WO2021003163A1 - Traitement du cancer au moyen d'un inhibiteur de la famille des protéines à bromodomaine et à domaine extra-terminal (bet) - Google Patents

Traitement du cancer au moyen d'un inhibiteur de la famille des protéines à bromodomaine et à domaine extra-terminal (bet) Download PDF

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WO2021003163A1
WO2021003163A1 PCT/US2020/040311 US2020040311W WO2021003163A1 WO 2021003163 A1 WO2021003163 A1 WO 2021003163A1 US 2020040311 W US2020040311 W US 2020040311W WO 2021003163 A1 WO2021003163 A1 WO 2021003163A1
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compound
patient
administered
pharmaceutically acceptable
acceptable salt
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PCT/US2020/040311
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Jeff Davis
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Forma Therapeutics, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to the treatment of cancer, using a BET inhibitor compound, optionally in combination with a hypomethylating agent.
  • Acute leukemias and relapsed/refractory mature B-cell non-Hodgkin lymphoma represent a collection of diseases that typically have poor outcomes.
  • the lack of significant new improvements in therapy for most acute leukemias and lymphomas highlights the unmet need in these diseases.
  • BET bromodomain inhibition has emerged as a novel approach to the treatment of (acute myeloid leukemia) AML and other cancer types. Suppression of the BET family member BRD4 directly decreases expression of the MYC oncogene, implicating BRD4 inhibition as an effective small-molecule approach to suppress MYC expression in cancer cells.
  • the BET family of bromodomains (BRD2, BRD3, BRD4 and BRDT) binds to acetylated lysine residues on histones.
  • the BET bromodomain family is part of the‘reader’ class of epigenetic proteins.
  • BRD4 acts as an adaptor protein to recruit the positive transcription elongation factor b (P-TEFb) to promoter sites leading ultimately to transcription of genes relevant to oncology and other diseases, such as MYC.
  • P-TEFb positive transcription elongation factor b
  • MYC myelongation factor b
  • the mechanistic consequence of BET inhibition is downregulation of gene expression from BET super-enhancer driven genes, with the subsequent loss of proteins by proteolytic turnover.
  • Compound A ((S)-(5-cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)- 3,4-dihydroquinolin-l(2H)-yl)(cyclopropyl)methanone) is one of many small molecule BET (Bromodomain and Extra-Terminal) family bromodomain inhibitor compounds disclosed in WO 2015/074064 (published May 21, 2015, the entirety of which is incorporated herein by reference) with significant structural differentiation from other more selective (+)-JQl based BET inhibitors.
  • BET Inhibitor FT-1101 in human clinical trials is disclosed under clinical trial identifier NCT02543879 at the website clinicaltrials.gov.
  • the present disclosure provides certain technologies for treating cancer (e.g., acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and/or non- Hodgkin lymphoma (NHL)) and/or other BET-mediated diseases, disorders, or conditions in a subject.
  • cancer e.g., acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and/or non- Hodgkin lymphoma (NHL)
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • NHL non- Hodgkin lymphoma
  • the present disclosure provides methods of treating, stabilizing, or lessening the severity or progression of one or more diseases, disorders, or conditions (e.g., a cancer, e.g., AML/MDS and/or NHL) comprising administering a BET Inhibitor Compound, such as (S)-(5-cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-3,4- dihydroquinolin-l(2H)-yl)(cyclopropyl)methanone (Compound A), or a pharmaceutically acceptable salt thereof.
  • a BET Inhibitor Compound such as (S)-(5-cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-3,4- dihydroquinolin-l(2H)-yl)(cyclopropyl)methanone (Compound A), or a pharmaceutically acceptable salt thereof.
  • the present disclosure encompasses the insight that particular dosing regimens of a BET Inhibitor Compound (e.g., Compound A, and compounds of Table 1) achieve one or more particular effects in a subject.
  • the present disclosure provides a method of administering a BET Inhibitor Compound (e.g., Compound A and compounds of Table 1) that achieves a particular plasma concentration, maintained over a certain time interval and/or for a particular fraction of time between doses.
  • the present disclosure provides a method of administering a BET Inhibitor Compound (e.g.,
  • the present disclosure provides a method of administering a BET Inhibitor Compound (e.g., Compound A and compounds of Table 1) that achieves a particular time over a threshold (“TOT”) plasma concentration.
  • a BET Inhibitor Compound e.g., Compound A and compounds of Table 1
  • TOT threshold
  • the present disclosure encompasses the insight that maintaining particular exposure levels of BET Inhibitor Compounds (e.g., Compound A and compounds of Table 1) is effective at treating, stabilizing, or lessening the severity or progression of one or more diseases, disorders, or conditions (e.g., a cancer, e.g., AML/MDS and/or NHL).
  • methods described herein achieve a plasma concentration of a BET Inhibitor Compound (e.g., Compound A) within the subject, greater than about 100 nM for a particular fraction of time between doses (e.g., about 30-50% of time between doses).
  • a BET Inhibitor Compound e.g., Compound A
  • the present disclosure also encompasses the recognition that such regimens can be used in combination with one or more known therapies, such as a hypomethylating agent (e.g., azacitidine).
  • the present disclosure provides novel intermittent dosing schedules for (S)-(5-cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-3,4- dihydroquinolin-l(2H)-yl)(cyclopropyl)methanone (Compound A) useful for the treatment of a disease, disorder, or condition (e.g., cancer).
  • a disease, disorder, or condition e.g., cancer
  • BET inhibitor compounds are being evaluated in human clinical trials (e.g., Table 1 below).
  • the characteristics of some BET inhibitors include high oral bioavailability and solubility and a long observed human blood half-life (e.g. 2-2.5 days), supporting intermittent administration (e.g., weekly (QW), biweekly (Q2W) or monthly (QM)) of a BET Inhibitor Compound, or a pharmaceutically acceptable salt thereof, to treat certain forms of cancer.
  • methods of administering a BET Inhibitor Compound achieve target exposure over an (approximate) 100 nM threshold for about 30-50% of the time between doses (time over threshold, or“TOT”).
  • methods of treatment do not include administration of a BET Inhibitor Compound on consecutive days or too frequently for prolonged periods of time (e.g., >7d) without intermittent dosing.
  • Compound A has been evaluated in human clinical trials (e.g.,
  • Examples 4-6 below).
  • the characteristics of Compound A including high oral bioavailability, solubility, and a long observed human blood half-life (e.g. 2-2.5 days), support intermittent administration (e.g., QW, Q2W or QM) of Compound A to treat certain forms of cancer.
  • intermittent administration e.g., QW, Q2W or QM
  • Preferred methods of administering Compound A achieve target exposure over an (approximate) 100 nM threshold for about 30-50% of the time between doses ( TOT).
  • TOT was found to provide tumor regressions, which is believed to correlate with -80% MYC suppression and regression in AML and lymphoma models.
  • 400 mg QOW yields TOT of 2 to 4 days (15%-28% of dosing period), while 400 mg QW may yield target TOT of 30 -50% of dosing period.
  • methods of treatment do not include administration of Compound A on consecutive days or too frequently for prolonged periods of time (e.g., >7d) without intermittent dosing.
  • Inhibitor at the intervals provided herein is useful for the treatment of certain diseases, disorders, or conditions (e.g., cancer, including AML/MDS and/or NHL).
  • the intermittent administration of therapeutically effective amounts of a Compound A, or a pharmaceutically acceptable salt thereof, at the intervals provided herein is useful for the treatment of certain diseases, disorders, or conditions (e.g., cancer, including AML/MDS and/or NHL).
  • Compound A can be administered in a total dose of about 300 mg - 600 mg (e.g., 300 mg or 600 mg) once every week or once every other week, depending on the patient being treated, and whether Compound A is administered as a single agent (SA) or in combination with other therapeutic agents (e.g. azacitidine), as disclosed herein.
  • SA single agent
  • other therapeutic agents e.g. azacitidine
  • Compound A can be administered in a total dose of about 300 mg - 400 mg (e.g., 300 mg or 400 mg) once every week or once every other week, depending on the patient being treated.
  • patients diagnosed with AML/MDS can be treated by administering a total of 400 mg of Compound A every other week (QOW), or by administering a total of 300 mg of
  • Compound A every week can be administered in a total dose of about 400 mg once every other week.
  • patients diagnosed with acute myeloid leukemia/myelodysplastic syndrome can be treated by administering a total of 400 mg of Compound A every other week (QOW), or by administering a total of 300 mg of Compound A every week (QW).
  • patients diagnosed with AML/MDS can be treated by administering a total of 400 mg of Compound A every other week (QOW).
  • patients diagnosed with NHL can be treated with 400 mg of Compound A QOW.
  • the administration of Compound A under conditions effective to inhibit the BET bromodomain can have antitumor activity in tumors that depend on BET-driven transcription programs.
  • the present disclosure encompasses the recognition that the efficacy of a BET family bromodomain inhibitor can be driven by short half-life genes and proteins, the loss of which drive an anti-tumor response.
  • a defined drug exposure followed by a holiday can result in the downregulation of target genes, while longer lived maintenance genes responsible for driving toxicity may be less affected.
  • Compound A is an equipotent inhibitor of all BET family bromodomains (Kd ⁇ 20 nM), as judged by a panel of biochemical binding assays. In cellular models, Compound A has sub-micromolar anti-proliferative activity across broad panels of both hematological and solid tumor-derived cell lines. In the MV-4-11 acute myeloid leukemia cell line, downregulation of the demonstrated BET target oncogene MYC by Compound A closely correlates to its potency on cellular proliferation, suggesting that the anti-proliferative effect is associated with the suppression of Myc protein levels.
  • MYC mRNA levels were suppressed by 80-90% by 4 hours post dose, and sustained suppression of >70% was observed through at least 12 hours post dose.
  • the maximum suppression of Myc protein (-80%) was associated with unbound plasma levels of Compound A at 1 to 2 fold above the cellular GEo. Oral dosing of Compound A in vivo led to significant tumor growth inhibition, including tumor regressions, as a single agent.
