gilbert's Syndrome was present, then bilirubin may be > 1.5 x ULN. Activated partial thromboplastin time (aPPT) and prothrombin time (PT) were not to exceed 1.5 x ULN.
9. Subjects must have had QT interval corrected for heart rate (QTc) interval <480 milliseconds (msec) on the baseline electrocardiogram.
Subject Exclusion Criteria For the solid tumor dose escalation cohort, the following exclusion criteria was utilized.
1. Subject 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. Subjects with unresolved toxicities 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 CYP3A
inhibitors, and/or strong/moderate CYP3A 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 esophagitis/gastritis.
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 For solid tumors, response by RECIST version 1.1 was utilized as described herein.
Additionally, for castration-resistant prostate cancer (CRPC) only, PCWG3 was utilized. For patients with CRPC, response assessment was performed via RECIST 1.1 for visceral and soft tissue lesions and PCWG3 for bone lesions. Additionally, PSA progression was defined per PCWG3 criteria as described herein. RECIST 1.1 Progression-free survival was measured using objective solid tumor assessments after every 2 cycles of therapy. Descriptive statistics were utilized for analyses of objective response rate (ORR), progression-free survival, duration of overall response, and ECOG performance status. Pharmacokinetic (PK) parameters included maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), and area under the plasma concentration-time curve (AUC) from time 0 to last measurable concentration. These PK parameters were determined utilizing non-compartmental methods. Descriptive statistics were utilized for demographic and safety variables. Adverse events were evaluated and summarized. ECG parameters were descriptively summarized and the relationship between AQTc (QTc change from time-matched baseline) and mivebresib concentration were explored.
Dosing Cohorts 72 total patients were enrolled in this study. The most common tumors included uveal/choroidal melanoma (n = 10); breast (n = 8); pancreatic (n = 6); head and neck (n = 5); and prostate (n =3). A complete list of the solid tumors is listed in TABLE 3 below. Median age was 61.5 years (range 23-83); median treatment duration was 7.6 weeks (range 0.9-39.6). Of the 72 patients, 18 total exhibited stable disease. In total, 23, 22, and 27 pts entered the daily schedule, 4 on/3 off schedule, and 3 times weekly (MWF) schedule respectively. The reasons for .. discontinuation were: adverse event (AE) related to progression, 2.8% (n =
2); AE not related to progression, 2.8% (n = 2); clinical progressive disease, 12.6% (n = 9);
radiologic progressive disease, 58.3% (n = 42); lost to follow-up, 2.8% (n = 2); withdrew consent, 9.7% (n = 7); and other, 11.1% (n = 8). A summary of subject demographics is shown in TABLE!
below. Patient enrollment by dosing cohort is shown in TABLE 2 below. A detailed breakdown of the dosing cohorts is shown in TABLE 3 below. A summary of adverse events is shown in TABLE 4 below.
TABLE!. Summary of subject demographics.
Characteristic N = 72 Age, median (range), years 61.5 (23.0-83.0) Gender, n (%) Female 49 (68.1) Male 23 (31.9) Race, n (%) White 68 (94.4) Black 2 (2.8) Asian 2 (2.8) ECOG PS, n (%) 0 28 (38.9) 1 44 (61.1) Primary tumor occurring in >4% of patients, n (%) Uveal/choroidal melanoma 10 (13.9) Breast 8(11.1) Pancreatic 6 (8.3) Head and neck 5 (6.9) Prostate 3 (4.2) Median number of prior therapies, n (%) 4(5.6) 0 6(8.3) 1 7(9.7) 2 16 (22.2) 3 39 (54.2) >4 ECOG = Eastern Cooperative Oncology Group; PS = performance status.

