Methods and Compositions Comprising Cardiac-Tolerant HDAC Inhibitors

Abstract

Provided herein are methods comprising an HDAC inhibitor (HDACi), and / or a PD-L1 and / or PD-1 inhibitor, and / or a CTLA-4 inhibitor, and / or an anti-cancer agent. Also provided herein are pharmaceutical compositions suitable for treating cancer.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 441,131, filed January 25, 2023, which is incorporated herein by reference in its entirety.

[0002] The present invention relates to compounds comprising HDAC inhibitors and uses of such compounds, and to methods comprising and uses of HDAC inhibitors, PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors, among other checkpoint inhibitors. [Background technology]

[0003] Many commonly used drugs are known to disrupt cardiac rhythm and cause QT interval prolongation, which can lead to fatal ventricular arrhythmias and sudden cardiac death. For example, drugs such as antihistamines, antibacterial agents, antidepressants, antibiotics, and anticancer drugs are known to affect cardiac rhythm.

[0004] Cancer is a significant cause of morbidity and mortality worldwide, and its standard of care has improved significantly over the years. It includes the combination of known anticancer drugs, including epigenetic modifiers such as histone deacetylase inhibitors (HDACi), with immuno-oncology agents targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death receptor 1 (PD-1), and its ligand PD-L1. However, many cancer chemotherapy agents are known to prolong the QT interval or increase the risk of QT interval prolongation. Because most drugs, especially anticancer drugs, are often structurally and pharmacologically diverse, predicting the risks associated with these drugs is difficult. Therefore, there is a need in the art for new anticancer therapies that minimize or eliminate cardiac rhythm disturbances. Solutions to these and other problems in the art are provided herein. Summary of the Invention

[0005] Provided herein, among other things, are methods involving compounds comprising HDAC inhibitors (HDACi). The methods include administering an effective amount of HDACi to a subject such that administration of the HDACi does not cause increases in QTc, QTcF, or heart rate (HR). In some embodiments, the methods further include administering a CTLA-4 inhibitor, a PD-L1 inhibitor, and / or a PD-1 inhibitor. In some embodiments, the CTLA-4 inhibitor, the PD-L1 inhibitor, and / or the PD-1 inhibitor is an antibody. In some embodiments, the methods are used to treat cancer.

[0006] In some embodiments of the present disclosure disclosed herein are methods for treating a subject with a therapeutically effective amount of an HDACi that does not cause an increase in QTc, QTcF, or heart rate (HR). The HDACi comprises a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, prodrug, enantiomer, diastereomer, hydrate, co-crystal, or polymorph thereof, wherein Formula I is: [ka] is.

[0007] In some embodiments, the compound of formula I is N-(2-amino-4-fluorophenyl)-4-[[[(2E)-1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]benzamide or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method further comprises administering a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.

[0008] Some other embodiments of the present disclosure include a method for treating cancer, comprising administering a therapeutically effective amount of HDACi to a subject, wherein administering the HDACi to the subject does not cause an increase in QTc, QTcF, or heart rate (HR). In some embodiments, the method does not cause an increase in mean QTc, median QTc, mean QTcF, median QTcF, mean heart rate (HR), or median HR. In some embodiments, administering the HDACi to the subject causes a decrease in mean QTc, median QTc, mean QTcF, median QTcF, mean heart rate (HR), or median HR. In some embodiments, administering the HDACi to each subject in increasing doses results in a decrease in mean QTcF or median QTcF. In some embodiments, administering the HDACi to each subject does not cause a change in mean HR or median HR, or causes a decrease in mean HR or median HR. In some embodiments, the method further comprises administering a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.

[0009] Some other embodiments of the present disclosure include pharmaceutical compositions comprising an effective amount of an HDACi, wherein the effective amount is effective in treating cancer and does not cause an increase in QTc, QTcF, or heart rate (HR).

[0010] In some embodiments, the HDACi inhibits class I and class IIb HDACs. In some embodiments, the HDACi inhibits one or more of HDAC1, HDAC2, HDAC3, or HDAC10. In some embodiments, the HDACi inhibits all of HDAC1, HDAC2, HDAC3, and HDAC10. In some embodiments, the HDACi is tucidinostat (chidamide / HBI-8000).

[0011] In some embodiments, combinations (e.g., combination therapies such as methods of treatment and uses, kits, and compositions) for treating diseases, including cancer, are described herein. The kits include any combination of the embodiments described herein or pharmaceutical compositions of the embodiments described herein. In some embodiments, the kits further include at least one administration device. In some embodiments, the components of the kits are sterile. In some embodiments, the combinations described herein include an HDAC inhibitor and an anti-cancer agent, a PD-L1 inhibitor, a PD-1 inhibitor, and / or a further CTLA-4 inhibitor. In some embodiments, the combinations described herein include an HDAC inhibitor and an anti-cancer agent.

[0012] In some embodiments, the effective amount of HDACi is an amount effective to treat cancer. In some embodiments, the cancer is an advanced solid tumor. In some embodiments, the solid tumor is a cancer such as malignant melanoma (melanoma), renal cell carcinoma, or non-small cell lung cancer (NSCLC). In some embodiments, the cancer may be a hematological cancer such as lymphoma, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, Reed-Sternberg disease, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), or chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is Hodgkin's lymphoma or Reed-Sternberg disease. In some embodiments, the cancer is relapsed or refractory peripheral T-cell lymphoma ("RR / PTCL") or relapsed or refractory aggressive adult T-cell lymphoma ("RR / ATL").

[0013] In some embodiments, the effective amount of the compound is about 5 mg to about 80 mg per day. In some embodiments, the HDACi is administered as an oral dose. In some embodiments, the HDACi is administered at a dose of about 20 mg, about 30 mg, or about 40 mg once daily during a cycle. In some embodiments, the cycle is at least about 2 days in duration. In some embodiments, the cycle is about 1 week to about 4 weeks in duration. In some embodiments, the method further comprises administering a PD-1 inhibitor or PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor is administered on day 2 of the cycle. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the PD-1 antibody is administered at a dose of 240 mg per administration every 2 (two) weeks. In some other embodiments, the anti-PD-1 antibody can be administered according to an established regimen, such as one provided in the package insert.

[0014] Some embodiments of the present disclosure include a first pharmaceutical composition and a second pharmaceutical composition. The first pharmaceutical composition comprises the HDACi, and the second pharmaceutical composition comprises the anticancer agent, the PD-1 inhibitor, the PD-L1 inhibitor, and / or the CTLA-4 inhibitor. In some embodiments, the first pharmaceutical composition is formulated for oral administration. In other embodiments, the second pharmaceutical composition is formulated for parenteral administration.

[0015] In some embodiments, the anti-cancer agent, the PD-1 inhibitor, the PD-L1 inhibitor, and / or the CTLA-4 inhibitor is a small molecule compound, a nucleic acid, a peptide, a protein, an antibody, a peptibody, a diabody, a minibody, a single-chain variable fragment (ScFv), or a fragment or variant thereof. In some embodiments, at least one of the CTLA-4 inhibitor, the PD-L1 inhibitor, or the PD-1 inhibitor is an antibody. In some embodiments, the inhibitor antibody is a monoclonal antibody. In some embodiments, the inhibitor antibody comprises a human antibody, a murine antibody, a chimeric antibody, a humanized antibody, or a chimeric-humanized antibody. In some embodiments, the inhibitor antibody is a human antibody or a humanized antibody. In some embodiments, the inhibitor antibody is present in an amount of about 0.1 mg / kg to about 30 mg / kg. In some embodiments, the inhibitor antibody is present in an amount of about 0.5 mg / kg to about 15 mg / kg. In some embodiments, the inhibitor antibody is present in an amount of about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, or about 20 mg / kg. In some embodiments, the combination is suitable for parenteral administration to cancer patients. In some embodiments, the parenteral administration comprises intravenous (IV) administration.

[0016] In other embodiments, the PD-L1 inhibitor is an antibody such as durvalumab, avelumab, atezolizumab, BMS-936559, STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014, or STI-A1015 (Sorrento Therapeutics).

[0017] In other embodiments, the PD-1 inhibitor is an antibody such as nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR001, SHR-1210, or MEDI0680.

[0018] In yet other embodiments, the CTLA-4 inhibitor is an antibody, including ipilimumab.

[0019] In some embodiments, the cancer is a solid tumor cancer such as squamous cell carcinoma, non-squamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, malignant melanoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, head and neck cancer, urothelial carcinoma, breast cancer, prostate cancer, glioblastoma, colorectal cancer, pancreatic cancer, lymphoma, leiomyosarcoma, liposarcoma, synovial sarcoma, or malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is non-small cell lung cancer (NSCLC), hepatocellular carcinoma, malignant melanoma, ovarian cancer, breast cancer, pancreatic cancer, renal cell carcinoma (RCC), bladder cancer, or colorectal cancer. In some embodiments, the cancer is lymphoma, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, Reed-Sternberg disease, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), or chronic lymphocytic leukemia (CLL). In some embodiments, the cancer patient is treatment-naive. In some embodiments, the cancer patient is treatment-naive for non-small cell lung cancer (NSCLC), hepatocellular carcinoma, malignant melanoma, ovarian cancer, breast cancer, pancreatic cancer, renal cell carcinoma, or colorectal cancer. In some embodiments, the combination is administered to the cancer patient as a first-line therapy. In some embodiments, the combination is administered to the cancer patient as a second-, third-, fourth-, fifth-, or sixth-line therapy. In some embodiments, the combination is administered to the cancer patient after treatment with at least one anti-cancer therapy. In some embodiments, the anti-cancer therapy comprises chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, or a combination thereof. In some embodiments, the cancer is resistant to at least one anti-cancer agent.

[0020] In some embodiments, the compound of Formula I and the inhibitor of the combination are administered simultaneously or sequentially. In some embodiments, the compound of Formula I is administered 2-3 times per week. In some embodiments, the compound of Formula I is administered daily. In some embodiments, the PD-L1 inhibitor, PD-1 inhibitor, and / or CTLA-4 inhibitor, and the compound of Formula I are administered simultaneously on day 1 of a dosing regimen. In some embodiments, the combination is administered to the patient as a regimen. In some embodiments, the regimen is repeated until disease progression or unacceptable toxicity occurs. In some embodiments, the regimen includes at least one day of rest between successive dosing periods. In some embodiments, the compound of Formula I of the combination is administered 2-3 times per week in the regimen, and the PD-L1 inhibitor, PD-1 inhibitor, and / or CTLA-4 inhibitor are administered every 2-3 weeks. In some embodiments, the compound of Formula I in the combination is administered once daily (“QD”) for 21 days in the regimen, and the inhibitor antibody is administered every 2-3 weeks.