  • the present disclosure also provides a novel combination therapy for the treatment of cancer, comprising administration of a BET Inhibitor Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) and a hypomethylating agent, such as azacitidine.
  • a BET Inhibitor Compound e.g., Compound A or a pharmaceutically acceptable salt thereof
  • a hypomethylating agent such as azacitidine.
  • the BET Inhibitor Compound e.g., Compound A or a pharmaceutically acceptable salt thereof
  • the present disclosure is based in part on the discovery of a synergistic effect of pretreatment of multiple cell lines with azacitidine prior to treatment with Compound A (Example 7).
  • the methods of treatment include a step of administering a therapeutically effective amount of Compound A or pharmaceutically acceptable salt thereof (e.g., 150 mg - 400 mg) about 24 hours after the administration of azacitidine.
  • a therapeutically effective amount of Compound A or pharmaceutically acceptable salt thereof e.g., 150 mg - 400 mg
  • Compound A is administered to the patient in need thereof using an intermittent dosing schedule (e.g., once every other week), including at least one administration of Compound A about 24 hours after administration of a hypomethylating agent (e.g., azacitidine).
  • a hypomethylating agent e.g., azacitidine
  • intermittent administration of therapeutically effective amounts of Compound A at the intervals provided herein is useful for the treatment of certain cancer patients, including adult patients diagnosed with acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) or NHL.
  • AML/MDS acute myeloid leukemia/myelodysplastic syndrome
  • NHL myelodysplastic syndrome
  • a hypomethylating agent e.g., azacitidine
  • Compound A can be dosed below the maximum tolerated dose (MTD), starting at about 50% of the MTD, and optionally increased in successive doses up to the MTD, if tolerated.
  • Figure l is a chemical synthesis of Compound A.
  • Figure 2 is a graph showing results from a mouse xenograft study described in
  • Figure 3 A is a graph showing the day 1, dose normalized (Cmax/dose in
  • Figure 3B is a graph showing the ratio of measured AUC values in a human clinical trial.
  • Figure 3C is a graph showing the plasma concentrations for the administration of 400 mg of Compound A in a human clinical trial.
  • Figure 3D is a graph showing the plasma concentrations for the administration of 260 mg of Compound A in a human clinical trial.
  • Figure 4 is a summary of Compound A dose escalation, as described in Example 6.
  • Figure 5 displays time on treatment for patients receiving certain dosing schedules of
  • Figure 6 is a plot of mean concentration of Compound A (ng/mL) at various time points after first oral dose.
  • Figure 7A is a box-and-whisker plot of CCR1 modulation at 4 hrs post-dose for various doses (80-600 mg) of Compound A.
  • the whiskers in Figure 7A represent maximum and minimum values, the box encompasses the middle two quartiles, and the line in the middle of the box plots the median.
  • Figure 7B is a box-and-whisker plot of HEXIM1 modulation at 4 hrs post-dose for various doses (80-600 mg) of Compound A.
  • the whiskers in Figure 7B represent maximum and minimum values, the box encompasses the middle two quartiles, and the line in the middle of the box plots the median.
  • Figure 8A is a plot of mean concentration of Compound A (ng/mL) at various time points after a single 300 mg oral dose of Compound A.
  • Figure 8B is a plot of HEXIM1 expression (relative quantification (RQ)) over time after a single 300 mg oral dose of Compound A.
  • Figure 8C is a plot of CCR1 expression (relative quantification (RQ)) over time after a single 300 mg oral dose of Compound A.
  • Figure 9 is a plate map of a combination experiment for analyzing synergy between Compound A and azacitidine.
  • administering typically refers to administration of a composition to a subject to achieve delivery of an active agent to a site of interest (e.g., a target site which may, in some embodiments, be a site of disease or damage, and/or a site of responsive processes, cells, tissues, etc.)
  • a site of interest e.g., a target site which may, in some embodiments, be a site of disease or damage, and/or a site of responsive processes, cells, tissues, etc.
  • a site of interest e.g., a target site which may, in some embodiments, be a site of disease or damage, and/or a site of responsive processes, cells, tissues, etc.
  • a site of interest e.g., a target site which may, in some embodiments, be a site of disease or damage, and/or a site of responsive processes, cells, tissues, etc.
  • one or more particular routes of administration may be feasible and/or useful in the practice of the present disclosure.
  • administration may be parenteral
  • pharmaceutically acceptable salt refers to a form of a relevant compound as a salt appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and/or lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in ./. Pharmaceutical Sciences, 66: 1-19 (1977).
  • the term“subject” refers an organism, typically a mammal (e.g., a human). In some embodiments, a subject is suffering from a relevant disease, disorder or condition. In some embodiments, a human subject is an adult, adolescent, or pediatric subject.
  • a subject is at risk of (e.g., susceptible to), e.g, at elevated risk of relative to an appropriate control individual or population thereof, a disease, disorder, or condition.
  • a subject displays one or more symptoms or characteristics of a disease, disorder or condition.
  • a subject does not display any symptom or characteristic of a disease, disorder, or condition.
  • a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition.
  • a subject is an individual to whom diagnosis and/or therapy and/or prophylaxis is and/or has been administered.
  • the terms“subject” and“patient” are used interchangeably herein.
  • the term“treat” refers to any administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition.
  • such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition.
  • such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
  • treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition.
  • the present disclosure provides certain technologies for treating cancer (e.g., acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and/or non- Hodgkin lymphoma (NHL)) and/or other BET-mediated diseases, disorders, or conditions in a subject.
  • cancer e.g., acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and/or non- Hodgkin lymphoma (NHL)
  • BET Inhibitor Compounds e.g., Compound A
  • administered to achieve one or more particular effects e.g., a particular exposure level for a particular duration and/or a particular area under the curve and/or a particular half-life
  • AML/MDS and NHL are serious, life threatening diseases, and have a high rate of relapse driven by genetic mutations and deregulated epigenetic control. Treatment options are limited, especially in cases where the disease has recurred.
  • BET bromodomain inhibition for treatment of certain diseases, disorders, and conditions, including AML/MDS and NHL.
  • Certain preclinical and clinical studies highlight the relevance of targeting the bromodomain and extra-terminal (BET) family as an efficient strategy of target transcription irrespective of the presence of epigenetic mutations.
  • the BET family of proteins are important epigenetic regulators involved in promoting gene expression of critical oncogenes by keeping an abnormal chromatin state in various hematologic malignancies, including MM, acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), and mantle cell lymphoma (MCL).
  • AML acute myelogenous leukemia
  • ALL acute lymphoblastic leukemia
  • DLBCL diffuse large B-cell lymphoma
  • BL Burkitt lymphoma
  • MCL mantle cell lymphoma
  • MYC mantle cell lymphoma
  • the present disclosure provides methods of treating, stabilizing, or lessening the severity or progression of one or more diseases, disorders, or conditions (e.g., a cancer, e.g., AML/MDS and/or NHL) comprising administering a BET Inhibitor Compound, such as (S)-(5-cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol-4- yl)-3,4-dihydroquinolin-l(2H)-yl)(cyclopropyl)methanone (Compound A), or a pharmaceutically acceptable salt thereof.
  • a BET Inhibitor Compound such as (S)-(5-cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol-4- yl)-3,4-dihydroquinolin-l(2H)-yl)(cyclopropyl)methanone (Compound A), or a pharmaceutically
  • the present disclosure encompasses the insight that particular dosing regimens of a BET Inhibitor Compound (e.g., Compound A, and compounds of Table 1) achieve one or more particular effects in a subject.
  • the present disclosure provides a method of administering a BET Inhibitor Compound (e.g., Compound A and compounds of Table 1) that achieves a particular plasma concentration, maintained over a certain time interval and/or for a particular fraction of time between doses.
  • the present disclosure provides a method of administering a BET Inhibitor Compound (e.g.,
  • the present disclosure provides a method of administering a BET Inhibitor Compound (e.g., Compound A and compounds of Table 1) that achieves a particular time over a threshold plasma concentration (“TOT”).
  • TOT threshold plasma concentration
  • the present disclosure encompasses the insight that maintaining particular exposure levels of BET Inhibitor Compounds (e.g., Compound A and compounds of Table 1) is effective at treating, stabilizing, or lessening the severity or progression of one or more diseases, disorders, or conditions (e.g., a cancer, e.g., AML/MDS and/or NHL).
  • methods described herein achieve a concentration of a BET Inhibitor Compound (e.g., Compound A) within the subject, greater than about 100 nM for a particular fraction of time between doses (e.g., about 30-50% of time between doses).
  • a BET Inhibitor Compound e.g., Compound A
  • the present disclosure also encompasses the recognition that such regimens can be used in combination with one or more known therapies, such as a hypomethylating agent (e.g., azacitidine).
  • BET Inhibitor Compound is (S)-(5-cyclobutoxy-2-methyl-6-(l- (piperidin-4-yl)-lH-pyrazol-4-yl)-3,4-dihydroquinolin-l(2H)-yl)(cyclopropyl)methanone (Compound A), which can be provided in a pharmaceutically acceptable salt form.
  • Compound A is provided in the form of a succinate salt.
  • Compound A is an orally bioavailable compound that demonstrates potent and equivalent biochemical activity against all BET family members. BET inhibition by Compound A is associated with modulation of expression of oncogenes, such as MYC.
  • Compound A demonstrates sub-micromolar growth inhibitory effects on a variety of hematological and solid tumor cell lines.
  • MV-4-11 significant anti -tumor activity, including regressions, were observed on a variety of schedules and at tolerated dose levels.
  • the anti-tumor activity observed in these studies coincided with downregulation of MYC.
  • BET inhibition by Compound A resulted in down-regulation of MYC gene and protein expression and displayed sub-micromolar growth inhibitory effects on a wide variety of hematological and solid tumor cell lines in vitro, including FLT3 mutated leukemia cell lines.