TABLE 2. Patient enrollment by dosing cohort.
Number of Patients who .== .==
.== .==
.= . Patients Patients with .
.== == =. Cohort. completed D LT DI:fg ..:
..
..
.=..:
:.
. enrolled DLTs .. =
.
..
:.==
. period .=
..:
.=
Cohort 1 (1 mg daily) Cohort 2 Thrombocytopenia, n (2 mg daily) 8 7 3 =2 GI hemorrhage, n = 1 Cohort 3 (1 mg 4 on/3 off) Cohort 4 (1 mg 3x Weekly 6 4 0 N/A
(MWF) Cohort 5 (1.5 mg daily) Cohort 6 11 8 1 Hypertension, n = 1 (2 mg 4/7 days) Cohort 7 (2 mg 3x Weekly 4 4 0 N/A
(MWF) Cohort 8 (3 mg 3x Weekly 7 5 0 N/A
(MWF) Cohort 9 2 2 3 Hypertension, n = 3 (3 mg 4 on/3 off) Cohort 10 (4.5 mg 3x 5 4 2 Thrombocytopenia, n = 2 Weekly (MWF) Cohort 11 (2.5 mg 4 on/3 4 3 0 N/A
off) Cohort 12 Decreased appetite, n (4 mg 3x Weekly 3 = 1 (MWF) Fatigue, n =

AST elevation, n = 1 AST = aspartate aminotransferase; DLT = dose-limiting toxicity; GI =
gastrointestinal; MWF =
5 Monday, Wednesday, Friday; N/A = not applicable TABLE 3. Detailed breakdown of dosing cohorts.
Identifier Cancer (solid tumors) Dose (mg.) DLT (YIN) SD
(Y/N) ' Daily (QD) Cohorts (PO) 10125E unknown primary 1.0 mg N Y
11106E small bowel 1.0 mg N Y
12104E bronchial carcinoid 1.0 mg N Y
10103E rectal carcinoma 1.0 mg N N
10102E adenocarcinoma 1.0 mg N N
11158 colorectal 1.5 mg N N
10157 uveal melanoma 1.5 mg N N
11150E prostate 1.5 mg N N
12149E pancreatic 1.5 mg N N
11146 ductal breast 1.5 mg N N
10145E choroidal melanoma 1.5 mg N Y
11139E colon 1.5 mg N Y
12137 pancreatic 1.5 mg N N
10136E prostate 1.5 mg Y Y
10133E ovarian 1.5 mg N N
10119E ovarian 2.0 mg Y N
10118E leiomyosarcoma 2.0 mg N N
12117E mesenchymal chondrosarcoma 2.0 mg Y N
11116 small cell lung cancer (SCLC) 2.0 mg N N
12113E endometrial adenocarcinoma 2.0 mg N N
10112E rectal carcinoma 2.0 mg N Y
12111E cholangiocarcinoma 2.0 mg Y N
10108 pancreatic carcinoma 2.0 mg N Y
3x Weekly (NIWF) Cohorts (PO) 13196 gastric 4.0 mg N N
10193 bile duct 4.0 mg N N
13195E breast 4.0 mg Y N

.................... _______________ ..................
identifier Cancer (solid tumors) ....
Dose (mg.) DLT (Y/N) SD (Y/N) ' 13192E cholangiocarcinoma 4.0 mg N N
10191E uveal melanoma 4.0 mg Y N
10186 osteosarcoma 4.5 mg N N
10185 uveal melanoma 4.5 mg Y N
13182 cholangiocarcinoma 4.5 mg Y N
11181 adenoid cystic carcinoma 4.5 mg N Y
10180 pancreatic 4.5 mg N N
13176 malignant melanoma 3.0 mg N N
11177 esophageal 3.0 mg N N
13174E synovial cell sarcoma 3.0 mg N N
10168E endometrial 3.0 mg N N
10166 breast 3.0 mg N N
12167E prostate 3.0 mg N N
12160 cervical 3.0 mg N N
13152E adenoid cystic carcinoma 2.0 mg N N
13151E acinic cell carcinoma 2.0 mg N Y
10148E choroidal melanoma 2.0 mg N N
12147E cervical cancer 2.0 mg N N
12141E duodenal 1.0 mg N Y
10138E uveal melanoma 1.0 mg N Y
10135E nasopharyngeal 1.0 mg N N
11130 small cell lung cancer (SCLC) 1.0 mg N N
11128 breast 1.0 mg N N
10124E ovarian 1.0 mg N N
............... ... .......................................
.............. .. .......................................
............... ... ......................................
4 Days On/ 3 Days Off Cohorts (PO) 11190E rectal 2.5 mg N N
10189 breast 2.5 mg N N
10188E merkel cell carcinoma 2.5 mg N N
10187E uveal melanoma 2.5 mg N N