[0021] In some embodiments, the method does not cause an increase in QTc, QTcF or heart rate (HR). In some embodiments, the method causes a decrease in QTc, QTcF or HR in a subject. In some embodiments, administering HDACi to a subject in need thereof at increasing dosages results in a decrease in QTcF. In some embodiments, the method does not cause a change in HR or causes a decrease in HR.

[0022] In some embodiments, the method for treating cancer inhibits metastasis of the cancer in the patient. In some embodiments, the method for treating cancer reduces the tumor or tumor burden in the patient. In some embodiments, the method for treating cancer inhibits existing metastasis of the cancer in the patient. In some embodiments, the method for treating cancer extends the time to disease progression of the cancer in the patient. In some embodiments, the method for treating cancer extends survival of the patient. In some embodiments, the method for treating cancer extends progression-free survival of the patient.

[0023] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [Brief explanation of the drawings]

[0024] [Figure 1A] 1 shows the mean HBI-8000 plasma concentrations of patient treatment groups comprising a combination of a compound of Formula I and a PD-1 inhibitor antibody. Dosing of each treatment is differentiated using different colors, as indicated in the figure legend. [Figure 1B] 1 shows the mean HBI-8000 plasma concentrations of patient treatment groups comprising a combination of a compound of Formula I and a PD-1 inhibitor antibody. Dosing of each treatment is differentiated using different colors, as indicated in the figure legend. [Figure 2] FIG. 1 shows a plot of log QTcF versus log RR for cycle 1, along with patient and population regression lines. [Figure 3]

[0023] Figure 1 shows the change from baseline QTcF versus HBI-8000 concentration, along with the population regression line and 90% confidence intervals. Each treatment dose is differentiated by a different color, as indicated in the figure legend. [Figure 4] FIG. 1 shows a waterfall plot of maximum change in target lesions by tumor type. [Figure 5] FIG. 1 shows swimmer plots of tumor response over the course of study treatment. Modes for carrying out the invention

[0025] definition All patents, applications, published applications, and other publications cited herein are incorporated by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The chemical structures and formulas depicted herein are constructed according to the standard rules of chemical valency known in the chemical arts. If there is a discrepancy between a depicted structure and the name given to that structure, more emphasis shall be placed on the depicted structure. If the stereochemistry of a structure or portion of a structure is not shown in the depicted structure or portion of the depicted structure, the depicted structure should be interpreted as encompassing all of its possible stereoisomers.

[0026] Any methods, devices, and materials similar or equivalent to those described herein can be used in the practice of the present invention. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not intended to limit the scope of the present disclosure. In the event that there are multiple definitions for terms of the present invention, those in this section prevail unless otherwise stated. The headings used herein are for organizational purposes only and do not limit the invention described herein in any way.

[0027] The "QT" interval is a measurement representing the total time from ventricular depolarization to full repolarization. This measurement begins at the onset of the "Q" wave and ends at the end of the "T" wave, with QT being expressed in milliseconds. As used herein, the "QT" interval shall have its plain and ordinary meaning as understood in the art.

[0028] "QTc" refers to corrected QT interval. The corrected QT interval estimates QT at a heart rate of 60 bpm (beats per minute) and allows for comparison of values ​​at different heart rates. As used herein, "QTc" will be given its plain and ordinary meaning as understood in the art.

[0029] For "QTc" correction, use Bazett's formula: QTc = QT / (RR) 1 / 2 is used, where RR is the distance from one R peak to the next.

[0030] For "QTc" correction, Fridericia: QT(Fri)=QT / (RR) 1 / 3 is used, where RR is the distance from one R peak to the next.

[0031] "QTcF" is Fridericia's cube root formula: QTcF=QT / (RR) 1 / 3 "QTcF" refers to the QT interval corrected for QTcF. As used herein, "QTcF" will be given its plain and ordinary meaning as understood in the art.

[0032] "Heart rate" (or "HR") refers to the number of heart beats per minute or 60 / RR, where RR is the interval from R to R expressed in seconds per beat.

[0033] The terms "P wave," "Q wave," "T wave," "RR," "QRS complex," "PR interval," "ST segment," and U wave, as used herein, shall be governed by their plain and ordinary meaning as understood in the art.

[0034] The term "PD-L1 inhibitor" refers to a moiety (e.g., a compound, nucleic acid, polypeptide, antibody) that reduces, inhibits, blocks, neutralizes, or interferes with the activity of PD-L1, the binding of PD-L1 to its receptor PD-1, or the expression of PD-L1 (e.g., programmed cell death 1 ligand; PD-L1 (CD274); GI:30088843), including variants, isoforms, species homologs (e.g., murine) of human PD-L1, and analogs that share at least one epitope with PD-L1. PD-L1 inhibitors include molecules and macromolecules such as compounds (small molecule compounds), nucleic acids, polypeptides, antibodies, peptibodies, diabodies, minibodies, single-chain variable fragments (ScFvs), and fragments or variants thereof. Thus, a PD-L1 inhibitor, as used herein, refers to any moiety that antagonizes PD-L1 activity, its binding to PD-1, or its expression. PD-L1 inhibitor efficacy can be measured, for example, by its 50% inhibitory concentration (half-maximal inhibitory concentration or IC 50 ) can be measured. PD-L1 inhibitors include the exemplary compounds and compositions described herein. PD-L1 inhibitor antibodies refer to PD-L1 inhibitors that are monoclonal or polyclonal antibodies described herein.

[0035] The terms "durvalumab," "avelumab," "atezolizumab," "BMS-936559," "STI-A1010," "STI-A1011," "STI-A1012," "STI-A1013," "STI-A1014," and "STI-A1015" are used in accordance with their plain and ordinary meaning as understood in the art.

[0036] The term "PD-1 inhibitor" refers to a moiety (e.g., a compound, nucleic acid, polypeptide, antibody) that reduces, inhibits, blocks, neutralizes, or prevents the activity or expression of PD-1 (e.g., programmed cell death protein 1; PD-1 (CD279), GI:145559515), including variants, isoforms, species homologs (e.g., murine) of human PD-1, and analogs having at least one epitope in common with PD-1. PD-1 inhibitors include, for example, molecules and macromolecules such as compounds, nucleic acids, polypeptides, antibodies, peptibodies, diabodies, minibodies, single-chain variable fragments (ScFv), and fragments or variants thereof. Thus, as used herein, PD-1 inhibitor refers to any moiety that antagonizes PD-1 activity or expression. PD-1 inhibitor efficacy can be measured, for example, by its 50% inhibitory concentration (half-maximal inhibitory concentration or IC 50 ) can be measured. PD-1 inhibitors include exemplary compounds and compositions described herein. PD-1 antibodies refer to PD-1 inhibitors that are monoclonal or polyclonal antibodies described herein.

[0037] The terms "nivolumab," "pembrolizumab," "pidilizumab," "AMP-224," "REGN2810," "PDR001," "SHR-1210," "SAR-439684," and "MEDI0680" are used in accordance with their plain and ordinary meaning as understood in the art.

[0038] The term "CTLA-4 inhibitor" refers to a moiety (e.g., a compound, nucleic acid, polypeptide, antibody) that reduces, inhibits, blocks, neutralizes, or prevents the activity or expression of CTLA-4, including variants, isoforms, species homologs (e.g., murine) of human CTLA-4, and analogs having at least one epitope in common with CTLA-4. CTLA-4 inhibitors include, for example, molecules and macromolecules such as compounds, nucleic acids, polypeptides, antibodies, peptibodies, diabodies, minibodies, single-chain variable fragments (ScFv), and fragments or variants thereof. Thus, as used herein, CTLA-4 inhibitor refers to any moiety that antagonizes CTLA-4 activity or expression. CTLA-4 inhibitor efficacy can be measured, for example, by its 50% inhibitor concentration (half-maximal inhibitory concentration or IC 50 CTLA-4 inhibitors include the exemplary compounds and compositions described herein. CTLA-4 antibodies refer to CTLA-4 inhibitors that are monoclonal or polyclonal antibodies described herein.

[0039] The terms "ipilimumab" are used in accordance with their plain and ordinary meaning as understood in the art.

[0040] As used herein, the terms "polypeptide" and "protein" are used interchangeably and refer to any molecule containing at least two or more amino acids.

[0041] The term "inhibitor antibody" refers to a monoclonal or polyclonal antibody that binds to a substrate or target with sufficient strength to inhibit the activity of that substrate or target. As used herein, "inhibitor antibody" includes PD-L1 inhibitor antibodies, PD-1 inhibitor antibodies, and / or CTLA-4 inhibitor antibodies.

[0042] The term "effective amount" refers to the amount of a therapy (e.g., used in the methods provided herein) sufficient to achieve a stated purpose or effect for which it is administered. An "effective amount" may be sufficient to reduce and / or ameliorate the progression, onset, recurrence, severity, and / or duration of a given disease, disorder, or condition, and / or symptoms associated therewith, or to reduce the level of activity or binding of a polypeptide (e.g., PD-L1, PD-1, CTLA-4). An "effective amount" may also be a "therapeutically effective amount," which refers to an amount sufficient to provide a therapeutic benefit, such as, for example, reducing or ameliorating the development or progression of a given disease, disorder, or condition, or reducing or ameliorating the recurrence, onset, or development of a given disease, disorder, or condition, and / or to improve or enhance the prophylactic or therapeutic effect of another therapy. A "therapeutically effective amount," as used in the methods provided herein, may enhance the therapeutic efficacy of another therapeutic agent.

[0043] The term "regimen" refers to a protocol of dosage and timing of administration of one or more therapies (e.g., methods described herein) to treat a disease, disorder, or condition described herein. A regimen may include active administration periods and holiday periods, as known in the art. Active administration periods include the administration of the combinations and compositions described herein and the duration of effectiveness of such combinations and compositions. Holiday periods of the regimens described herein include periods during which compounds are not actively administered, and in some cases, include periods during which the effectiveness of such compounds may be minimal. The combination of active administration and holiday periods in the regimens described herein can increase the effectiveness and / or duration of administration of the combinations and compositions described herein.

[0044] The terms "therapies" and "therapy" refer to any protocol, method, and / or agent that can be used in the prevention, treatment, management, and / or amelioration of a disease, disorder, or condition, or one or more symptoms thereof. In some cases, the term refers to an active agent, such as an anti-cancer agent described herein. The term "therapy" can refer to antiviral therapy, antibacterial therapy, antifungal therapy, anti-cancer therapy, biological therapy, supportive therapy, and / or other therapy useful in the treatment, management, prevention, or amelioration of a disease, disorder, or condition, or one or more symptoms thereof, known to a medical professional of ordinary skill in the art, e.g., a physician.

[0045] The term "patient" or "subject" refers to a mammal, such as a human, cow, rat, mouse, dog, monkey, ape, goat, sheep, bovine, or deer. Generally, a patient as described herein is a human.