  • Treatment of mice bearing human tumor xenografts in vivo with Compound A resulted in significant anti-tumor activity including tumor regression in the FLT-3 mutated MV-4-11 leukemia model on a variety of dosing schedules and at tolerated doses.
  • the in vivo anti-tumor activity was associated with down-regulation of MYC gene expression in tumors.
  • Compound A is provided and/or utilized in accordance with the present disclosure as a pharmaceutically acceptable salt. As already noted herein, pharmaceutically acceptable salts are well known in the art. In some embodiments, Compound A is provided and/or utilized as a succinate salt.
  • Compound A is provided and/or utilized in accordance with the present disclosure in a solid form. In some embodiments, Compound A is provided and/or utilized in accordance with the present disclosure in an amorphous solid form, in a crystalline solid form, or in a mixture thereof. The use of any and all such forms are contemplated by the present disclosure.
  • Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ⁇ 0.2) of 4.4, 6.8, 9.1, 15.3, and 38.8.
  • Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ⁇ 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8.
  • Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ⁇ 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8, corresponding to d-spacing (angstroms ⁇ 0.2) of 20.1, 13.0, 9.7, 6.8, 5.8, 5.5, 4.5, 2.5, and 2.3 (respectively).
  • XRPD X-ray Powder Diffraction
  • Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) having three or more characteristic diffractions at angles (2 theta ⁇ 0.2) of 4.4, 6.8, 9.1, 15.3, and 38.8.
  • Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) having three or more characteristic diffractions at angles (2 theta ⁇ 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8.
  • Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) having three or more characteristic diffractions at angles (2 theta ⁇ 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8, corresponding to d-spacing (angstroms ⁇ 0.2) of 20.1, 13.0, 9.7, 6.8, 5.8, 5.5, 4.5, 2.5, and 2.3 (respectively).
  • Compound A is provided and/or utilized in accordance with the present disclosure as a succinate salt solid form characterized by X-ray Powder Diffraction (XRPD) as described in Example 1.
  • an amount (e.g., in mg) of Compound A means the amount of Compound A in free base form. Accordingly, Compound A may be provided and/or utilized as, e.g., a salt form of Compound A such that the amount of the salt (or other form) is an amount that corresponds to the“free base equivalent” of Compound A.
  • “300 mg Compound A” means, e.g., approx. 300 mg of Compound A Free Base, 381.8 mg of Compound A Monosuccinate, etc.
  • kits for treating a patient suffering from a disease, disorder or condition comprising administering Compound A (e.g., by administering a composition that comprises and/or delivers Compound A as described herein) to the patient.
  • provided methods comprise administering Compound A or a
  • a relevant population of patients is or comprises patients with relapsed/refractory (R/R) AML/MDS, or non-Hodgkin lymphoma (NHL).
  • R/R relapsed/refractory
  • NDL non-Hodgkin lymphoma
  • a particular effect is or comprises a particular mean maximum concentration (Cmax). In some embodiments, a particular effect is or comprises a mean Cmax of greater than about 200 ng/mL, greater than about 300 ng/mL, greater than about 600 ng/mL, greater than about 900 ng/mL, greater than about 1000 ng/mL, or greater than about 1400 ng/mL.
  • a particular effect is or comprises a mean Cmax of from about 200 ng/mL to about 1400 ng/mL, about 300 ng/mL to about 1400 ng/mL, about 600 ng/mL to about 1400 ng/mL, about 900 ng/mL to about 1400 ng/mL, about 600 ng/mL to about 1000 ng/mL or about 900 ng/mL to about 1000 ng/mL.
  • a particular effect is or comprises a particular mean plasma concentration maintained over a particular period of time. In some embodiments, a particular effect is or comprises a particular mean plasma concentration maintained for about 3 days, about 7 days, about 14 days, or about 28 days. In some embodiments, a particular effect is or comprises a mean plasma concentration of greater than about 50 ng/mL, greater than about 75 ng/mL, greater than about 100 ng/mL, greater than about 150 ng/mL, greater than about 200 ng/mL, or greater than about 250 ng/mL maintained for about 3 days, about 7 days, about 14 days, or about 28 days.
  • a particular effect is or comprises a particular mean Cmax and a particular mean plasma concentration maintained over a particular period of time.
  • a particular effect is or comprises a mean Cmax of greater than about 200 ng/mL, greater than about 300 ng/mL, greater than about 600 ng/mL, greater than about 900 ng/mL, greater than about 1000 ng/mL, or greater than about 1400 ng/mL; and a mean plasma concentration of greater than about 50 ng/mL, greater than about 75 ng/mL, greater than about 100 ng/mL, greater than about 150 ng/mL, greater than about 200 ng/mL, or greater than about 250 ng/mL maintained for about 3 days, about 7 days, about 14 days, or about 28 days.
  • a particular effect is or comprises a particular mean area under the curve over 168 hours or one week (AUC ( oi 68) ).
  • a particular effect is or comprises a mean AU 0168) of greater than about 8000 ng*hr/mL, greater than about 11000 ng*hr/mL, greater than about 16000 ng*hr/mL, greater than about 26000 ng*hr/mL, greater than about 52000 ng*hr/mL, greater than about 55000, or greater than about 93000 ng*hr/mL.
  • a particular effect is or comprises a mean AUC(oi68) of from about 8000 ng*hr/mL to about 93000 ng*hr/mL, from about 11000 ng*hr/mL to about 93000 ng*hr/mL, from about 16000 ng*hr/mL to about 93000 ng*hr/mL, from about 26000 ng*hr/mL to about 93000 ng*hr/mL, from about 52000 ng*hr/mL to about 93000 ng*hr/mL, from about 55000 ng*hr/mL to about 93000 ng*hr/mL, from about 11000 ng*hr/mL to about 55000 ng*hr/mL, from about 16000 ng*hr/mL to about 55000 ng*hr/mL, from about 26000 ng*hr/mL to about 55000 ng*hr/mL, or
  • a particular effect is or comprises a particular half-life (ti/2).
  • a particular effect is or comprises a ti/2 of greater than about 40 hours, greater than about 50 hours, or greater than about 55 hours. In some embodiments, a particular effect is or comprises a ti/2 of from about 40 hours to about 60 hours, from about 50 hours to about 60 hours, or from about 55 hours to about 60 hours.
  • a particular effect is or comprises a target plasma
  • concentration over about 100 nM, e.g., for about 30% to about 50% of time between doses.
  • Methods of treating a patient diagnosed with cancer that depends on a BET-driven transcription program are provided herein.
  • methods of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program are provided herein.
  • a method comprises administering to the patient in need thereof a therapeutically effective dose of a BET Inhibitor Compound every week in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.
  • BET Inhibitor Compounds can be administered to a patient in need thereof in an amount to achieve target exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • a BET Inhibitor Compound is administered to a patient in need thereof once a week (QW) in an amount sufficient to achieve target exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • QW a week
  • provided methods comprise administering Compound A or a pharmaceutically acceptable salt thereof as a single agent (SA) therapy. In some embodiments, provided methods comprise administering Compound A or a pharmaceutically acceptable salt thereof as part of a combination therapy (e.g., as described herein).
  • provided methods comprise administering Compound A or a pharmaceutically acceptable salt thereof once a week (QW). In some embodiments, provided methods comprise administering Compound A or a pharmaceutically acceptable salt thereof once every other week (QOW). In some embodiments, provided methods comprise administering Compound A or a pharmaceutically acceptable salt thereof once a month (QM).
  • provided methods comprise administering Compound A or a pharmaceutically acceptable salt thereof in a dose of about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, or about 800 mg.
  • Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof in a total dose of about 300 mg-400 mg of Compound A every week (QW).
  • Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof in a total dose of about 300 mg-400 mg of Compound A every other week (Q2W or QOW).
  • Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof in a total dose of about 300 mg-600 mg of Compound A once per month (QM or Q4W).
  • Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof in a total dose of about 400 mg of Compound A every other week (Q2W or QOW).
  • Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per week (QW) in an amount of 200 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per week (QW) in an amount of 300 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per week (QW) in an amount of 400 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per week (QW) in an amount of 600 mg.
  • Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once every other week (QOW) in an amount of 200 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is
  • Compound A or a pharmaceutically acceptable salt thereof is
  • Compound A or a pharmaceutically acceptable salt thereof is
  • Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof every other week (QOW) in an amount of 500 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof every other week (QOW) in an amount of 600 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once every other week (QOW) in an amount of 800 mg.
  • Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per month (QM) or once every four weeks (Q4W) in an amount of 300 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per month (QM) or once every four weeks (Q4W) in an amount of 400 mg. In some embodiments, Compound A or a
  • pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per month (QM) or once every four weeks (Q4W) in an amount of 600 mg.
  • Compound A or a pharmaceutically acceptable salt thereof is preferably administered to a patient in need thereof as a single agent (SA) every other week. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered at a total dose of about 400 mg of Compound A every other week (QOW), preferably once per day.
  • SA single agent
  • QOW Compound A every other week
  • provided methods are useful for treating cancer (e.g., cancer
  • provided methods are useful for treating cancer (e.g., AML/MDS or NHL) that is relapsed or refractory to standard therapies. In some embodiments, provided methods are useful for treating AML/MDS. In some embodiments, provided methods are useful for treating relapsed or refractory AML (e.g., with intermediate or unfavorable risk cytogenetics and/or lacking FLT3 ITD or TKD alterations). In some embodiments, provided methods are useful for treating FLT3-mutated AML. In some embodiments, provided methods are useful for treating NHL.
  • Compound A or a pharmaceutically acceptable salt thereof is administered for the treatment of patients with relapsed or refractory AML with intermediate or unfavorable risk cytogenetics and lacking FLT3 ITD or TKD alterations.
  • Compound A or a pharmaceutically acceptable salt thereof is administered for the treatment of patients with AML harboring FLT3(ITD) or FLT3(TKD) alterations that is relapsed or refractory to standard therapies.