Identifier Cancer (solid tumors) Dose (mg.) DLT (Y/N) SD (Y/N) I
10179 ductal carcinoma 3.0 mg Y Y
10178 ductal carcinoma 3.0 mg Y N
10173E uveal melanoma 2.0 mg N N
13172E GI primary 2.0 mg N N
10171E uveal melanoma 2.0 mg N Y
13170E head and neck 2.0 mg N N
11169 pancreatic 2.0 mg N N
13165E ovarian 2.0 mg N N
11159E colon 2.0 mg N N
10156 uveal melanoma 2.0 mg N N
12154 unknown primary 2.0 mg N N
10142E pancreatic 2.0 mg Y N
12140 fallopian tube 2.0 mg N N
11134E colon 1.0 mg N Y
11131E breast 1.0 mg N Y
10129E head and neck 1.0 mg N Y
10127 endometrial 1.0 mg N N
10122E desmoplastic small round cell 1.0 mg N Y
DLT = dose limiting toxicity; MWF = Monday, Wednesday, Friday; PO = oral administration;
SD = stable disease (RECIST 1.1) DoseEscalation n (O/0) All Grade grades 3/4 i'AL in >20% of all ii 70 (97) 52 (72) patients Thrombocytopenia 38 (53) 24 (33) Dysgeusia 36(50) 2(3) Fatigue 29 (40) 3 (4) Nausea 25 (35) 1(1) Decreased appetite 20 (28) 3 (4) Anemia 19(26) 13 (18) Diarrhea 18 (25) 4(6) Vomiting 17 (23) 1(1) Dyspnea 14(19) 7(10) Mivebresib in >5% of 64 (89) 40 (56) all patients Dysgeusia 36(50) 2(3) Thrombocytopenia 35 (49) 24 (33) Fatigue 20 (28) 3 (4) Nausea 17 (24) 1(1) Decreased appetite 16 (22) 2 (3) Diarrhea 16 (22) 4 (6) Anemia 12(17) 4(6) Vomiting 10 (14) 1(1) Hypertension 7 (10) 4 (6) Hyperbilirubinaemia 7 (10) 1 (1) Weight decreased 4 (6) 0 Rash maculo-papular 5 (7) 0 Any serious AE in 25 05) >S% of all patients __ Malignant neoplasm 6 (8) progression Abdominal pain 6 (8) Dyspnea 6 (8) Any serious AE related 4 (6) to Mivebresib ________ Thrombocytopenia 1 (1) Anemia 0 Pneumonia 0 GI hemorrhage 1 (1) Hypertension 1 (1) Nausea 0 Fatigue 0 AE = adverse event; GI = gastrointestinal Pharmacokinetics (PK) Mivebresib has a high plasma protein binding and is mainly metabolized by CYP3As.
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. Surprisingly, exposure modeling from subjects treated with continuous daily mivebresib showed comparable Cmax after the first dose on the 3 times weekly dosing schedule as well as showing extended periods near Calla after each dose. The same results were seen for dosing consecutively 4 days on/3 days off. A regression analysis of Cmax (ng/mL) v. dose (mg) of mivebresib for the different dosing cohorts is illustrated in Figure 2A. A
regression analysis of AUC. (ng.hr/mL) v. dose (mg) of mivebresib for the different dosing cohorts is illustrated in Figure 2B.
Maximum tolerated dose (MTD)¨Solid Tumors In total, 23 patients entered the daily dosing schedule, 27 entered the 3x weekly (MWF) schedule and 22 patients entered the 4 days on/3 days off schedule. Overall, 71 patients (98.6%) reported >1 treatment-emergent adverse events (TEAEs); thrombocytopenia (56.9%), dysgeusia (48.6%), fatigue (43.1%) and nausea (34.7%) were most common. Grade 3/4 TEAEs were reported in 52 patients (72.2%); thrombocytopenia (30.6%) and anemia (15.3%) were most common. 11 total patients died, however none were considered study drug related. Dose-limiting toxicities (DLTs) included thrombocytopenia, fatigue, aspartate aminotransferase elevation, gastrointestinal bleed and hypertension. The main DLT observed was severe thrombocytopenia. There were 56 evaluable patients. Of these, 35 (62.5%) of patients had stable disease (SD) and 21(37.5%) had progressive disease. 10 patients on the daily schedule, 12 patients on the 4 days on/3 days off schedule, and 13 patients on the 3x weekly (MWF) schedule had SD. Additionally, 8 patients who had < 7 mg. mivebresib per week, 11 patients on 7- <10 mg. mivebresib per week and 16 patients on >10 mg. mivebresib per week had SD; see Figure 3 for a waterfall plot.
The maximum tolerated dose (MTD) was evaluated in each of the three different dosing schedules (daily, 4 on/3 off, and 3 times weekly/MWF). For the once daily (QD) schedule, the MTD was established as about 1.5 mg. mivebresib daily. For the 4 on/3 off schedule, the MTD
was established as about 2.5 mg. mivebresib. For the 3 times weekly/MWF
schedule, the MTD
was established as about 3.0 mg. mivebresib. The MTD for each of the dosing schedules corresponds to the recommended dose of mivebresib to be administered to patients suffering from cancer characterized by the presence of a solid tumor. Median progression-free survival (PFS) for all cancer types (solid tumors) was 1.8 months. For uveal melanoma in particular, median PFS was 2.0 months and survival was 7.4 months. The best observed response was stable disease (SD) per RECIST 1.1 scoring criteria. The conclusion was that mivebresib has a tolerable safety profile at the doses established in this study and led to stable disease in many of the patients suffering from cancer characterized by the presence of solid tumors.
2. Phase I Dose Escalation Study¨Prostate Cancer Expansion Cohort Study Design and Dosing Cohort In addition to the 72 patients with solid tumors described in Example 1 supra, additional patients having prostate cancer were enrolled in an expansion cohort. These patients were administered mivebresib according to the 3 times weekly/MWF dosing regimen, i.e. 3.0 mg. mivebresib administered 3x weekly. For this cohort, patients had histologically confirmed prostate cancer that was refractory after standard of care therapy. Metastatic castrate resistant prostate cancer (CRPC) was defined as adenocarcinoma without neuroendocrine features, which had progressed during previous therapy with androgen synthesis inhibitor and/or androgen receptor antagonist. The prostate expansion cohort patients were generally older than those in the dose-escalation cohort, with a higher percentage of patients having >4 prior therapies, including both hormonal therapies and chemotherapeutic agents. See TABLE 5 below for patient demographics. The most common sites of baseline metastases for the prostate cancer expansion subjects were bone (10/12), lymph node (9/12), and liver (4/12). Primary reasons for discontinuation of mivebresib were similar for expansion cohort patients, including radiologic progressive disease (58%), clinical progressive disease (25%), withdrew consent (8%), and other (8%).
Disease progression on during previous therapy was defined as either increase of prostate specific antigen (PSA progression: (2 consecutive rises in serum PSA, obtained at a minimum of 1-week intervals, and each value > 2.0 ng/mL) or as radiographic progression (using RECIST 1.1 criteria for visceral or soft tissue lesions and PCWG3 criteria for bone lesions). All patients had an Eastern Cooperative Oncology Group performance status of 0-1, adequate bone marrow, renal and hepatic function, and QT interval corrected for heart rate (QTc) interval <480 milliseconds on the baseline electrocardiogram (ECG). All patients consented to provide an archived tissue sample of tumor lesion for biomarker analysis. Additionally, patients in this expansion cohort had: 1) optional pre-treatment and on-treatment tumor biopsies; 2) triplicate ECG at screening; and 3) PK, serial BP, and triplicate ECG through 8 hours after dosing on C2D1. Blood samples (3 mL) for plasma mivebresib concentration analysis were collected by venipuncture K2EDTA-containing collection tubes at 0 (pre-dose) 1, 2, 3, 4, 6, 8, and 24 hours post-dose on C2D1.
TABLE 5. Summary of subject demographics.
Pro$tattExpansion Characteristic, n (%) = 1!#.91m12 Age, median (range), years 70.0 (57-81) Female 0 Male 12 (.100)...
White 11(92) Black 1 (8) Asian 0 iiECOGpe.rfor.mantestatttgggggggggggugi, 0 4(33) 1 8(67) iititiWAIWW*Oitiii-0000j#kiii-WF4NOtpatients Prostate 12 (100) i=iNiodiawnomtoorofprioutperapiOMMENEM