[0046] The terms "inhibit," "inhibit," and "inhibiting" refer to a reduction in polypeptide activity, binding, or expression, or a reduction or amelioration of a disease, disorder, or condition, or a symptom thereof. "Inhibiting," as used herein, may include partially or totally blocking a stimulus, reducing, preventing, or delaying activation or binding, or inactivating, desensitizing, or downregulating protein or enzyme activity or binding.

[0047] Antibodies as described herein may be polyclonal or monoclonal, and include xenogeneic, allogeneic, or syngeneic forms, as well as modified forms thereof (e.g., humanized or chimeric). An "antibody" is intended to mean a polypeptide product of a lymphocyte within the immunoglobulin class of polypeptides, capable of binding to a specific molecular antigen and composed of two identical pairs of polypeptide chains, each pair having one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), the amino-terminal portion of each chain containing a variable region of about 100 to about 130 or more amino acids, and the carboxy-terminal portion of each chain containing a constant region. (See, e.g., Borrebaeck (ed.), Antibody Engineering, 2nd ed., Oxford University Press; Kuby (1997), Immunology, 3rd ed., W.H. Freeman and Company, New York City.) Specific molecular antigens to which the antibodies described herein can bind include PD-L1, PD-1, CTLA-4, and epitopes thereof.

[0048] The term "monoclonal antibody" refers to a population of antibody molecules that contain one species of antigen-binding site capable of immunoreacting with a particular epitope of an antigen, and the term "polyclonal antibody" refers to a population of antibody molecules that contain multiple species of antigen-binding sites capable of interacting with a particular antigen. A monoclonal antibody typically exhibits a single binding affinity for the particular antigen with which it immunoreacts. For example, the monoclonal antibodies used in accordance with the present invention can be produced using, for example, hybridoma techniques (e.g., Kohler and Milstein, Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14(3):253-260 (1995); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed., 1988); Hammerling et al., Monoclonal Antibodies and T-Cell Hybridomas, 563-681 (Elsevier, New York, 1981)), recombinant DNA techniques (see, e.g., U.S. Pat. No. 4,816,567), phage display techniques (e.g., Clackson et al., Nature, 352:624-628 (1991); Marks et al., J. Immunol. 1999:101-102 (2000)). See Mo / .Biol. 222:581-597 (1992); Sidhu et al., J.Mal.Biol. 338(2):299-310 (2004); Lee et al., J.Mal.Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); Lee et al., J.Immunol. Methods 284(1-2):119-132 (2004), techniques for producing human or human-like antibodies in animals having part or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (e.g., WO 1998 / 24893; WO 1996 / 34096; WO 1996 / 33735; WO 1991 / 10741; Jakobovits et al., Proc.Natl. Acad. Sci. USA 90:2551 (1993); Jakobovits et al., Nature 362:255-258 (1993); Bruggemann et al., Year in Immunol. 7:33 (1993); U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016; Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-813 (1994); Fishwild et al., Nature Biotechnol. 14:845-851 (1996); Neuberger, Nature Biotechnol. 14:826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol. 13:65-93 (1995)).

[0049] As used herein, monoclonal antibodies also include "chimeric" antibodies (immunoglobulins) in which portions of the heavy and / or light chains are identical to or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chains are identical to or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, pp. 6851-6855 (1984)). "Humanized antibodies" can be considered a subset of the chimeric antibodies described herein.

[0050] The term "human," when used in reference to an antibody or functional fragment thereof (e.g., a "humanized antibody"), refers to an antibody or functional fragment thereof having a human variable region or a portion thereof that corresponds to human germline immunoglobulin sequences. Such human germline immunoglobulin sequences are described by Kabat et al. (1991), Sequences of Proteins of Immunological Interest, 5th ed., U.S. Department of Health and Human Services, NIH Publication No. 91-3242. Human antibodies in the context of the present invention can include antibodies that bind to PD-L1 or a variant thereof as described herein.

[0051] In some cases, a human antibody has an amino acid sequence corresponding to that of an antibody produced by a human and / or is produced using any of the techniques for producing human antibodies disclosed herein. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries. Hoogenboom and Winter, J., Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Human monoclonal antibodies can also be prepared using the methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, 77 (1985); Boemer et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 2:368-74 (2001). Human antibodies can be prepared by administering antigen to transgenic animals, e.g., immunized xenogeneic mice, that have been engineered to produce such antibodies in response to antigen challenge, but in which the endogenous gene locus has been disabled (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 for XENOMOUSE technology). For human antibodies produced using human B cell hybridoma technology, see, e.g., Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006).

[0052] A "humanized antibody" refers to an antibody produced by a non-human cell with variable regions or variable and constant regions that have been altered to more closely resemble antibodies produced by human cells, e.g., by altering the amino acid sequence of the non-human antibody to incorporate amino acids found in human germline immunoglobulin sequences. The humanized antibodies of the invention may include, for example, in the CDRs, amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). Humanized antibodies also include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0053] Humanized forms of non-human (e.g., murine) antibodies are antibodies that contain minimal sequence derived from non-human immunoglobulin. In some embodiments, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and / or capacity. In some cases, framework ("FR") residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or the donor antibody. Such modifications can be made to further refine antibody performance, such as binding affinity. Generally, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the FR regions are those of a human immunoglobulin sequence, although the FR regions may include one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. The number of such amino acid substitutions in the FRs will typically be no more than six in the H chain and no more than three in the L chain. The humanized antibody may also optionally comprise at least a portion of an immunoglobulin constant region (Fc), which may be a human immunoglobulin. Exemplary methods and humanized antibodies include those described in Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992); Vaswani and Hamilton, Ann. Allergy. Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Burle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Pat. Nos. 6,982,321 and 7,087,409.

[0054] The term "functional fragment," when used with respect to an antibody, refers to a portion of an antibody, including a heavy or light chain polypeptide, that retains some or all of the binding activity of the antibody from which the fragment was derived. Such functional fragments include, for example, Fd, Fv, Fab, F(ab'), F(ab)2, F(ab')2, single-chain Fv (ScFv), diabodies, triabodies, tetrabodies, and minibodies. Other functional fragments include, for example, heavy or light chain polypeptides, variable region polypeptides, or CDR polypeptides, or portions thereof, so long as such functional fragments retain binding activity. Such antibody-binding fragments can be found, for example, in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York City (1989); Myers (ed.), Molec. Biology and Biotechnology: A Comprehensive Desk Reference, New York City: VCH Publishers, Inc.; Huston et al., Cell Biophysics, 22:189-224 (1993); Phickthun and Skerra, Meth. Enzymol., 178:497-515 (1989), and Day, ED, Advanced Immunochemistry, 2nd ed., Wiley-Liss, Inc., New York, NY (1990). Antibody Engineering, 2nd ed., Oxford University Press, 1995.

[0055] The term "heavy chain," when used with reference to an antibody, refers to a polypeptide chain of approximately 50 to 70 kDa, the amino-terminal portion of which contains a variable region of approximately 120 to 130 or more amino acids, and the carboxy-terminal portion of which contains a constant region. The constant region may be one of five different types, termed alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the heavy chain constant region. Different heavy chains vary in size, with α, δ, and γ containing approximately 450 amino acids, and μ and ε containing approximately 550 amino acids. These different types of heavy chains, when combined with light chains, form the five well-known antibody classes: IgA, IgD, IgE, IgG, and IgM, respectively. IgG includes four subclasses: IgG1, IgG2, IgG3, and IgG4. The heavy chain may be a human heavy chain.

[0056] The term "light chain," when used in reference to an antibody, refers to a polypeptide chain of approximately 25 kDa, the amino-terminal portion of which contains a variable region of about 100 to about 110 or more amino acids, and the carboxy-terminal portion of which contains a constant region. The approximate length of a light chain is 211 to 217 amino acids. Based on the amino acid sequence of the constant domain, there are two different types, called kappa (κ) and lambda (λ). Light chain amino acid sequences are well known in the art. The light chain may be a human light chain.

[0057] The term "variable domain" or "variable region" refers to the portion of an antibody light or heavy chain, generally located at the amino terminus of the light or heavy chain, approximately 120-130 amino acids in length for heavy chains and approximately 100-110 amino acids in length for light chains, that is used for binding and specificity of each particular antibody to its specific antigen. Variable domains can vary significantly in sequence among different antibodies. Sequence variability is concentrated in the CDRs, and the less variable portions of variable domains are called framework regions (FRs). The CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with the antigen. The numbering of amino acid positions used herein is according to the EU index, as in Kabat et al. (1991), Sequences of proteins of immunological interest. (US Department of Health and Human Services, Washington, DC), 5th ed. The variable region may be a human variable region.

[0058] CDR refers to one of the three hypervariable regions (H1, H2, or H3) in the non-framework region of the immunoglobulin (Ig or antibody) VH β-sheet framework, or one of the three hypervariable regions (L1, L2, or L3) in the non-framework region of the antibody VL β-sheet framework. Thus, CDRs are variable region sequences interspersed within framework region sequences. CDR regions are well known to those skilled in the art, and have been defined, for example, by Kabat as the most hypervariable region within the antibody variable (V) domain (Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat, Adv. Prot. Chem. 32:1-75 (1978)). CDR region sequences have been structurally defined by Chothia as residues that are not part of a conserved β-sheet framework and therefore can adopt different conformations (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). Both terms are well recognized in the art. The positions of CDRs within standard antibody variable domains have been determined by comparing numerous structures (Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); Morea et al., Methods 20:267-279 (2000)). Because the number of residues within hypervariable regions varies among antibodies, it is customary to number additional residues relative to the standard positions with letters such as a, b, and c next to the residue number in the standard variable domain numbering scheme (Al-Lazikani et al., supra (1997)). Such nomenclature is also well known to those skilled in the art.

[0059] For example, as shown in Table 1 below, CDRs defined according to either Kabat (hypervariable), Chothia (structural), or MacCallum (J. Mol. Biol. 262:732-745 (1996)) designations:

[0060] [Table 1]

[0061] The term "cancer" refers to any physiological condition in a mammal characterized by unregulated cell growth. Cancers as described herein include solid tumors and hematological (blood) cancers. "Hematologic cancer" refers to any blood-borne cancer, including, for example, myeloma, lymphoma, and leukemia. "Solid tumor" or "tumor" refers to lesions and neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues that result in abnormal tissue growth. "Neoplastic," as used herein, refers to any form of deregulated or uncontrolled cell growth, whether malignant or benign, that results in abnormal tissue growth.

[0062] The term "treating" or "treatment" refers to any objective or subjective parameter such as alleviation, remission, or reduction of symptoms, or any indication of success or improvement in the progression, severity, and / or duration of a disease, condition, or state, including making the injury, pathology, or condition more tolerable to the patient, slowing the rate of degeneration or decline, mitigating decline in the final stages of degeneration, or improving the patient's physical or mental well-being.