  • preclinical methods of treatment of patients diagnosed with FLT3 mutated AML comprise the administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof as a single agent (SA) in some embodiments.
  • preclinical methods of treatment of patients diagnosed with FLT3 mutated AML comprise the administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof in combination with other therapeutic agents.
  • Methods of treatment are illustrated in the Examples for the treatment of patients diagnosed with AML/MDS or NHL.
  • patients diagnosed with AML, NHL, and AML/MDS can be treated with therapeutically effective amounts of Compound A as a single agent.
  • Other patients diagnosed with AML, NHL, and AML/MDS can be treated with therapeutically effective amounts of Compound A or a pharmaceutically acceptable salt thereof in combination with azacitidine.
  • the present disclosure also provides methods of administering combination therapy comprising a BET Inhibitor Compound (e.g., Compound A) and a hypomethylating agent (e.g., azacitidine).
  • a BET Inhibitor Compound e.g., Compound A
  • a hypomethylating agent e.g., azacitidine
  • provided methods comprise administering Compound A (e.g., according to a dosing regimen described herein) to a patient who is receiving or has received a hypomethylating agent (e.g., azacitidine).
  • combination therapy may require that timing of intermittent dosing regimens for BET Inhibitor Compounds (e.g., Compound A) be adjusted (e.g., in dose, frequency, and/or timing in relation to dosing of another therapy) in order to provide one or more desirable outcomes.
  • provided combination therapies comprise a first lower dose of BET Inhibitor Compound (e.g., Compound A) followed by one or more higher doses, e.g., separated by a particular time period.
  • “combination therapy” or“in combination with” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents).
  • the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all“doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
  • “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).
  • azacitidine is recommended for patients suffering from AML that are unable to tolerate intensive salvage therapy. This guidance is based on studies showing azacitidine at a dose of 75 mg/m 2 can induce Complete Remission (CR) rates of 16% to 21% and median survival times of 6 to 9 months in older patients with relap sed/refractory AML.
  • CR Complete Remission
  • MDS myelodysplastic syndrome
  • OS median overall survival
  • CMML chronic myelomonocytic leukemia
  • AML acute myeloid leukemia
  • the recommended starting dose for the first treatment cycle is 75 mg/m 2 of body surface area, injected subcutaneously, daily for 7 days, followed by a rest period of 21 days (28-day treatment cycle).
  • Compound A or a pharmaceutically acceptable salt thereof can be administered with azacitidine to treat certain forms of cancer.
  • Compound A displayed synergistic growth inhibitory activity in combination with azacitidine in leukemia cell lines.
  • the hypomethylating agent (HMA) azacitidine is approved for the treatment of subtypes of MDS and is a recommended treatment option in AML patients who are not candidates for or who have failed intensive cytotoxic induction/consolidation regimens. Resistance to azacitidine therapy in AML has been shown to be mediated by BET proteins.
  • Compound A in combination with azacitidine is synergistic in vitro in human leukemia cell lines; the greatest synergy was observed when cells were pre-treated with azacitidine for 24 h followed by Compound A.
  • Compound A and azacitidine in AML/MDS patients are administered in combination with azacitidine for the treatment of patients with relapsed or refractory AML, or previously untreated AML unfit for intensive therapy.
  • provided combination therapies are useful for treating cancer (e.g., AML/MDS or NHL).
  • provided combination therapies are useful for treating cancer (e.g., AML/MDS or NHL) that is relapsed or refractory to standard therapies.
  • provided combination therapies are useful for treating AML/MDS.
  • provided combination therapies are useful for treating relapsed or refractory AML (e.g., with intermediate or unfavorable risk cytogenetics and/or lacking FLT3 ITD or TKD alterations).
  • provided combination therapies are useful for treating FLT3- mutated AML.
  • provided combination therapies are useful for treating NHL.
  • Compound A or a pharmaceutically acceptable salt thereof is administered for the treatment of patients with relapsed or refractory AML with intermediate or unfavorable risk cytogenetics and lacking FTL3 ITD or TKD alterations.
  • Compound A or a pharmaceutically acceptable salt thereof is administered for the treatment of patients with AML harboring FLT3(ITD) or FLT3(TKD) alterations that is relapsed or refractory to standard therapies.
  • methods of treatment of patients diagnosed with FLT3 mutated AML comprise the administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof in combination with azacitidine.
  • Methods of treatment are illustrated in the Examples, for the treatment of patients diagnosed with AML/MDS or NHL.
  • patients diagnosed with AML, NHL, and AML/MDS can be treated with therapeutically effective amounts of Compound A or a pharmaceutically acceptable salt thereof in combination with azacitidine.
  • Compound A or a pharmaceutically acceptable salt thereof is administered at least about 24 hours after azacitidine.
  • provided combination therapies comprise administering a hypomethylating agent (e.g., azacitidine) according to its labeled dosing regimen.
  • a hypomethylating agent e.g., azacitidine
  • provided combination therapies comprise administering Compound A or a pharmaceutically acceptable salt thereof once a week (QW). In some embodiments, provided combination therapies comprise administering Compound A or a pharmaceutically acceptable salt thereof once every other week (QOW).
  • provided combination therapies comprise administering Compound A or a pharmaceutically acceptable salt thereof in a dose of about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg.
  • Compound A or a pharmaceutically acceptable salt is administered to a patient in need thereof in a therapeutically effective dose amount and at dose intervals that achieve target exposure over an (approximate) 100 nM threshold for about 30-50% of the time between doses.
  • Compound A or a pharmaceutically acceptable salt is administered to a patient in need thereof in a therapeutically effective dose amount and at dose intervals that achieve target exposure over an (approximate) 100 nM threshold for about 30-50% of the time between doses.
  • Compound A or a pharmaceutically acceptable salt is administered to a patient in need thereof in a therapeutically effective dose amount and at dose intervals that achieve target exposure over an (approximate) 100 nM threshold for about 30-50% of the time between doses.
  • Compound A or a pharmaceutically acceptable salt is administered to a patient in need thereof in a therapeutically effective dose amount and at dose intervals that achieve target exposure over an (approximate) 100 nM threshold for about 30-50% of the time between doses.
  • compositions of formula I are administered as a total dose of about 150 mg - 300 mg (e.g., 150 mg, 200 mg, 250 mg, or 300 mg) of Compound A every week (QW).
  • Compound A or pharmaceutically acceptable salt thereof is administered to a patient in need thereof at a total dose of about 200 mg - 400 mg (e.g., 200 mg, 250 mg, 300 mg, 350 mg or 400 mg) of Compound A every other week (Q2W or QOW).
  • the dose of Compound A can be optionally increased in successive administrations, when given in combination with a hypomethylating agent.
  • a hypomethylating agent for example, in some embodiments, 150 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof on the first day of treatment, in combination with azacitidine (e.g., 75 mg/m 2 ). Subsequently, the same daily dose of azacitidine can be administered to the patient for a total of 7 consecutive days. The following day, a once daily dose of 150 mg - 300 mg (e.g., 150 mg,
  • Compound A or a pharmaceutically acceptable salt thereof can be administered to the patient without azacitidine (i.e., about 24 hours after the most recent prior administration of azacitidine).
  • a hypomethylating agent is a therapeutic agent that inhibits DNA methylation, preferably azacitidine or decitabine.
  • a hypomethylating agent is administered in a 28 day treatment cycle.
  • the decitabine (DAC) can be administered at a dose of 20 mg/m 2 x 5 days, every 28 days.
  • the present disclosure provides a method of treating a patient comprising administering a therapeutically effective amount of a BET Inhibitor Compound (e.g., Compound A) about 24 hours after administration of a hypomethylating agent.
  • Compound A or a pharmaceutically acceptable salt thereof is administered in a dosing regimen with azacitidine during a 28-day cycle. In some embodiments, a 28-day cycle is repeated. In some embodiments, azacitidine is administered during days 1 - 7 of a 28-day cycle, and Compound A or a pharmaceutically acceptable salt thereof is administered during days 8 - 28 of a 28-day cycle (e.g., on Day 8, Day 15, and Day 22). In some embodiments, patients receive 75 mg/m 2 of azacitidine QD on days 1 - 7.
  • patients receive 150 mg - 300 mg QW Compound A or a pharmaceutically acceptable salt thereof on days 1, 8, 15 and 22 every 28 days, or 200 mg to 400 mg QOW Compound A or a pharmaceutically acceptable salt thereof on days 1 and 15 every 28 days.
  • Compound A or a pharmaceutically acceptable salt thereof is administered to a patient who is receiving or has received azacitidine.
  • Compound A or a pharmaceutically acceptable salt thereof e.g., about 150 mg to about 400 mg
  • Compound A or a pharmaceutically acceptable salt thereof (e.g., about 150 mg to about 400 mg) is administered to a patient who is receiving or has received 75 mg/m 2 azacitidine once per day for the first seven consecutive days of a 28-day course of treatment and wherein Compound A or a pharmaceutically acceptable salt thereof is administered at least about 24 hours after the seventh dose of azacitidine and prior to any subsequent dose of azacitidine after the 28-day course of treatment.
  • Compound A or a pharmaceutically acceptable salt thereof (e.g., 150 mg or 200 mg) is administered on the first day of the 28-day course of treatment and on the same day as the first dose of azacitidine, and then is subsequently administered once every week (e.g., 300 mg QW) or once every other week (e.g., 400 mg QOW) throughout the 28-day course of treatment.
  • Week e.g. 300 mg QW
  • Week e.g., 400 mg QOW
  • Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a hypomethylating agent (e.g., azacitidine) to a patient in need thereof at a dose of about 50% of the MTD at least once about 24 hours (or greater than 24 hours) after administering the final dose of the hypomethylating agent every 28 days to the patient in need thereof.