1 1(8) 3 2(17) >4 9 (75) ECOG = Eastern Cooperative Oncology Group; PS = performance status.
Results TEAEs were reported in 92% of subjects enrolled in the prostate expansion cohort.
Grade 3 or 4 TEAEs related to mivebresib were reported in 67% of the prostate expansion cohort, with thrombocytopenia being the most common. Serious TEAEs related to mivebresib occurred in 33% of prostate expansion cohort. For this cohort, 6 (60%) patients had stable disease and 4 (40%) patients had progressive disease. See TABLE 5 below for a summary of adverse events. New liver lesions were reported for 2 patients and a new lung lesion was reported for one patient. No new bone lesions were reported. Prostate-specific antigen (PSA) levels were measured at multiple time points for 11/12 prostate patients but did not show a consistent trend with clinical response. Slightly higher stable disease rates were observed (60%) in the prostate cancer expansion cohort, and median time to progression was 1.9 months (95%
CI: 1.1,2.1).
TABLE 6. Summary of adverse events Prostati =
Expansion n(%) (tm12) All Grade grades 3/4 'AE in >20% of all 11 (92) 10 (83) patients Thrombocytopenia 5 (42) 5 (42) Dysgeusia 5 (42) 0 Fatigue 7 (58) 2 (17) Nausea 5 (42) 1 (8) Decreased appetite 5 (42) 0 Anemia 4 (33) 3 (25) Diarrhea 3 (25) 0 Vomiting 3 (25) 0 Dyspnea 4 (33) 0 Njy4()*$Ipiiiif>5% of 10 (83) 8 (67) all patients Dysgeusia 5 (42) 0 Thrombocytopenia 5 (42) 5 (42) Fatigue 2 (17) 1(8) Nausea 4 (33) 1 (8) Decreased appetite 4 (33) 0 Diarrhea 2(17) 0 Anemia 3 (25) 1 (8) Vomiting 1 (8) 0 Hypertension 0 0 Hyperbilirubinaemia 0 0 Weight decreased 1 (8) 0 Rash maculo-papular 0 0 AnyseriottsAEin 7 (58) -5i1WiptgjVp-Oxpots Malignant neoplasm 1 (8) progression Abdominal pain 1 (8) Dyspnea 0 Any serious AE related 4 (33) to Mivebres.b Thrombocytopenia 1 (8) Anemia 1 (8) Pneumonia 1 (8) GI hemorrhage 0 Hypertension 0 Nausea 1 (8) Fatigue 1 (8) AE = adverse event; GI = gastrointestinal 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 (16)