[0063] The term "enhance" refers to an increase or improvement in the function or activity of a protein or cell after administration or contact with a combination described herein compared to the protein or cell before such administration or contact.

[0064] The term "administering" refers to the act of delivering a combination or composition described herein to a subject by a route such as oral, mucosal, topical, suppository, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration. Parenteral administration includes intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Administration generally occurs after the onset of a disease, disorder, or condition, or a symptom thereof, but in some cases may occur before the onset of a disease, disorder, or condition, or a symptom thereof (e.g., administration to a patient susceptible to such a disease, disorder, or condition).

[0065] The term "co-administration" refers to the administration of two or more active agents (e.g., a combination described herein and another active agent, such as an anti-cancer agent described herein). The timing of co-administration depends in part on the combination and composition administered and may include administration simultaneously with, immediately before, or immediately after the administration of one or more additional therapies, e.g., cancer therapies such as chemotherapy, hormonal therapy, radiation therapy, or immunotherapy. The compounds of the present invention may be administered alone or co-administered to a patient. Co-administration is meant to include the administration of compounds individually or in combination (more than one compound or agent), simultaneously or sequentially. Thus, if necessary, the preparation can also be combined with other active substances (e.g., to reduce metabolic degradation). The compounds described herein can be used in combination with each other and with other active agents known to be useful in the treatment of cancer.

[0066] The term "anti-cancer agent" is used according to its plain and ordinary meaning to refer to a composition having anti-neoplastic properties or the ability to inhibit cell growth or proliferation. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the anti-cancer agent is an agent identified herein that has utility in methods for treating cancer. In some embodiments, the anti-cancer agent is an agent approved for the treatment of cancer by the FDA or similar regulatory agency in a country other than the United States.

[0067] The terms "chemotherapeutic agent" or "chemotherapeutic agent" are used according to their plain and ordinary meaning to refer to chemical compositions or compounds having anti-neoplastic properties or the ability to inhibit cell growth or proliferation. "Chemotherapy" refers to a treatment or regimen that includes the administration of a chemotherapeutic agent or anti-cancer agent as described herein.

[0068] combination In some embodiments, the present disclosure provides combinations for treating cancer (e.g., combination therapies, such as methods of treatment and use, kits, and compositions). In some embodiments, the combinations described herein include an HDACi and an anticancer agent, a PD-1 inhibitor, a PD-L1 inhibitor, and / or a CTLA-4 inhibitor. In some embodiments, the HDACi includes a general benzamide structure belonging to subclass I (HDAC1 / 2 / 3 and 8) HDACs, class II (HDAC4 / 5 / 6 / 7 / 9 / 10) HDACs, or class IV (HDAC11) HDACs. In some embodiments, the combination may include a first pharmaceutical composition and a second pharmaceutical composition. In some embodiments, the first pharmaceutical composition includes an HDACi, and the second pharmaceutical composition includes a PD-1 inhibitor. In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are packaged together as a kit, and the kit may further include instructions for co-administration of the first pharmaceutical composition and the second pharmaceutical composition. In some embodiments, the first and second compositions may be packaged separately for combination in a clinical setting by administration to a patient within a time frame that allows the patient to simultaneously derive clinical benefit from the first and second pharmaceutical compositions. In some embodiments, the combination comprises a unit dosage form of a pharmaceutical composition comprising an HDACi and a PD-1 inhibitor. In some embodiments, the combination comprises a first pharmaceutical composition comprising an HDACi for use in treating cancer in combination with a second pharmaceutical composition comprising a PD-1 inhibitor. In some embodiments, the combination comprises use of an HDACi to prepare a first pharmaceutical composition for use in treating cancer in combination with a second pharmaceutical composition comprising a PD-1 inhibitor.

[0069] composition Provided herein are combinations (e.g., combination therapies and compositions) useful for treating various diseases, disorders, and their symptoms, including, for example, cancer. The combinations described herein include an HDAC inhibitor, a PD-L1 inhibitor and / or a PD-1 inhibitor, and a CTLA-4 inhibitor. The combinations described herein also include an HDAC inhibitor and an anti-cancer agent. In one non-limiting example, a benzamide HDAC inhibitor of Formula I is provided, and examples of PD-L1 inhibitors, PD-1 inhibitors, CTLA-4 inhibitors, and anti-cancer agents are described herein. Some embodiments are combinations comprising a therapeutically effective amount of a PD-L1 inhibitor and / or a PD-1 inhibitor, a CTLA-4 inhibitor, and a therapeutically effective amount of a compound of Formula I. [ka] The compounds of Formula I described herein include pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, prodrugs, enantiomers, diastereomers, hydrates, co-crystals, and polymorphs thereof.

[0070] In some cases, the compound of Formula I is present in an amount greater than about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. The compound of Formula I may be present in an amount greater than about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some cases, the compound of Formula I is present in an amount greater than about 5 mg or about 10 mg. The compound of formula I may be present in an amount greater than about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg.

[0071] The combination may include a compound present in an amount of at least about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. The combination may include a compound of Formula I present in an amount of at least about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some cases, the compound of Formula I is present in an amount of at least about 5 mg or about 10 mg. The combination may include a compound of Formula I present in an amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg.

[0072] The combination may include a compound of Formula I present in an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. The combination may include a compound of Formula I present in an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some cases, the compound of Formula I is present in an amount of about 5 mg or about 10 mg. The combination may include a compound of Formula I present in an amount of about 1 mg to about 10 mg, about 1 mg to about 25 mg, about 1 mg to about 50 mg, about 5 mg to about 10 mg, about 5 mg to about 25 mg, about 5 mg to about 50 mg, about 10 mg to about 25 mg, about 10 mg to about 50 mg, about 20 mg to about 50 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 50 mg to about 100 mg, or about 100 mg to about 200 mg.

[0073] The compound of Formula I may be present in the combinations described herein relative to the patient's body weight (e.g., mg / kg). In some cases, the compound of Formula I may be present in an amount of about: 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.01 mg / kg to about 200 mg / kg, 0.01 mg / kg to about 150 mg / kg, 0.01 mg / kg to about 100 mg / kg, 0.01 mg / kg to about 50 mg / kg, 0.01 mg / kg to about 25 mg / kg, 0.01 mg / kg to about 10 mg / kg, or 0.01 mg / kg to about 5 mg / kg, 0.05 mg / kg to about 200 mg / kg, 0.05 mg / kg to about 150 mg / kg. , 0.05 mg / kg to about 100 mg / kg, 0.05 mg / kg to about 50 mg / kg, 0.05 mg / kg to about 25 mg / kg, 0.05 mg / kg to about 10 mg / kg, or 0.05 mg / kg to about 5 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg. In other cases, the compound of formula I is present in an amount equivalent to about: 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg.

[0074] PD-L1 inhibitors PD-L1 inhibitors useful in the combinations described herein include any molecule capable of inhibiting, blocking, neutralizing, or interfering with the binding of PD-L1 to PD-1, or the activity or expression of PD-L1. In particular, the PD-L1 inhibitor may be a small molecule compound, a nucleic acid, a polypeptide, an antibody, a peptibody, a diabody, a minibody, a single-chain variable fragment (ScFv), or a functional fragment or variant thereof. In one case, the PD-L1 inhibitor is a small molecule compound (e.g., a compound having a molecular weight of less than about 1000 Da). In some embodiments, the PD-L1 inhibitor is CA-170 (AUPM-170, Curis, Inc.). In other cases, PD-L1 inhibitors useful in the combinations described herein include nucleic acids and polypeptides. The PD-L1 inhibitor may be a polypeptide (e.g., a macrocyclic polypeptide), such as those exemplified in U.S. Patent Application Publication No. 2014 / 0294898, which is incorporated herein by reference in its entirety for all purposes. In one example, the PD-L1 inhibitor is an antibody, peptibody, diabody, minibody, ScFv, or functional fragment thereof. In another example, the PD-L1 inhibitor is a PD-L1 inhibitor antibody. The PD-L1 inhibitor antibody may be a monoclonal antibody or a polyclonal antibody. In some embodiments, the PD-L1 inhibitor antibody is a monoclonal antibody.

[0075] PD-L1 antibodies include all known types of antibodies and functional fragments thereof, including, but not limited to, those exemplified herein, such as human antibodies, murine antibodies, chimeric antibodies, humanized antibodies, or chimeric-humanized antibodies.

[0076] In some embodiments, the PD-L1 inhibitor antibody is a human antibody. In another embodiment, the PD-L1 inhibitor antibody is a murine antibody. In some other embodiments, the PD-L1 inhibitor antibody is a chimeric antibody. In some other embodiments, the PD-L1 inhibitor antibody is a humanized antibody. In some other embodiments, the PD-L1 inhibitor antibody is a chimeric, humanized antibody. The PD-L1 inhibitor antibody may be a human antibody or a humanized antibody. The PD-L1 inhibitor antibody may be durvalumab, avelumab, atezolizumab, BMS-936559, STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014, or STI-A1015. In some embodiments, two or more PD-L1 antibodies are administered in combination with a compound of Formula I described herein.

[0077] The PD-L1 inhibitor antibody may be durvalumab. Durvalumab is an Fc-optimized monoclonal antibody directed against PD-L1 and has the potential for immune checkpoint inhibition and antineoplastic activity. Without being bound by any particular theory, durvalumab binds to PD-L1, thereby blocking its receptor PD-1, which may be expressed on activated T cells, from binding to and activating it. This reverses T cell inactivation and activates the immune system to mount a cytotoxic T lymphocyte (CTL) response against PD-L1-expressing tumor cells. The Fc region of durvalumab has been modified so that it does not induce either antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).

[0078] The PD-L1 inhibitor antibody may be avelumab. Avelumab is a human immunoglobulin G1 (IgG1) monoclonal antibody directed against PD-L1 and has potential immune checkpoint inhibitory and antineoplastic activity. Without being bound by any particular theory, avelumab binds to PD-L1 and prevents its interaction with its receptor PD-1. This inhibits PD-1 activation and its downstream signaling pathway. This can restore immune function by activating cytotoxic T lymphocytes (CTLs) that target PD-L1-overexpressing tumor cells. Avelumab is thought to induce an antibody-dependent cellular cytotoxicity (ADCC) response against PD-L1-expressing tumor cells.