  • a hypomethylating agent e.g., azacitidine
  • Compound A or a pharmaceutically acceptable salt thereof is administered once weekly or once every other week in a dose that achieves target exposure over an (approximate) 100 nM threshold for about 30-50% of the time between doses (“TOT”).
  • TOT time between doses
  • Compound A or a pharmaceutically acceptable salt thereof can be administered in a total dose of about 150 mg - 400 mg, once every week or once every other week.
  • Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per week (QW) in combination with azacitidine on at least one day and on at least one day that is without azacitidine administration but within about 24 hours after the last prior dose of azacitidine.
  • the first QW dose of Compound A or a pharmaceutically acceptable salt thereof is a first dose of 150 mg, and subsequent doses that are the same or higher, preferably within the range of 150 mg - 300 mg per dose.
  • Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once per week (QW) in an amount of 300 mg.
  • Compound A or a pharmaceutically acceptable salt thereof is administered to the patient in need thereof once every week.
  • Compound A or a pharmaceutically acceptable salt thereof is administered in a total dose of about 150 mg - 300 mg (e.g., 150 mg, 200 mg, 250, mg, or 300 mg) once every week or 200 mg to 400 mg (e.g., 200 mg, 300 mg or 400 mg) once every other week, depending on the patient being treated, when administered in combination with azacitidine, as disclosed herein.
  • patients diagnosed with AML/MDS are treated by administering an initial dose of 150 mg of Compound A or a pharmaceutically acceptable salt thereof every week (QW), and optionally increasing the individual dose of Compound A or a pharmaceutically acceptable salt thereof administered in subsequent doses QW up to 300 mg (e.g., subsequent doses of 150 mg-300 mg, including doses of 150 mg, 200 mg, 250, mg, or 300 mg).
  • QW daily dose of 150 mg of Compound A or a pharmaceutically acceptable salt thereof every week
  • subsequent doses of 150 mg-300 mg including doses of 150 mg, 200 mg, 250, mg, or 300 mg.
  • patients diagnosed with AML, MDS or NHL are treated with an initial dose of 150 mg - 300 mg (e.g.,
  • Compound A or a pharmaceutically acceptable salt thereof in combination with azacitidine on the same day, followed by six consecutive days of receiving the azacitidine without Compound A, followed by a second dose of Compound A or a pharmaceutically acceptable salt thereof about 24 hours after the seventh dose of azacitidine.
  • Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once every other week (QOW) in combination with azacitidine on at least one day and on at least one day that is without azacitidine administration but greater than about 24 hours after the last prior dose of azacitidine.
  • the first QOW dose of Compound A or a pharmaceutically acceptable salt thereof is a first dose of 200 mg, and subsequent doses that are the same or higher, preferably within the range of 200 mg - 400 mg per dose.
  • Compound A or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once every other week (QOW) in an amount of 400 mg.
  • Compound A or a pharmaceutically acceptable salt thereof is administered to the patient in need thereof once every other week.
  • 200 mg to 400 mg (e.g., 200 mg, 300 mg or 400 mg) of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient once every other week, depending on the patient being treated, when administered in combination with azacitidine, as disclosed herein.
  • patients diagnosed with AML/MDS or NHL are treated by administering an initial dose of 200 mg of Compound A or a pharmaceutically acceptable salt thereof every other week (QOW), and optionally increasing the individual dose of Compound A administered in subsequent doses QOW up to 400 mg (e.g., subsequent doses of 200 mg-400 mg, including doses of 200 mg or 300 mg or 400 mg, each given QOW) of Compound A every week (QOW).
  • QOW an initial dose of 200 mg of Compound A or a pharmaceutically acceptable salt thereof every other week
  • patients are selected to receive Compound A as described herein based on one or more markers and/or characteristics, such as, for example, diagnosis, response to prior therapy and/or mutation status.
  • a patient is suffering from a cancer (e.g., AML/MDS or NHL) that is relapsed or refractory to standard therapies.
  • a patient has received one or more prior therapies (e.g., prior chemotherapies).
  • a patient is suffering from AML/MDS.
  • a patient is suffering from relapsed or refractory AML (e.g., with intermediate or unfavorable risk cytogenetics and/or lacking FLT3 ITD or TKD alterations).
  • a patient is suffering from AML characterized by a FLT3 mutation.
  • a patient is suffering from NHL.
  • patients are selected based on one or more inclusion criteria.
  • One or more (preferably, all) of the following inclusion criteria can be used in selecting patients: • Patients > 18 years old
  • AST aspartate transaminase
  • ALT alanine transaminase
  • alkaline alkaline
  • patients diagnosed with AML/MDS can be selected to receive a BET Inhibitor Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) as a single agent based on the presence of histologically or cytologically proven AML or intermediate risk, high risk, or very high-risk MDS as defined by the World Health Organization (WHO) criteria and Revised International Prognostic Scoring System (IPSS-R), respectively, that is relapsed/refractory (R/R) to standard therapy or for whom standard treatments are
  • WHO World Health Organization
  • IIPSS-R Revised International Prognostic Scoring System
  • patients diagnosed with AML/MDS can be selected to receive a BET Inhibitor Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) as a single agent based on the presence of histologically or cytologically proven AML with a FLT3 internal tandem duplication (FLT3-ITD) or tyrosine kinase domain (FLT3-TKD) mutation previously determined by local testing that is R/R to standard therapy or for whom standard treatments are contraindicated.
  • a BET Inhibitor Compound e.g., Compound A or a pharmaceutically acceptable salt thereof
  • patients diagnosed with AML/MDS can be selected to receive a BET Inhibitor Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) as a single agent based on the presence of histologically or cytologically proven AML with intermediate or unfavorable risk cytogenetics in the absence of a detectable FLT3 ITD or TKD mutation as previously determined by local testing that is R/R to standard therapy or for whom standard treatments are contraindicated.
  • a BET Inhibitor Compound e.g., Compound A or a pharmaceutically acceptable salt thereof
  • patients can be selected based on either or both criteria: (a) Mature B-cell NHL as defined by WHO (2008) with the following histologies: follicular, marginal zone (splenic, nodal, and extranodal), mantle cell, primary mediastinal, diffuse large B-cell (DLBCL, including Richter’s transformation and follicular grade 3b) lymphomas, and B-cell lymphomas not specified (with features of DLBCL/Burkitt’s lymphoma), that is R/R to standard therapy and for whom standard treatments are
  • ANC absolute neutrophil count
  • Hgb hemoglobin
  • patients who are on chronic red blood cell (RBC) transfusions or erythropoietin to maintain a Hgb of > 8 g/dL are eligible.
  • a BET Inhibitor Compound e.g., Compound A or a pharmaceutically acceptable salt thereof
  • patients can be selected based on the criteria: Mature B-cell NHL as defined by WHO (2008) with the following histologies:
  • DLBCL diffuse large B-cell lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • B-cell lymphomas not specified with features of DLBCL/Burkitt’s lymphoma
  • a BET Inhibitor Compound e.g., Compound A or a pharmaceutically acceptable salt thereof
  • patients can be selected based on the criteria: measurable lymph node or tumor mass > 1.5 cm in at least 1 dimension by computed tomography (CT) or magnetic resonance imaging (MRI) requiring treatment at the discretion of the Investigator.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • Compound (e.g., Compound A or a pharmaceutically acceptable salt thereof) and azacitidine patients can be selected based on the criteria of histologically or cytologically proven AML or MDS (intermediate risk, high-risk or very high risk) as defined by the WHO criteria and IPSS-R, respectively, that is: (a) R/R to standard therapy, or (b) AML: who are unfit for, or unwilling to receive standard induction therapy, or (c) MDS: eligible to receive azacitidine.
  • the methods of treatment disclosed herein exclude the treatment of patients who meet one or more of the following exclusion criteria: • Considered surgically cured. Patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses) provided these are definitively treated prior to enrollment
  • CNS central nervous system
  • GvHD active acute or chronic graft vs host disease
  • hyperleukocystosis must be stopped prior to start of study drug
  • Pulmonary disease e.g., chronic obstructive pulmonary disease [COPD], asthma, etc.
  • COPD chronic obstructive pulmonary disease
  • Uncontrolled disease-related metabolic disorder e.g., hypercalcemia
  • patients with leukocytosis at baseline or who develop leukocytosis after initiation of therapy with Compound A may receive hydroxyurea.
  • Suggested guidelines for administering hydroxyurea are as follows:
  • hydroxyurea or CNS prophylaxis is administered to patients receiving a BET Inhibitor Compound (e.g., Compound A).
  • a BET Inhibitor Compound e.g., Compound A
  • a method of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program comprising administering to the patient in need thereof a therapeutically effective dose of Compound A every week in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.
  • a method of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program comprising administering to the patient in need thereof a therapeutically effective dose of Compound A every other week in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.
  • a method of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program comprising administering to the patient in need thereof a therapeutically effective dose of Compound A every 4 weeks in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.
  • A4 The method of any one of embodiments A1-A3, wherein the therapeutically effective amount is a total of 300 mg of Compound A administered in each dose.
  • A5. The method of any one of embodiments A1-A3, wherein the therapeutically effective amount is a total of 400 mg of Compound A administered in each dose.
  • A6 The method of any one of embodiments A1-A3, wherein the therapeutically effective amount is a total of 300 - 400 mg of Compound A administered in each dose.
  • a method of treating a patient diagnosed with relapsed or refractory hematologic cancer malignancies comprising administering to the patient in need thereof 400 mg of Compound A every other week (QOW) or 300 mg of Compound A every week (QW).
  • A8 The method of any one of embodiments A1-A7, wherein the patient is diagnosed with Acute myelogenous leukemia (AML), MDS or Non-Hodgkin lymphoma (NHL).
  • AML Acute myelogenous leukemia
  • MDS MDS
  • NDL Non-Hodgkin lymphoma
  • A13 A method of treating a patient diagnosed with an acute leukemia or
  • the method comprising administering to the patient in need thereof a total of about a 400 mg dose of (S)-(5- cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-3,4-dihydroquinolin-l(2H)- yl)(cyclopropyl)methanone or a pharmaceutically acceptable salt thereof, once every other week (QOW) to the patient in need thereof.