WO 2019/222331 PCT/US2019/032391What is claimed is:

1. A method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient about 1.5 mg. to about 3.0 mg. of mivebresib.

2. The method of claim 1, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, colorectal cancer, pancreatic cancer, head and neck cancer, and melanoma.

3. The method of any of claims 1-2, wherein mivebresib is administered to the patient for a period of time sufficient to treat the cancer.

4. The method of any of claims 1-3, wherein the patient achieves at least a stable disease response per RECIST 1.1 criteria.

5. A method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient about 1.5 mg. of mivebresib daily.

6. The method of claim 5, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, colorectal cancer, pancreatic cancer, head and neck cancer, and melanoma.

7. The method of any of claims 5-7, wherein mivebresib is administered to the patient for a period of time sufficient to treat the cancer.

8. The method of any of claims 5-8, wherein the patient achieves at least a stable disease response per RECIST 1.1 criteria.

9. A method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient about 2.5 mg. of mivebresib once daily for about four days, discontinuing administration for about three days, and re-administering after about three days has ended.

10. The method of claim 9, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, colorectal cancer, pancreatic cancer, head and neck cancer, and melanoma.

11. The method of any of claims 9-10, wherein mivebresib is administered to the patient for a period of time sufficient to treat the cancer.

12. The method of any of claims 9-11, wherein the patient achieves at least a stable disease response per RECIST 1.1 criteria.

13. A method for treating a patient suffering from cancer characterized by the presence of a solid tumor comprising orally administering to the patient about 3.0 mg. of mivebresib once daily not more than three times in about one week.

14. The method of claim 13, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, colorectal cancer, pancreatic cancer, head and neck cancer, and melanoma.

15. The method of any of claims 13-14, wherein mivebresib is administered to the patient for a period of time sufficient to treat the cancer.

16. The method of any of claims 13-15, wherein the patient achieves at least a stable disease response per RECIST 1.1 criteria.