[0079] The PD-L1 inhibitor antibody may be atezolizumab. Atezolizumab is a human Fc-optimized monoclonal antibody directed against the protein ligand PD-L1 and has the potential to inhibit immune checkpoints and antineoplastic activity. Without being bound by any particular theory, atezolizumab binds to PD-L1 and inhibits its binding to and activation of its receptor PD-1 expressed on activated T cells. This can enhance T cell-mediated immune responses against neoplasms and reverse T cell inactivation. In addition, by binding to PD-L1, atezolizumab is thought to prevent the binding of PD-L1 to B7.1 expressed on activated T cells, thereby further enhancing T cell-mediated immune responses. The Fc region of atezolizumab has been modified so that it does not induce either antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).

[0080] The PD-L1 inhibitor antibody may be BMS-936559, a fully human IgG4 monoclonal antibody directed against PD-L1, with potential immune checkpoint inhibitory activity. Without being bound by any particular theory, BMS-936559 binds to PD-L1 and inhibits its binding to both PD-1 and CD80.

[0081] The PD-L1 inhibitor antibody may be STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014, or STI-A1015. STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014, and STI-A1015 (Sorrento Therapeutics) are each fully human monoclonal antibodies directed against PD-L1. In some other embodiments, the PD-L1 inhibitor can be administered according to an established regimen, such as one provided in the package insert.

[0082] PD-1 inhibitors PD-1 inhibitors useful in the combinations described herein include any molecule capable of inhibiting, blocking, neutralizing, or interfering with the activity or expression of PD-1. In particular, PD-1 inhibitors may be small molecule compounds, nucleic acids, polypeptides, antibodies, peptibodies, diabodies, minibodies, single-chain variable fragments (ScFv), or functional fragments or variants thereof. In one case, the PD-1 inhibitor is a small molecule compound (e.g., a compound having a molecular weight of less than about 1000 Da). In other cases, PD-1 inhibitors useful in the combinations described herein include nucleic acids and polypeptides. The PD-1 inhibitor may be a polypeptide (e.g., a macrocyclic polypeptide), such as those exemplified in U.S. Patent Application Publication No. 2014 / 0294898, which is incorporated herein by reference in its entirety for all purposes. In one example, the PD-1 inhibitor is an antibody, peptibody, diabody, minibody, ScFv, or functional fragment thereof. In one example, the PD-1 inhibitor is AMP-224 (GSK).

[0083] AMP-224 is a recombinant fusion protein containing the extracellular domain of the PD-1 ligand programmed cell death ligand 2 (PD-L2) and the Fc region of human IgG. Certain cancers are thought to evade and suppress the immune system, in part, through the interaction of PD-1 with B7-H1, without being bound by any particular theory. AMP-224 is thought to block this interaction, thereby overcoming immune suppression.

[0084] In another example, the PD-1 inhibitor is a PD-1 antibody. The PD-1 antibody may be a monoclonal antibody or a polyclonal antibody. In some embodiments, the PD-1 antibody is a monoclonal antibody.

[0085] PD-1 antibodies include all known types of antibodies and functional fragments thereof, including, but not limited to, those exemplified herein, such as human antibodies, murine antibodies, chimeric antibodies, humanized antibodies, or chimeric-humanized antibodies.

[0086] In some embodiments, the PD-1 antibody is a human antibody. In some other embodiments, the PD-1 antibody is a murine antibody. In some other embodiments, the PD-1 antibody is a chimeric antibody. In some other embodiments, the PD-1 inhibitor antibody is a humanized antibody. In some embodiments, the PD-1 antibody is a chimeric humanized antibody. The PD-1 antibody may be a human antibody or a humanized antibody. The PD-1 antibody may be nivolumab, pembrolizumab, pidilizumab, REGN2810, PDR001, or MEDI0680. In some embodiments, two or more PD-1 antibodies are administered in combination with a compound of Formula I described herein.

[0087] The PD-1 antibody may be nivolumab. Nivolumab (sold as Opdivo) is a fully human monoclonal antibody directed against PD-1 with immune-enhancing activity. Without being bound by any particular theory, nivolumab binds to PD-1 and blocks its activation by its cognate ligand, resulting in T cell activation and a cell-mediated immune response against tumor cells or pathogens.

[0088] The PD-1 antibody may be pembrolizumab. Pembrolizumab (MK-3475, marketed as Keytruda) is a humanized monoclonal IgG4 antibody directed against the human cell surface receptor PD-1 and has potential immune-enhancing activity. Without being bound by any particular theory, pembrolizumab binds to the inhibitory signaling receptor PD-1 expressed on the surface of activated T cells and blocks the binding and activation of PD-1 by its cognate ligand. Blockade of binding and activity results in the activation of a T cell-mediated immune response against tumor cells.

[0089] The PD-1 antibody may be pidilizumab. Pidilizumab (CT-011) is a humanized monoclonal antibody directed against human PD-1, which has immunomodulatory and antitumor activity. Without being bound by any particular theory, pidilizumab blocks the interaction between the receptor PD-1 and its ligand, resulting in the attenuation of the apoptotic process in lymphocytes, mainly effector / memory T cells, and the enhancement of the antitumor activity of NK cells.

[0090] The PD-1 antibody may be REGN2810. REGN2810 is a human monoclonal antibody directed against PD-1 and has the potential to inhibit immune checkpoints and have anti-neoplastic activity. Without being bound by any particular theory, REGN2810 binds to PD-1, inhibits its binding to its cognate ligand, and prevents the activation of its downstream signaling pathway. This can restore immune function by activating cytotoxic T cells.

[0091] The PD-1 antibody may be PDR001. PDR001 is a fully humanized monoclonal antibody directed against PD-1 and has immune checkpoint inhibitory and anti-neoplastic activity. Without being bound by any particular theory, PDR001 binds to PD-1 expressed on activated T cells and blocks its interaction with its cognate ligand. Inhibition of ligand binding prevents PD-1-mediated signal transduction, resulting in both T cell activation and the induction of a T cell-mediated immune response against tumor cells.

[0092] The PD-1 antibody may be MEDI0680 (AMP-514), a human monoclonal antibody directed against PD-1, which has potential immunomodulatory and antineoplastic activity. Without being bound by any particular theory, MEDI0680 is believed to inhibit PD-1 activation and its downstream signaling pathways. This inhibition can restore immune function by activating both T cells and cell-mediated immune responses against PD-1-overexpressing tumor cells. In some other embodiments, the PD-1 inhibitor can be administered according to established regimens, such as those provided in the package insert.

[0093] CTLA-4 inhibitors CTLA-4 inhibitors useful in the combinations described herein include any molecule capable of inhibiting, blocking, neutralizing, or interfering with the activity or expression of CTLA-4. In particular, CTLA-4 inhibitors may be small molecule compounds, nucleic acids, polypeptides, antibodies, peptibodies, diabodies, minibodies, single-chain variable fragments (ScFv), or functional fragments or variants thereof. In one case, the CTLA-4 inhibitor is a small molecule compound (e.g., a compound having a molecular weight of less than about 1000 Da). In other cases, CTLA-4 inhibitors useful in the combinations described herein include nucleic acids and polypeptides. CTLA-4 inhibitors may also be polypeptides (e.g., macrocyclic polypeptides). In one example, the CTLA-4 inhibitor is an antibody, peptibody, diabody, minibody, ScFv, or functional fragments thereof. In one example, the CTLA-4 inhibitor is ipilimumab.

[0094] In another example, the CTLA-4 inhibitor is a CTLA-4 antibody. The CTLA-4 antibody may be a monoclonal antibody or a polyclonal antibody. In some embodiments, the CTLA-4 antibody is a monoclonal antibody.

[0095] CTLA-4 antibodies include all known types of antibodies and functional fragments thereof, including, but not limited to, those exemplified herein, such as human antibodies, murine antibodies, chimeric antibodies, humanized antibodies, or chimeric-humanized antibodies.

[0096] In some embodiments, the CTLA-4 antibody is a human antibody. In other embodiments, the CTLA-4 antibody is a murine antibody. In some embodiments, the CTLA-4 antibody is a chimeric antibody. In some embodiments, the CTLA-4 antibody is a humanized antibody. In some embodiments, the CTLA-4 antibody is a chimeric humanized antibody. The CTLA-4 antibody may be a human antibody or a humanized antibody. The CTLA-4 antibody may be administered in combination with a compound of Formula I described herein. In some other embodiments, the CTLA-4 inhibitor may be administered according to an established regimen, such as one provided in the package insert.

[0097] CD276 inhibitors CD276 (B7-H3) is a relatively recently discovered, but important member of the immune checkpoint family. CD276 is expressed on antigen-presenting cells in the active / inflammatory "hot" tumor microenvironment (TME) and mediates the expression of CD8 + Suppresses cytotoxic T cells. CD276 expression is upregulated by administering a compound of Formula I described herein. CD276 inhibitors useful in the combinations described herein include any molecule capable of inhibiting, blocking, neutralizing, or interfering with the activity or expression of CD276. In particular, CD276 inhibitors may be small molecule compounds, nucleic acids, polypeptides, antibodies, peptibodies, diabodies, minibodies, single-chain variable fragments (ScFv), or functional fragments or variants thereof. In one case, the CD276 inhibitor is a small molecule compound (e.g., a compound having a molecular weight of less than about 1000 Da). In another example, CD276 inhibitors useful in the combinations described herein include nucleic acids and polypeptides. CD276 inhibitors may also be polypeptides (e.g., macrocyclic polypeptides). In one example, the CD276 inhibitor is an antibody, peptibody, diabody, minibody, ScFv, or functional fragments thereof.

[0098] In another example, the CD276 inhibitor is a CD276 antibody. The CD276 antibody may be a monoclonal antibody or a polyclonal antibody. In some embodiments, the CD276 antibody is a monoclonal antibody.

[0099] CD276 antibodies include all known types of antibodies and functional fragments thereof, including, but not limited to, those exemplified herein, such as human antibodies, murine antibodies, chimeric antibodies, humanized antibodies, or chimeric-humanized antibodies.

[0100] In some embodiments, the CD276 antibody is a human antibody. In some embodiments, the CD276 antibody is a murine antibody. In some embodiments, the CD276 antibody is a chimeric antibody. In some embodiments, the CD276 antibody is a humanized antibody. In some embodiments, the CD276 antibody is a chimeric humanized antibody. The CD276 antibody may be a human antibody or a humanized antibody. The CD276 antibody may be administered in combination with a compound of Formula I described herein or in combination with any of the other compositions described herein. In some other embodiments, the CD276 antibody may be administered according to an established regimen, such as one provided in the package insert.

[0101] PD-L1 inhibitor antibodies, PD-1 inhibitor antibodies, CTLA-4 inhibitor antibodies, and / or CD276 inhibitor antibodies (any one of which is referred to herein as an "inhibitor antibody") may be of any antibody isotype. The term isotype refers to the antibody class encoded by the heavy chain constant region genes. The heavy chain of a given antibody or functional fragment determines the class of that antibody or functional fragment: IgM, IgG, IgA, IgD, or IgE. Each class has either a kappa light chain or a lambda light chain. The term subclass refers to slight differences in the amino acid sequence of the heavy chain that distinguish the subclass. In humans, there are two subclasses of IgA (subclasses IgA1 and IgA2) and four subclasses of IgG (subclasses IgG1, IgG2, IgG3, and IgG4). Such classes and subclasses are well known to those skilled in the art.