  • QOW once every other week
  • A14 A method of treating a patient diagnosed with an acute leukemia or
  • the method comprising administering to the patient in need thereof a total of about a 400 mg dose of Compound A:
  • A15 A method of treating a patient diagnosed with an acute leukemia or
  • the method comprising administering to the patient in need thereof a total of about a 300 mg dose of (S)-(5- cyclobutoxy-2-methyl-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-3,4-dihydroquinolin-l(2H)- yl)(cyclopropyl)methanone or a pharmaceutically acceptable salt thereof, once every week (QW) to the patient in need thereof.
  • A16 A method of treating a patient diagnosed with an acute leukemia or
  • the method comprising administering to the patient in need thereof a total of about a 300 mg dose of Compound A:
  • A17 The method of any one of embodiments A13-A16, wherein the patient is diagnosed with AML.
  • AML acute myelogenous leukemia
  • MDS myelodysplastic syndrome
  • NHS non-Hodgkin lymphoma
  • Compound A is about 400 mg of Compound A administered to the patient in need thereof once every other week (QOW).
  • AML acute myelogenous leukemia
  • MDS myelodysplastic syndrome
  • NHS non-Hodgkin lymphoma
  • Compound A is about 400 mg of Compound A administered to the patient in need thereof once every other week (QOW).
  • Compound A as a pharmaceutically acceptable succinate salt once every other week throughout a course of treatment.
  • AML acute myelogenous leukemia
  • MDS myelodysplastic syndrome
  • NHS non-Hodgkin lymphoma
  • AML acute myelogenous leukemia
  • a method of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program comprising administering to the patient in need thereof a therapeutically effective dose of a BET Inhibitor Compound every week in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.
  • a method of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program comprising administering to the patient in need thereof a therapeutically effective dose of a BET Inhibitor Compound every other week in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.
  • a method of treating a patient diagnosed with cancer having a tumor that depends on a BET-driven transcription program comprising administering to the patient in need thereof a therapeutically effective dose of a BET Inhibitor Compound every 4 weeks in an amount to achieve target exposure over about 100 nM for 30-50% of the time between doses.
  • Compound is selected from the group consisting of BET Inhibitor Compound A, B, C, D,
  • Compound is administered once every week to the patient in need thereof.
  • Compound is administered once every other week to the patient in need thereof.
  • a method of treating a patient diagnosed with cancer comprising
  • pharmaceutically acceptable salt thereof and azacitidine are both administered to the patient on day 1 of a first treatment cycle.
  • Compound A or a pharmaceutically acceptable salt thereof is administered to the patient without azacitidine on days 8, 15 and 22 of the 28-day treatment cycle.
  • pharmaceutically acceptable salt thereof is only administered to the patient on days 1, 8, 15 and 22 of the 28-day treatment cycle.
  • pharmaceutically acceptable salt thereof is only administered to the patient on days 1, 8, 15 and 22 of the 28-day treatment cycle, and azacitidine is only administered to the patient on days 1-7 of the 28-day treatment cycle.
  • Dl l The method of embodiment Dl, wherein Compound A is administered once every other week throughout a 28-day treatment cycle, and the azacitidine is administered for seven consecutive days during the first week of the 28-day treatment cycle.
  • pharmaceutically acceptable salt thereof and azacitidine are both administered to the patient on day 1 of a first treatment cycle.
  • pharmaceutically acceptable salt thereof is only administered to the patient on days 1 and 15 of the 28-day treatment cycle.
  • pharmaceutically acceptable salt thereof is only administered to the patient on days 1 and 15 of the 28-day treatment cycle, and azacitidine is only administered to the patient on days 1-7 of the 28-day treatment cycle.
  • a method of treating a patient diagnosed with cancer selected from the group
  • the method comprising administering to the patient in need thereof a hypomethylating agent in combination with a BET inhibitor, wherein the BET inhibitor is administered throughout a course of treatment of at least 28 consecutive days, and wherein the BET inhibitor is administered to the patient:
  • D24 The method of any one of embodiments D22-D23, wherein the hypomethylating agent is azacitidine.
  • D25 The method of any one of embodiments D22-D24, wherein the BET inhibitor is further administered to the patient with the hypomethylating agent on the first day of the course of treatment.
  • D28 The method of any one of embodiments D1-D27, wherein the patient is diagnosed with AML.
  • D29 The method of any one of embodiments D1-D27, wherein the patient is diagnosed with MDS.
  • D30 The method of any one of embodiments D1-D27, wherein the patient is diagnosed with NHL.
  • Compound A has a molecular and formula weight of 434.58 Da, and a melting point of 80.9 °C (DSC).
  • Compound A has potent and equivalent biochemical activity against all 4 BET family members (BRD2, BRD3, BRD4, BRDT), and shows additional activity towards several non-BET bromodomain proteins
  • Compound A is a BET bromodomain inhibitor that exhibits significant anti -tumor activity in vivo in mouse xenograft models of human leukemia/lymphoma. Importantly, optimal activity and tolerability were observed on intermittent dosing schedules. These data support the clinical trial of Compound A in leukemias/lymphomas.
  • BET family member BRD4 has been shown to positively regulate transcription of the oncogene MYC through its localization to super-enhancer transcriptional regulatory elements.
  • BET family member BRD4 has been shown to positively regulate transcription of the oncogene MYC through its localization to super-enhancer transcriptional regulatory elements.
  • the safety and tolerability of Compound A has been assessed in a number of in vitro and multi-dosing in vivo experiments, suggesting that the therapeutic index can be modulated through dose and schedule.
  • Compound A was active in in vivo xenograft models under a variety of schedules, in both solid and hematological tumors.
  • Compound A has shown superior efficacy to comparative BET inhibitor OTX015 in the AML model MV-4-11, showing regressions, whereas the best response observed with competitor molecules has been tumor stasis.
  • Compound A can be obtained by a series of synthetic reactions using commercially available materials. Oxidative cyclization of 2-chloro-5-methoxyaniline (i), and crotonaldehyde, using chloranil as the oxidant, afforded methoxyquinoline (ii) as its hydrochloride salt. Catalytic hydrogenation in the presence of base reductively removed the chlorine to provide (iii) in good yield. Catalytic asymmetric hydrogenation of the quinoline with a chiral ?’-arene-N-tosylethylenediamine-Ru(II) complex at high pressure afforded the desired (iv).
  • a Compound A succinate salt was prepared according to the following method. Compound A was slurried in acetone with succinic acid (1 : 1 molar ratio) and solid was isolated at 4 °C. About 20 mg of resulting solid was suspended in 0.3 mL of a solvent. The suspension was stirred for 6 days at room temperature, and the solids were isolated.
  • the X-ray powder diffraction pattern of the crystalline Compound A Succinate is summarized below:
  • the finished product, Compound A Capsules, used in human clinical trials described in the remaining Examples is Compound A succinate active pharmaceutical ingredient (API) powder filled in empty, hard gelatin, opaque, plain (or unmarked) capsules.
  • Compound A Capsules were initially presented as three unit strengths for oral administration. The capsules contain 5, 20, or 100 mg Compound A fill weight per capsule. Each dose strength was filled in capsules that have distinctive size and color combinations.
  • Compound A Capsules were presented for oral administration. The capsules had distinctive sizes and colors to designate the capsule strength: 5 mg capsules; 20 mg capsules; and 100 mg capsules.
  • Bromodomain 2 (BD2) was measured using AlphaScreen assay technology. His-BRD4 BD1 and His-BRD4 BD2 binding and inhibition was assessed by monitoring the engagement of biotinylated Histone H4 (1-21) K5/8/12/16 tetra-acetylated (H4K4) peptide with the targets. Compound A inhibited BRD4 BD1 binding to the H4K4 peptide with an ICso of ⁇ 1.0 micromolar and inhibited BRD4 BD2 binding to the H4K4 peptide with an ICso of ⁇ 0.1 micromolar. The testing of Compound A in an alternative ligand binding competition assay, which showed equipotent binding activity of Compound A for BRD4, BD1, and BD2.
  • Compound A was further profiled in a bromodomain assay panel (BROMOscan, DiscoveRx) to determine its selectivity against other bromodomain-containing proteins using a ligand binding site-directed competition assay to quantitatively measure interactions between test compound and bromodomains.
  • Compound A was screened at a primary screening concentration of 10 micromolar against thirty -two bromodomains.
  • Compound A bound six non-BET bromodomains in the panel with sub -micromolar affinity: CECR2, BRD9, BRD7, CREBBP, BRPF1 and EP300.
  • Example 3 MV-4-11 Murine Xenograft Testing of Compound A
  • MV-4-11 xenografted nude mice were dosed with Compound A at various doses and schedules (Compound A 15 mg/kg QD x 3, 55 mg/kg single dose, 100 mg/kg single dose), followed by collection of plasma and tumors at several time points. MYC downregulation (mRNA), free plasma and tumor levels (total tumor levels corrected for plasma fraction unbound) of Compound A were then compared. The data from these experiments suggest that MYC expression was reduced in MV-4-11 tumors (in comparison to vehicle treated tumors) by approximately 60 to 80% by Compound A at 4 h post final dose, at all dose levels. Interestingly, the extent of MYC suppression was consistent with the in vitro experiments described above.
  • the MYC downregulation increased only marginally in going from 15 mg/kg to 55 mg/kg, with suppression plateauing at around 80% for the 55 mg/kg and 100 mg/kg doses.
  • the ratio of free tumor (assuming corrections for binding are equivalent to plasma protein binding) versus free plasma concentrations was consistent with the higher volume of distribution observed for Compound A (Vss 8.9 L/kg). [0121] This analysis was extended to longer time points post dose.
  • the level of MYC downregulation was sustained at levels greater than 50% between 12-24 hours.
  • the dose of Compound A was increased from 15 mg/kg to 55 mg/kg, and then to 100 mg/kg, the extent of MYC downregulation increased at later time points.
  • the MYC downregulation appeared to be associated with the free plasma levels, as it was evident that as the compound was cleared, the MYC mRNA levels began to rise back towards vehicle treated levels.
  • Figure 2 is a graph showing the effect of treatment on tumor volume in MV-4-11 human tumor xenograft model (MLL-fusion, Flt3-ITD+) described in Example 4.
  • the in vivo anti-tumor activity of Compound A was investigated as a single agent in the MV-4-11 acute myeloid leukemia human (subcutaneous tumor) xenograft model in mice.
  • MV-4-11 was chosen as a model that is MYC-dependent, sensitive to Compound A in vitro.
  • Human dose can be modeled to produce unbound plasma concentrations over this threshold for one third of the dosing period, for the Q7D dose.
  • a time period over threshold of 56 hours (1/3 of dosing period) can be selected.
  • the initial human use of Compound A is disclosed as BET Inhibitor FT-1101 in human clinical trials under clinical trial identifier NCT02543879 at the website clinicaltrials.gov.
  • the results of 28-day definitive toxicity studies were used to calculate a safe clinical starting dose for Compound A in the proposed Phase 1 trial.
  • the clinical starting dose for the proposed Phase 1 trial was 10 mg administered orally once weekly (Schedule 1 in Example 5).
  • Based on an analysis of the preliminary PK profiles of the initial patients receiving at least one 10 mg dose of Compound A (n 8), alternative dosing schedules of every month (QM, Schedule 2 in
  • Example 5 and every other week (QOW, Schedule 3 in Example 5) involving less frequent dosing will be explored.
  • Compound A can be administered as a single agent (SA) in patients with relapsed or refractory (R/R) AML/MDS or R/R non-Hodgkin lymphomas (NHL).
  • SA single agent
  • R/R refractory
  • NHL non-Hodgkin lymphomas
  • SA Single agent
  • a single schedule of Compound A administered in combination will be selected from schedules (and doses) disclosed herein.
  • Dose escalation studies are initiated with SA Compound A with each hematologic malignancy treatment cohort evaluated utilizing a 3+3 strategy. Once an MTD is identified for a treatment cohort, additional patients may be enrolled in expansion cohorts each of select populations of patients with either AML/MDS or NHL. On the initial schedule for each treatment cohort, study drug will be taken once weekly in 28-day continuous cycles from Day 1 until study withdrawal criteria are met.
  • a human clinical trial study evaluates multiple potential schedules for SA Compound A in separate hematologic malignancy treatment cohorts: an AML/MDS treatment cohort and an NHL treatment cohort.
  • a Compound A dosing schedule (Schedule 1) for each treatment cohort of
  • AML/MDS or NHL patients consists of Compound A given orally according to a level and schedule shown in Table 2 below.
  • Compound A is administered between 10-400 mg QW.
  • Compound A is administered between 20-400 mg QM.
  • Compound A is administered between 40-900 mg QOW. Table 2
  • Compound A shows consistent pharmacokinetics across various doses in human clinical trials.
  • Figure 3 A shows the day 1, dose normalized (Cmax/dose in ng/mL/(mg)) ratio measured in patients receiving Compound A according to certain doses provided in Table 2.
  • Figures 3 A-3D are graphs showing the ratio of measured AUC values (Figure 3B), and plasma concentrations (Figure 3C and Figure 3D) for the administration of various doses of Compound A (80-400 mg in Figure 3A; 400 mg in Figure 3C and 260 mg in Figure 3D) in a human clinical trial.
  • the SA dose escalation portion of the clinical trial allows a dose increase of 100% with the dose escalation from Dose Level 1 to Dose Level 2 for each dose schedule. Thereafter, a maximum of up to -50% increase (adjusted based on pill strength) between dose-escalation cohorts within a schedule is allowed until the MTD is determined.
  • Intermediate dose levels from those proposed above may be explored based on AEs, tolerability, PK, other clinical data as clinically indicated, or on available pill strengths and sizes.
  • the MTD is the highest dose level within a schedule that does not meet the dose limiting toxicity (DLT) dose level definition for a treatment cohort (AML/MDS or NHL).
  • DLT dose limiting toxicity
  • the DLT dose level is defined as the lowest dose level at which a DLT is experienced in > 2 patients out of a maximum of 6 evaluable patients within a treatment cohort (AML/MDS or NHL).
  • Dose escalation to define a SA MTD may occur in 1 or more selected schedules for each treatment cohort. Each dose level must be evaluated and found to be safe by at least 1 treatment cohort before dose escalation can occur. For any treatment cohort, a within-schedule dose level may be skipped if the dose level was previously tolerated by the other treatment cohort or the dose level was previously tolerated in a more frequent dosing schedule.
  • patients from at least 1 treatment cohort (AML/MDS or NHL) can initially be enrolled at that dose level. If exactly 1 of the initial 3 evaluable patients has a DLT before the end of Cycle 1, the dose level is expanded to up to 6 evaluable patients. If 5 of a total of ⁇ 6 evaluable patients complete the full cycle absent a DLT, escalation may continue.
  • the dose level at which > 2 of up to 6 evaluable patients have a DLT is at least 1 dose level above the MTD for that treatment cohort.
  • the next lower dose is more fully evaluated by treating a total of up to 6 evaluable patients. If > 2 patients have a DLT at this lower dose level, de-escalation continues until a dose level is identified at which 0 or 1 of a total of 6 patients has a DLT. This is identified as the MTD for the schedule evaluated for that treatment cohort.
  • the recommended phase II dose (RP2D) may be a dose level equivalent or lower than the MTD.
  • a Phase 1 study evaluated the safety, PK/PD, and clinical activity of Compound A in patients with relapsed/refractory (R/R) AML/MDS, or non-Hodgkin lymphoma (NHL).
  • Dose escalation evaluated a range of dose levels, from 10 mg to 600 mg, oral Compound A in three different oral dosing schedules: weekly (QW), every other week (QOW), and once a month (QM).
  • QW weekly
  • QOW every other week
  • QM once a month
  • a total of 84 AML/MDS patients and 10 NHL patients received Compound A in a dose escalation study. Patients received Compound A in dose escalation with a median of 2 (range: 1-13) treatment cycles and a median exposure of 43 (range: 1-401) days for AML/MDS patients and 51.5 (range: 1-183) days for NHL patients. Most AML/MDS patients (n 80) received Compound A as a single agent. Disease characteristics of the patient population are summarized in Table 3. Table 3
  • Geometric mean AUC ( o-i 68) and Cmax values ranged from 795-97100 ng*h/mL and from 18-1220 ng/mL, respectively.
  • a summary of pharmacokinetic parameters (mean AU o- 168), mean Cmax, and mean ti/2) is provided in Table 4.
  • FIG. 7A is a box-and-whisker plot of CCR1 modulation at 4 hrs post-dose for various doses (80-600 mg) of Compound A.
  • Figure 7B is a box-and-whisker plot of HEXIM1 modulation at 4 hrs post-dose for various doses (80-600 mg) of Compound A.
  • both CCR1 and HEXIM1 levels were modulated in a dose-dependent manner (e.g., for doses >180 mg) after a single dose of
  • FIG. 8A is a plot of mean concentration of Compound A (ng/mL) at various time points after a single 300 mg oral dose of Compound A.
  • Figure 8B is a plot of HEXIM1 expression (relative quantification (RQ)) over time after a single 300 mg oral dose of Compound A.
  • Figure 8C is a plot of CCR1 expression (relative quantification (RQ)) over time after a single 300 mg oral dose of Compound A.
  • FIGs 8A-8C levels of the PD biomarkers CCR1 and HEXIM1 tracked with plasma pharmacokinetics.
  • TEAEs treatment-emergent adverse events
  • All adverse events were recorded and categorized by severity according to the NCI CTCAE guidelines (http://ctep.cancer.gov/reporting/ctc.html).
  • the most common TEAEs were diarrhea (32%), fatigue (30%), dyspnea (29%), nausea (27%), and anemia (24%) among AML/MDS patients, and diarrhea (60%) among NHL patients.
  • the most common severe (> grade 3) TEAEs were anemia (21%), decreased platelets (19%), pneumonia (16%), and sepsis (13%) among AML/MDS patients, and pleural effusion and disease progression (20% each) among NHL patients.
  • AML/MDS patients 22 AML/MDS patients (26%) had at least one AE leading to treatment discontinuation (5 discontinuations due to disease progression, and 3 AEs assessed as related to treatment).
  • 2 NHL patients (20%) had at least one AE leading to treatment discontinuation, both for disease progression.
  • Disease progression was the most common fatal TEAE in AML/MDS and NHL patients (10% and 20%, respectively).
  • Compound A as a single agent showed acceptable safety in R/R AML/MDS and NHL patients.
  • Gastrointestinal toxicity was mostly low-grade, and higher-grade gastrointestinal AEs occurred in ⁇ 5% of AML/MDS patients and in 0% of NHL patients. TEAEs are summarized in Table 5.
  • the maximum tolerated dose (MTD) on the QOW schedule was 400 mg Compound A, though MTD was not determined for other dosing schedules (QW and QM).
  • MTD maximum tolerated dose
  • Some clinical activity was observed in R/R AML/MDS patients, wherein one patient (3%) achieved CRi and 19 patients (63%) achieved SD, including 2 patients receiving >7 cycles of treatment.
  • Compound A and azacitidine exhibit a combinatorial effect.
  • the combinatorial effects of Compound A and azacitidine were assessed using a Cell Titer Glo readout assay (Promega). Kasumi-1 and MV-4-11 cells were plated in white flat bottom 96 well plates.