[0102] Useful inhibitor antibodies bind to a substrate (e.g., PD-L1, PD-1, CTLA-4, and / or CD276) with sufficient strength to inhibit the activity of the substrate. As used herein, the term "binding" refers to the interaction between molecules that form a complex. The interaction may be a non-covalent interaction, including, for example, hydrogen bonding, ionic bonding, hydrophobic interactions, and / or van der Waals interactions. A complex may also comprise the binding of two or more molecules held together by covalent or non-covalent bonds, interactions, or forces. Binding of an antibody or functional fragment thereof can be detected, for example, using an enzyme-linked immunosorbent assay, or any one of numerous methods well known to those of skill in the art.

[0103] The strength of the total non-covalent interactions between a single antigen-binding site on an inhibitor antibody or functional fragment and a single epitope on a target molecule is the affinity of the antibody or functional fragment for that epitope. The binding (k1) of an antibody or functional fragment to a monovalent antigen is expressed as the dissociation (k -1 ) to the ratio (k1 / k -1) is the binding constant K, which is a measure of affinity. The value of K varies for different antibody or functional fragment and antigen complexes, and k and k -1 The binding constant K of an antibody or functional fragment of the invention can be determined using any of the methods provided herein or any other method known to one of skill in the art.

[0104] The affinity at one binding site does not necessarily reflect the true strength of the interaction between an antibody or functional fragment and an antigen. When a complex antigen containing multiple repeating antigenic determinants comes into contact with an antibody containing multiple binding sites, the interaction of such an antibody or functional fragment with the antigen at one site increases the likelihood of reaction at a second site. The strength of such multiple interactions between a multivalent antibody and an antigen is called avidity. The avidity of an antibody or functional fragment may be a better measure of its binding capacity than the affinity of each individual binding site. For example, high avidity can compensate for lower affinity, as can be found in pentameric IgM antibodies, which may have lower affinity than IgG, but the high avidity of IgM due to its multivalency allows it to bind effectively to the antigen.

[0105] The specificity of an inhibitor antibody or functional fragment thereof refers to the ability of an individual antibody or functional fragment thereof to react with only one antigen (e.g., a single epitope of PD-L1, PD-1, and CTLA-4). An antibody or functional fragment can be considered specific if it can distinguish differences in the primary, secondary, or tertiary structure of the antigen or antigen isomers.

[0106] The inhibitor antibody may be present in an amount that is a measure of the body weight of a patient in need thereof, for example, about 0.1 mg / kg to about 50 mg / kg, 0.1 mg / kg to about 40 mg / kg, 0.1 mg / kg to about 30 mg / kg, 0.1 mg / kg to about 25 mg / kg, 0.1 mg / kg to about 20 mg / kg, 0.1 mg / kg to about 15 mg / kg, 0.1 mg / kg to about 10 mg / kg, 0.1 mg / kg to about 7.5 mg / kg, 0.1 mg / kg to about 5 mg / kg, 0.1 mg / kg to about 2.5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. The inhibitor antibody may be present in an amount of about 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 40 mg / kg, 0.5 mg / kg to about 30 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 20 mg / kg, 0.5 mg / kg to about 15 mg / kg, 0.5 mg / kg to about 10 mg / kg, 0.5 mg / kg to about 7.5 mg / kg, 0.5 mg / kg to about 5 mg / kg, 0.5 mg / kg to about 2.5 mg / kg, or about 0.5 mg / kg to about 1 mg / kg. The inhibitor antibody may be present in an amount of about 0.5 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 10 mg / kg. The inhibitor antibody may be present in an amount of about 0.1 mg / kg to about 20 mg / kg, or about 0.1 mg / kg to about 30 mg / kg.

[0107] In yet some other embodiments, the inhibitor antibody may be present in an amount of about: 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, or 50 mg / kg. The inhibitor antibody may be present in an amount of about: 1 mg / kg, 2 mg / kg, 3 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, or 30 mg / kg. The inhibitor antibody may be present in an amount of about: 3 mg / kg, 10 mg / kg, 20 mg / kg, or 30 mg / kg.

[0108] The inhibitor antibody may be present in the combination in an amount of about: 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, or 200 mg. The inhibitor antibody may be present in the combination in an amount of about: 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg. The inhibitor antibody may be present in the combination in an amount of about 1000 mg to about 2000 mg. The inhibitor antibody may be present in the combination in an amount of about: 1 mg to about 10 mg, 10 mg to about 20 mg, 25 mg to about 50 mg, 30 mg to about 60 mg, 40 mg to about 50 mg, 50 mg to about 100 mg, 75 mg to about 150 mg, 100 mg to about 200 mg, 200 mg to about 500 mg, 500 mg to about 1000 mg, 1000 mg to about 1200 mg, 1000 mg to about 1500 mg, 1200 mg to about 1500 mg, or 1500 to about 2000 mg.

[0109] The inhibitor antibody may be present in the combination in an amount of about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 150 mg / mL, 200 mg / mL, 250 mg / mL, 300 mg / mL, 400 mg / mL, or 500 mg / mL. In some embodiments, the inhibitor antibody is present in the combination in an amount of about: 1 mg / mL to about 10 mg / mL, 5 mg / mL to about 10 mg / mL, 5 mg / mL to about 15 mg / mL, 10 mg / mL to about 25 mg / mL, 20 mg / mL to about 30 mg / mL, 25 mg / mL to about 50 mg / mL, or 50 mg / mL to about 100 mg / mL.

[0110] In some cases, a therapeutically effective amount of an inhibitor antibody is determined to be the amount provided on the package insert provided with the inhibitor antibody. The term package insert refers to instructions customarily included in commercial packaging for pharmaceutical products approved by the FDA or similar regulatory authority in countries other than the United States, which contain, for example, information regarding the use, dosage, administration, contraindications, and / or warnings regarding the use of such pharmaceutical product.

[0111] The compound of Formula I described herein can be provided in a synergistic amount with the amount of a PD-L1 and / or PD-1 inhibitor and a CTLA-4 inhibitor. The term synergistic refers to a combination described herein (e.g., a compound of Formula I and a PD-L1 and / or PD-1 inhibitor, plus co-administration with another active agent, such as an anti-cancer agent described herein) or combination of regimens, such as those described herein, that is more effective than the additive effects of each individual therapy or regimen.

[0112] The synergistic effect of the combinations described herein can permit the use of lower dosages of one or more of the components of the combination (e.g., a compound of Formula I, or a PD-L1 inhibitor, or a PD-1 inhibitor, or a CTLA-4 inhibitor). The synergistic effect can permit less frequent administration of at least one of the therapies (e.g., a compound of Formula I, or a PD-L1 inhibitor, or a PD-1 inhibitor, or a CTLA-4 inhibitor, or an anti-cancer agent) administered to a subject having a disease, disorder, or condition described herein. Such lower dosages and reduced administration frequency can reduce toxicity associated with the administration of at least one of the therapies (e.g., a compound of Formula I, or a PD-L1 inhibitor, or a PD-1 inhibitor, or a CTLA-4 inhibitor, or an anti-cancer agent) to a subject without reducing the efficacy of the treatment. The synergistic effect described herein can avoid or reduce adverse or unwanted side effects associated with the use of any of the therapies.

[0113] Pharmaceutical Composition The combinations described herein can be provided as pharmaceutical compositions suitable for administration to a patient by any route described herein, including, but not limited to, oral, mucosal (e.g., nasal, inhalation, pulmonary, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intra-arterial), topical (e.g., eye drops or other ophthalmic formulations), transdermal, or transdermal administration to a patient.

[0114] Examples of dosage forms include tablets, caplets, capsules (e.g., gelatin capsules), cachets, lozenges, suppositories, powders, gels, liquid dosage forms suitable for parenteral administration to a patient, and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

[0115] The pharmaceutical compositions and dosage forms described herein typically contain one or more excipients.Suitable excipients are well known to those skilled in the art of pharmacy.Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors, such as the intended route of administration to patients.The pharmaceutical compositions described herein may also contain other agents, such as stabilizers, lubricants, buffers, and disintegrants, which can reduce the decomposition rate of active ingredients in certain formulations.

[0116] The pharmaceutical compositions described herein may, in some cases, contain additional active agents other than the combinations described herein (e.g., anti-cancer agents described herein) in the amounts provided herein.

[0117] In some embodiments, the compound of Formula I is provided in an oral dosage form, such as a tablet or capsule. In some embodiments, the compound of Formula I is supplied as a powder (e.g., a lyophilized powder) that can be resuspended in a liquid suitable for parenteral administration.

[0118] The PD-L1 inhibitors, PD-1 inhibitors, and CTLA-4 inhibitors described herein can be provided in a form that is convenient or easy to administer to a patient. For example, when the inhibitor is an inhibitor antibody described herein, the inhibitor can be formulated as a ready-to-use solution for parenteral administration. In other examples, the inhibitor, including, for example, an inhibitor antibody, can be formulated as a powder (e.g., a lyophilized powder) that can be resuspended in a liquid suitable for parenteral administration. In some embodiments, the combination includes an inhibitor antibody formulated for intravenous administration. In some other embodiments, the combination includes a compound of Formula I formulated as an oral dosage form (e.g., a tablet or capsule) and an inhibitor antibody formulated for intravenous administration.

[0119] The combinations described herein can be provided as controlled-release pharmaceutical products, aiming to improve drug therapy beyond that achieved by non-controlled-release pharmaceutical products.Controlled-release formulations can extend the activity of drugs, reduce dosing frequency, and improve patient compliance.In addition, controlled-release formulations can be used to affect other characteristics, such as the onset of action or blood level of drugs, and thus affect the occurrence of side effects (e.g., adverse effects).

[0120] kit The combinations and pharmaceutical compositions described herein can be provided as part of a kit. Such kits can, for example, improve patient compliance or improve the accuracy or ease of preparing the combination for administration. The kits include a compound of Formula I provided in the formulations described herein.

[0121] The kit of the present invention may comprise the combinations described herein with the same or different formulations. Each component of the combinations described herein in the kit can be provided separately in individual containers. Alternatively or additionally, the components of the combinations described herein can be provided in a single container. In such cases, the container may be, for example, an IV bag, an ampoule, or a syringe, which can be immediately administered to a patient in need thereof. In some embodiments, the compound of Formula I in the kit is formulated for oral administration (e.g., tablet, capsule, or sachet).

[0122] The contents of the kit described herein can be provided in a sterile form.The kit and its contents can be provided in a form that can be immediately administered to a subject in need.In such cases, the components of the kit combination are provided as a formulation, and optionally provided in an administration device, and administration requires little or no further manipulation by the user.When the kit includes an administration device, such devices include, but are not limited to, syringes, pumps, bags, cups, inhalers, droppers, patches, creams, or injectors, which are known and understood by those skilled in the art for the administration routes described herein.

[0123] method The combinations, pharmaceutical compositions, and kits described herein are useful for treating diseases, disorders, or for alleviating or eliminating symptoms of diseases and disorders, such as cancer. It should be understood that the methods described herein relate to the administration of the combinations and pharmaceutical compositions described herein, and that such combinations and pharmaceutical compositions can be provided in the form of kits described herein. Provided herein are methods for treating cancer by administering a therapeutically effective amount of the combinations described herein to a patient in need thereof. Also provided herein are methods for managing cancer by administering a therapeutically effective amount of the combinations described herein to a patient in need thereof.

[0124] In some embodiments, the combination is used to treat cancer, hi some embodiments, the cancer is a cancer described herein.

[0125] In some embodiments, the combination is an HDAC inhibitor (HDACi), a PD-L1 inhibitor, and a CTLA-4 inhibitor. In some embodiments, the combination is an HDAC inhibitor (HDACi), a PD-1 inhibitor, and a CTLA-4 inhibitor. In some other embodiments, the combination is an HDAC inhibitor (HDACi), a PD-1 inhibitor, and an anti-cancer agent.

[0126] Combinations useful in the methods described herein include compounds of Formula I: [ka]

[0127] The PD-L1 inhibitor, PD-1 inhibitor, and CTLA-4 inhibitor for use in the methods described herein are inhibitors described herein. For example, the PD-L1 inhibitor, PD-1 inhibitor, and CTLA-4 inhibitor may be a small molecule compound, a nucleic acid, a polypeptide, an antibody, a peptibody, a diabody, a minibody, a single-chain variable fragment (ScFv), or a functional fragment or variant thereof. In another example, the inhibitor may be an inhibitor antibody as described above.

[0128] Targeted Cancer The cancer may be a solid tumor. The cancer may be a blood cancer. In some cases, the cancer is a solid tumor such as squamous cell carcinoma, non-squamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, malignant melanoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, head and neck cancer, urothelial carcinoma, breast cancer, prostate cancer, glioblastoma, colorectal cancer, pancreatic cancer, lymphoma, leiomyosarcoma, liposarcoma, synovial sarcoma, or malignant peripheral nerve sheath tumor (MPNST).

[0129] In some embodiments, the cancer is a solid tumor such as non-small cell lung cancer (NSCLC), hepatocellular carcinoma, malignant melanoma, ovarian cancer, breast cancer, pancreatic cancer, renal cell carcinoma, or colorectal cancer. The cancer may be non-small cell lung cancer (NSCLC). The cancer may be hepatocellular carcinoma. The cancer may be melanoma. The cancer may be ovarian cancer. The cancer may be breast cancer. The cancer may be pancreatic cancer. The cancer may be renal cell carcinoma. The cancer may be colorectal cancer.

[0130] Provided herein are methods for treating NSCLC by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and an inhibitor antibody. In some embodiments, the NSCLC is stage IIA or stage IIB. The NSCLC may be stage IIIA or stage IIIB cancer. The NSCLC may be stage IV cancer. The cancer staging described herein is described according to the American Joint Committee on Cancer TNM classification of malignant tumors cancer staging notation, as is well known in the art. Those skilled in the art will readily appreciate that other staging systems are available and applicable to the methods described herein. In some cases, the method is for treating stage IIIA or IIIB NSCLC by administering a combination described herein comprising a compound of Formula I and an inhibitor antibody.

[0131] Still further provided herein is a method for treating malignant melanoma by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and an inhibitor antibody. In some embodiments, the malignant melanoma is stage IIA, IIB, or IIC cancer. In some embodiments, the malignant melanoma is stage IIIA, IIIB, or IIIC cancer. In some other embodiments, the malignant melanoma is stage IV cancer. In some embodiments, the method is a method for treating stage II (e.g., stage IIA, IIB, or IIC) malignant melanoma by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and an inhibitor antibody.

[0132] Also provided herein are methods for treating breast cancer by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and an inhibitor antibody. The breast cancer may be HER2-negative breast cancer. The breast cancer may be HER2-positive breast cancer. The breast cancer may be triple-negative breast cancer. In some embodiments, the breast cancer is stage IA or stage D3 cancer. In some embodiments, the breast cancer is stage IIA or stage IIB cancer. In some embodiments, the breast cancer is stage IIIA, stage IIIB, or stage IIIC cancer. In some embodiments, the breast cancer is stage IV cancer.

[0133] In other embodiments, the cancer is a hematological cancer such as lymphoma, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, Reed-Sternberg disease, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), or chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is Hodgkin's lymphoma or Reed-Sternberg disease.

[0134] The combinations described herein can be administered to cancer patients at any time after diagnosis. For example, the cancer patient may be treatment-naive (e.g., not having received cancer therapy for the diagnosed cancer). The cancer patient may be treatment-naive for one cancer, but may have been diagnosed with one or more other cancers, for example, due to metastasis or malignancy. The cancer patient may be immune checkpoint naive for one or more cancers. The cancer patient may have a refractory cancer. In some cases, the combinations described herein are administered to a patient in need thereof as first-line therapy (e.g., the first therapy administered to a treatment-naive cancer patient).

[0135] However, cancer morbidity and mortality are often associated with ineffective therapy or cancer resistance or refractory to one or more cancer therapies.Therefore, the combinations described herein can be administered to patients in need thereof as second, third, fourth, fifth, sixth, or subsequent line of treatment.The combinations described herein can also be administered to cancer patients who have been treated with at least one anticancer therapy or anticancer agent.In some cases, the patient has received at least one anticancer therapy, including, for example, chemotherapy, radiotherapy, surgery, targeted therapy, immunotherapy, or a combination thereof.The patient may have cancer that is resistant / refractory to treatment with at least one anticancer agent.

[0136] The methods for treating cancer herein include treating subjects who have been treated with a checkpoint inhibitor and experienced no response, partial response, or stable disease, but then developed resistance to the treatment with disease progression, or subjects who experienced a complete response to the treatment but then developed resistance to the treatment with disease progression (as defined by RECIST or other criteria). Resistance is defined as disease progression during treatment or lack of response to treatment. Such failure of inhibitor antibody treatment can be treated with an inhibitor antibody in combination with an HDAC inhibitor, such as, but not limited to, HBI-8000, or an HDAC inhibitor that inhibits cancer-related class I HDACs selected from one or more of HDAC1, HDAC2, or HDAC3. In some cases, the HDAC inhibitor also inhibits class IIb HDAC1.

[0137] Response Criteria RECIST: RECIST is a set of internationally recognized, established criteria or standards for assessing patient response, stability, and progression in clinical trials and clinical practice. RECIST was first published in 2000 as a collaborative effort of the European Organization for Research and Treatment of Cancer, the National Cancer Institute of the United States, and the National Cancer Institute of Canada Clinical Trials Group, and was revised in 2009 (Eisenhauer EA et al.; "New response criteria in solid tumors: revised RECIST guideline (version 1.1)," Eur. J. Cancer 2009, 45:228-47). RECIST is traditionally used to evaluate response to chemotherapy. Target Lesion Assessment: Complete response (CR): disappearance of all target lesions; partial response (PR): reduction in the sum of the LD (longest diameter) of the target lesions by at least 30% based on the baseline sum LD; stable disease (SD): neither a shrinkage sufficient to meet the criteria for PR nor an increase sufficient to meet the criteria for PD based on the smallest sum LD since the start of treatment; progressive disease (PD): an increase in the sum of the LD of the target lesions by at least 20% based on the smallest sum LD recorded since the start of treatment, or the appearance of one or more new lesions. Non-target lesion evaluation: Complete response (CR): disappearance of all non-target lesions and normalization of tumor marker levels; Incomplete response / Stable disease (SD): persistence of one or more non-target lesions and / or maintenance of tumor marker levels above the normal range; Progressive disease (PD): appearance of one or more new lesions and / or clear progression of existing non-target lesions. Other response criteria: Other response criteria include the Immune-Related Response Criteria or iRECIST defined by Wolchok et al. in 2009 (Wolchok JD et al.: Immune-Related Response Criteria. Clin. Cancer Res 2009;15(23):7412-20) and the revised International Working Group Response Criteria (Cheson BD et al., Revised response criteria for malignant lymphoma. J. Clin. Oncol. 2007;25:579-586). Assessment of the effects of HDACi on heart rate: In conjunction with pharmacokinetic analysis, 12-lead continuous digital ECGs were recorded (under controlled conditions to minimize digital noise) using a Holter monitor on baseline (within 1–7 days prior to C1D1) and C1D1 (Phase 1b only). Triplicate 10-second ECGs were extracted from Holter flashcards on baseline and pre-dose days (0.5 h before breakfast), C1D1, and at matching time points up to 4 h post-dose. PR, QRS, RR, and QT intervals were analyzed in a central ECG laboratory. Meal times (breakfast) were standardized on both days. Measured QT data were heart rate corrected using the Fridericia correction (QTcF). QTcF was calculated using the following formula: Fridericia: QTcFri=QT / (RR) 1 / 3 (Fridericia LS. Die systolendauer im elektrokardiogramm bei normalenmenschen und bei herzkranken. Acta Med Scand. 1920; vol. 53: pp. 469-486)

[0138] The methods for treating cancer herein include treating a subject with an HDACi such that administration of the HDACi does not cause an increase in QTc, QTcF, or heart rate (HR).

[0139] Methods for treating cancer include methods for inhibiting cell proliferation by administering a therapeutically effective amount of a combination described herein, wherein the combination includes a compound of Formula I and a PD-L1 inhibitor and / or a PD-1 inhibitor, in addition to a CTLA-4 inhibitor described herein.