  • Dilution series were made for each compound (10 mM top dose, 8 points, 1 :3 dilution in DMSO) and added to cells after plating. Compounds were also added individually, and some wells were treated with DMSO only. Cells were treated as follows: compounds were added according to the diagram in Figure 9. Compounds were initially added at the same time. MV-4-11 cells were treated for 72 hours and Kasumi-1 were treated for 120 hours. Cell Titer Glo was added at the end and viability was read out on the Envision Multilabel Reader. Data was analyzed using online software from Horizon (http://chalice.horizondiscovery.com/analyzer- server/cwr/analyze.jsp).
  • Compound A can be administered in combination with azacitidine (for example, in patients with R/R AML/MDS or AML who are unfit for, or unwilling to receive, standard induction therapy, or in patients with MDS eligible to receive azacitidine).
  • BET proteins are believed to mediate resistance to azacitidine. Strong synergy between azacitidine and Compound A in AML cell lines. Based on immune surveillance data, azacitidine is believed to upregulate PD-L-1/PD-L2 in AML, while Compound A down regulates PDL-l/PDL-2 expression in TME (M2 and MDSC).
  • Azacitidine is supplied as a lyophilized powder in 100 mg single-use vials containing no preservative and is packaged in cartons of one vial. Unreconstituted vials of azacitidine must be stored according to storage conditions provided in the VIDAZA® package insert. Azacitidine should be reconstituted aseptically with 4 mL of sterile water for injection. The resulting suspension will contain azacitidine, 25 mg/mL. Azacitidine will be administered via
  • Compound A in combination with azacitidine is synergistic in vitro in human leukemia cell lines. Upregulation of PD-L1/PD-L2 after HMA treatment in both AML and MDS patients has been reported, indicating a diminished response to azacitidine therapy via immunotolerance may play a role in HMA treatment failures in AML/MDS.
  • hypomethylating agent (HMA) azacitidine is approved for the treatment of subtypes of myelodysplastic syndrome (MDS) and is a recommended treatment option in acute myelogenous leukemia (AML) patients who are not candidates for or who have failed intensive cytotoxic induction/consolidation regimens. Resistance to azacitidine therapy in AML has been shown to be mediated by BET proteins.
  • the starting dose of Compound A in combination is administered on Day 1 of each 28-day treatment cycle and will be a dose approximately ⁇ 50% the MTD identified for the AML/MDS SA treatment cohorts in that schedule.
  • azacitidine 75 mg/m 2 is administered via subcutaneous injection or intravenous infusion for seven days starting on Day 1 of each 28-day treatment cycle. A 48-hour dose-interruption of the azacitidine for weekends or holidays is allowed. Alternate schedules of azacitidine dosing (e.g., starting azacitidine dosing on Day 8 of each treatment cycle) can be used if concurrent dosing of Compound A/azacitidine on Day 1 of each treatment cycle is found to be intolerable.
  • azacitidine administration about 24 hours prior to administration of Compound A exhibited a synergistic effect. Accordingly, a dosing regimen is administered to a patient where azacitidine is administered on days 1 - 7 of a 28-day cycle followed by Compound A administration on days 8 - 28 of a 28-day cycle.
  • the standard dose of azacitidine (75 mg/m 2 ) is administered via subcutaneous injection or intravenous infusion each day on days 1 - 7 of a 28 day cycle.
  • On Day 8 about 24 hours after the final dose of azacitidine (of a 28 day cycle), Compound A is administered.
  • Compound A is administered on Day 8, Day 15, and Day 22.
  • the 28-day cycle can be repeated as needed.
  • Sample QW dosing schedules include the following (* indicates neither azacitidine nor Compound A is administered on days 9-14 or days 16-21; N/A indicates not administered):
  • Sample QOW dosing schedules include the following (N/A indicates not administered):
  • Dose 0, Dose 1, Dose 2, and Dose 3 can be the same or different. In some
  • Dose 1 is greater than Dose 0
  • Dose 2 is greater than Dose 1
  • Dose 3 is greater than Dose 2.
  • Dose 0 and Dose 1 can be any one of the following combinations for QOW dosing:
  • the method of treatment can be the following QOW dosing schedule:
  • Another method of treatment can be the following QW dosing schedule:
  • the dose level at which > 2 of up to 6 evaluable patients have a DLT is considered to be at least 1 dose level above the MTD for that treatment cohort.
  • the next lower dose is then evaluated by treating a total of up to 6 evaluable patients. If > 2 patients have a DLT at this lower dose level, de-escalation will continue until a dose level is identified at which 0 or 1 of a total of 6 patients has a DLT. This identifies the MTD for the combination treatment cohort.
  • the RP2D can be a dose level equivalent or lower than the MTD.
  • a Compound B intermittent dosing schedule for treatment of AML or metastatic castration-resistant prostate cancer comprises administering to a patient in need thereof an amount of Compound B sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • an amount of Compound B sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • 1-500 mg of Compound B is administered every week to a patient in need thereof.
  • 1-500 mg of Compound B is administered every other week to a patient in need thereof.
  • a Compound C intermittent dosing schedule for treatment of AML, MM, breast cancer, NSCLC, prostate cancer, SCLC, or NHL comprises administering to a patient in need thereof an amount of Compound C sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • an amount of Compound C sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • 1-500 mg of Compound C is administered every week to a patient in need thereof.
  • 1-500 mg of Compound C is administered every other week to a patient in need thereof.
  • a Compound D intermittent dosing schedule for treatment of solid tumors, lymphoma, or ovarian CA expansion comprises administering to a patient in need thereof an amount of Compound D sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • an amount of Compound D sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • 1-80 mg of Compound D is administered every week to a patient in need thereof.
  • 1-80 mg of Compound D is administered every other week to a patient in need thereof.
  • a Compound E intermittent dosing schedule for treatment of HCC, NMC, melanoma, or lymphoma comprises administering to a patient in need thereof an amount of Compound E sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • an amount of Compound E sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • 1-80 mg of Compound E is administered every week to a patient in need thereof.
  • 1-80 mg of Compound E is administered every other week to a patient in need thereof.
  • a Compound F intermittent dosing schedule for treatment of TNBC, ovarian cancer (serous histology for expansion phase), SCLC, or other solid tumors comprises administering to a patient in need thereof an amount of Compound F sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • an amount of Compound F sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • 1-500 mg of Compound F is administered every week to a patient in need thereof.
  • Compound F is administered every other week to a patient in need thereof.
  • a Compound G intermittent dosing schedule for treatment of MM, lymphoma, leukemia, MDS, MPN, or nerve sheath tumors comprises administering to a patient in need thereof an amount of Compound G sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • an amount of Compound G sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • 1-200 mg of Compound G is administered every week to a patient in need thereof.
  • 1-200 mg of Compound G is administered every other week to a patient in need thereof.
  • a Compound H intermittent dosing schedule for treatment of breast cancer or diffuse large B cell lymphoma comprises administering to a patient in need thereof an amount of Compound H sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses. For example, 1-500 mg of Compound H is administered every week to a patient in need thereof. In another example, 1-500 mg of Compound H is administered every other week to a patient in need thereof.
  • Example 16 Dosing of Compound I
  • a Compound I intermittent dosing schedule for treatment of AML, SCLC, NSCLC, colorectal cancer, TNBC, ER+ BrCA, CRPC, MYC-amp solids, or ras-mutant solid tumors comprises administering to a patient in need thereof an amount of Compound I sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • an amount of Compound I sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • 1-50 mg of Compound I is administered every week to a patient in need thereof.
  • 1-50 mg of Compound I is administered every other week to a patient in need thereof.
  • a Compound J intermittent dosing schedule for treatment of lymphoma, solid tumors, AML, MDS, MF, or MM comprises administering to a patient in need thereof an amount of Compound J sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • an amount of Compound J sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • 1-70 mg of Compound J is administered every week to a patient in need thereof.
  • 1-70 mg of Compound J is administered every other week to a patient in need thereof.
  • a Compound K intermittent dosing schedule for treatment of solid and heme escalation comprises administering to a patient in need thereof an amount of Compound K sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • an amount of Compound K sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • 1-500 mg of Compound K is administered every week to a patient in need thereof.
  • 1-500 mg of Compound K is administered every other week to a patient in need thereof.
  • a Compound L intermittent dosing schedule for treatment of AML/DLBCL, solid tumors (NMC, TNBC, NSCLC, CRPC), heme, glioblastoma multiforme, lymphoma, or MDS comprises administering to a patient in need thereof an amount of Compound L sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • an amount of Compound L sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • 1-200 mg of Compound L is administered every week to a patient in need thereof.
  • 1-200 mg of Compound L is administered every other week to a patient in need thereof.
  • a Compound M intermittent dosing schedule for treatment of solid tumors, lymphoma, MDS, or AML comprises administering to a patient in need thereof an amount of Compound M sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • an amount of Compound M sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.
  • 1-500 mg of Compound M is administered every week to a patient in need thereof.
  • 1-500 mg of Compound M is administered every other week to a patient in need thereof.
  • a BET Inhibitor Compound is administered to a patient in need thereof according to a dosing schedule described in Table 7, e.g., according to a dosing schedule sufficient to achieve exposure (e.g., 100 nM or greater) for 30-50% of the time between doses.

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Abstract

L'invention concerne des méthodes de traitement de patients chez lesquels on a diagnostiqué un cancer au moyen d'un composé inhibiteur de protéines BET, comprenant des programmes de dosage intermittent pour administrer le composé en tant qu'agent unique ou dans le cadre d'une polythérapie. Par exemple, des patients atteints de cancer de type leucémie myéloblastique aiguë (LMA)/syndrome myélodysplasique (SMD) et lymphome non hodgkinien (LNH) peuvent être traités au moyen d'un composé inhibiteur de protéines BET à l'aide de programmes de dosage intermittent proposés dans la présente invention.
PCT/US2020/040311 2019-07-01 2020-06-30 Traitement du cancer au moyen d'un inhibiteur de la famille des protéines à bromodomaine et à domaine extra-terminal (bet) WO2021003163A1 (fr)

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