[0140] Also provided herein are methods for inhibiting cancer metastasis in a patient in need thereof by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-L1 inhibitor and / or a PD-1 inhibitor, in addition to a CTLA-4 inhibitor described herein. In some embodiments, metastasis is inhibited by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0141] Some embodiments are methods for reducing existing tumor metastases in a cancer patient in need thereof by administering a therapeutically effective amount of a combination described herein, the combination comprising a compound of Formula I and a PD-L1 inhibitor and / or a PD-1 inhibitor, in addition to a CTLA-4 inhibitor described herein. In some embodiments, existing tumor metastases are reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0142] In some other embodiments, methods for treating cancer also provide methods for reducing tumor burden in an individual by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-L1 inhibitor and / or a PD-1 inhibitor, in addition to a CTLA-4 inhibitor described herein. In some embodiments, the tumor burden is reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0143] In some embodiments, methods for treating cancer also provide methods for reducing tumor burden in an individual by administering a therapeutically effective amount of a combination described herein, the combination comprising a compound of Formula I and a PD-L1 inhibitor and / or a PD-1 inhibitor, in addition to a CTLA-4 inhibitor described herein. In some embodiments, the tumor burden is reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0144] The methods for treating cancer described herein also provide methods for increasing or otherwise extending the time to disease progression of certain stages (including advanced cancers such as stage III and stage IV cancers described herein). The time to disease progression in a patient can be extended by administering a therapeutically effective amount of a combination described herein, where the combination includes a compound of Formula I and a PD-L1 inhibitor and / or a PD-1 inhibitor, in addition to a CTLA-4 inhibitor described herein. In some embodiments, the increase is a comparison of the time to disease progression without treatment and the time to disease progression with treatment with a combination described herein. In some embodiments, the methods described herein extend the time to disease progression by at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or longer, inclusive.

[0145] The methods for treating cancer described herein also provide methods for increasing or otherwise extending the survival (including overall survival) of patients diagnosed with a cancer described herein. Patient survival can be extended by administering a therapeutically effective amount of a combination described herein, where the combination comprises a compound of Formula I and a PD-L1 inhibitor and / or a PD-1 inhibitor, in addition to a CTLA-4 inhibitor described herein. In some embodiments, the increase is a comparison of survival without treatment to survival with treatment with a combination described herein. In some embodiments, the methods described herein extend survival by at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or longer, inclusive.

[0146] The methods for treating cancer described herein also provide methods for increasing progression-free survival in patients diagnosed with a cancer described herein. Progression-free survival can be extended by administering a therapeutically effective amount of a combination described herein, where the combination comprises a compound of Formula I and a PD-L1 inhibitor and / or a PD-1 inhibitor, in addition to a CTLA-4 inhibitor described herein. In some embodiments, the increase is a comparison of progression-free survival without treatment to progression-free survival with treatment with a combination described herein. In some embodiments, the methods described herein increase progression-free survival by at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or longer, inclusive.

[0147] Also provided herein is a method for reducing myeloid-derived suppressor cell (MDSC) levels in a patient in need thereof by administering an effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-L1 inhibitor and / or a PD-1 inhibitor, as well as a CTLA-4 inhibitor described herein. Reduction of MDSCs can be beneficial in treating the cancers described herein. MDSC levels can be measured in a human patient before, during, and after administration of a combination described herein. In some embodiments, it can be useful to compare the amount of MDSCs in a patient before and after administration. A reduction in the amount, level, or number of MDSCs after administration can indicate, for example, the effectiveness of the combination in treating a cancer described herein. MDSC levels can be monitored over the course of a treatment or regimen described herein with a combination described herein. In such cases, determining MDSC levels at various time points during the course of administration can indicate the effectiveness of the regimen.

[0148] Also provided herein are methods for reducing the percentage or level of Treg cells in a patient in need thereof. Such methods include administering an effective amount of a combination described herein, where the combination includes a compound of Formula I and a PD-L1 inhibitor and / or a PD-1 inhibitor, as well as a CTLA-4 inhibitor described herein. Reduction of Treg cells can be beneficial in treating cancers described herein. The level of Treg cells in a human patient can be measured before, during, and after administration of a combination described herein. In some embodiments, it can be useful to compare the amount of Treg cells in the patient before and after administration. A reduction in the amount, level, or number of Treg cells after administration can indicate the effectiveness of the combination, for example, in treating cancers described herein. Treg cell levels can be monitored over the course of a treatment or regimen described herein with a combination described herein. In such cases, determining the level of Treg cells at various time points during the course of administration can indicate the effectiveness of the regimen.

[0149] The combinations described herein may be useful in methods for enhancing the activity of natural killer (NK) cells. The combinations described herein may be useful in methods for enhancing the activity of cytotoxic T cells. The enhancement method includes contacting NK cells or cytotoxic T cells with a combination described herein, and the combination enhances the activity of the NK cells or cytotoxic T cells compared to the activity before the contact. In some embodiments, the enhanced activity of NK cells or cytotoxic T cells is in a cancer patient to which the combination described herein is administered.

[0150] The combinations described herein may also enhance antibody-dependent cell-mediated cytotoxicity in cancer patients upon administration of the combinations described herein.

[0151] The combinations described herein can include administration of each therapy (e.g., a compound of Formula I, and a PD-L1 inhibitor and / or PD-1 inhibitor, plus a CTLA-4 inhibitor), where administration is simultaneous or sequential (in any order). In some embodiments, the compound of Formula I, and the PD-L1 inhibitor and / or PD-1 inhibitor, plus a CTLA-4 inhibitor, are administered simultaneously (e.g., within at least 1-5 minutes of each other). In some embodiments, the compound of Formula I, and the PD-L1 inhibitor and / or PD-1 inhibitor, plus a CTLA-4 inhibitor, are administered sequentially (e.g., within at least 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 10 hours, 12 hours, 1 day, 2 days, 5 days, 7 days, 14 days, or 21 days of each other).

[0152] The compound of Formula I may be administered continuously or intermittently on a regular basis, for example, once daily (QD), twice daily (BID), once weekly (QW), twice weekly (BIW), three times weekly (TIW), or once monthly (QM). For example, it may be administered BIW for three months and then resumed after one month. For example, the compound of Formula I may be administered BID. The compound of Formula I may be administered TIW. In some embodiments, the compound of Formula I is administered two to three times weekly. In some embodiments, the compound of Formula I is administered QD. The compound may be administered QD daily for about 1 day to about 7 days, about 1 day to about 14 days, about 1 day to about 21 days, about 1 day to about 28 days, or until disease progression or unacceptable toxicity occurs. Administration of the compound of Formula I depends in part on patient tolerance; greater tolerance allows for more frequent or more frequent administration. Alternatively, a lower amount of the compound or less frequent dosing may be administered if the patient tolerates the compound of Formula I poorly. The compound of Formula I can be administered in any regimen described herein.

[0153] For example, a compound of formula I may be administered QD in an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. For example, a compound of formula I may be administered BIW in an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. For example, a compound of Formula I may be administered TIW in an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. For example, a compound of Formula I may be administered QW in an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. For example, the compound of Formula I may be administered Q2W in an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. For example, the compound of Formula I may be administered QD in an amount of about 5 mg or about 10 mg. For example, the compound of Formula I may be administered BIW in an amount of about 5 mg or about 10 mg. For example, the compound of Formula I may be administered TIW in an amount of about 5 mg or about 10 mg. For example, the compound of Formula I may be administered QW in an amount of about 5 mg or about 10 mg. For example, the compound of Formula I may be administered Q2W in an amount of about 5 mg or about 10 mg. The administration of the compound of Formula I may be continuous.The administration of the compound of formula I may be intermittent.

[0154] For example, a compound of Formula I may be administered QD in an amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg. For example, a compound of Formula I may be administered BIW in an amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg. For example, a compound of Formula I may be administered TIW in an amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg. For example, a compound of Formula I may be administered QW in an amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg. For example, the compound of Formula I may be administered Q2W in an amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg. The administration of the compound of Formula I may be continuous. The administration of the compound of Formula I may be intermittent.

[0155] For example, the compound of formula I may be administered at a dose of about: 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.01 mg / kg to about 200 mg / kg, 0.01 mg / kg to about 150 mg / kg, 0.01 mg / kg to about 100 mg / kg, 0.01 mg / kg to about 50 mg / kg, 0.01 mg / kg to about 25 mg / kg, 0.01 mg / kg to about 10 mg / kg, or 0.01 mg / kg to about 5 mg / kg, 0.05 mg / kg to about 200 mg / kg, 0.05 mg / kg to about 150 mg / kg, 0.05 It may be administered QD in an amount of 0.5 mg / kg to about 100 mg / kg, 0.05 mg / kg to about 50 mg / kg, 0.05 mg / kg to about 25 mg / kg, 0.05 mg / kg to about 10 mg / kg, or 0.05 mg / kg to about 5 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg. For example, a compound of Formula I may be administered BIW in an amount of about: 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg. For example, a compound of Formula I may be administered TIW in an amount of about: 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg.For example, a compound of formula I may be administered QW in an amount of about: 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg. For example, a compound of Formula I may be administered Q2W in an amount of about: 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg. In one example, a compound of Formula I may be administered QD in an amount of about 15 mg / kg to about 75 mg / kg. In another example, a compound of Formula I may be administered in an amount of about 20 mg / kg to about 50 mg / kg. In yet another example, the compound of Formula I may be administered in an amount of about 0.001 mg / kg, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg. The administration of the compound of Formula I may be continuous. The administration of the compound of Formula I may be intermittent.

[0156] For example, a compound of Formula I may be administered QD in an amount of about: 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg. For example, a compound of Formula I may be administered BIW in an amount of about: 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg. For example, a compound of Formula I may be administered TIW in an amount of about: 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg. For example, a compound of Formula I may be administered QW in an amount of about: 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg. For example, a compound of Formula I may be administered Q2W in an amount of about: 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg. In one example, a compound of Formula I may be administered QD in an amount of about 15 mg / kg to about 75 mg / kg. In another example, a compound of Formula I may be administered in an amount of about 20 mg / kg to about 50 mg / kg.In yet another example, the compound of Formula I may be administered in an amount of about 0.001 mg / kg, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg. The administration of the compound of Formula I may be continuous. The administration of the compound of Formula I may be intermittent.

[0157] As used herein, the term "daily" is intended to mean that a combination therapy compound described herein, e.g., a compound of Formula I, is administered once or more than once daily for a period of time. The term "continuous" is intended to mean that a combination therapy compound described herein, e.g., a compound of Formula I, is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The terms "intermittent" or "intermittently," as used herein, are intended to mean stopping and starting at regular or irregular intervals. For example, intermittent administration of a combination therapy compound described herein, e.g., a compound of Formula I, can include administration 1 to 6 days per week (e.g., 2 to 3 times per week or QD), cyclic administration (e.g., daily administration for 2 to 8 consecutive weeks followed by a drug holiday of at least 1 day without administration), or administration, e.g., every other day.

[0158] When the inhibitor is an inhibitor antibody, it can be administered according to an established regimen, such as that provided in the package insert. The inhibitor antibody may be administered in the amounts described herein and may be administered QW, once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W). In some embodiments, the inhibitor antibody is administered Q2W or Q4W. In some other embodiments, the inhibitor antibody is administered Q2W. In some embodiments, the inhibitor antibody is administered Q3W. In some embodiments, the inhibitor antibody is administered B1W for at least three weeks. In some embodiments, the inhibitor antibody is administered Q4W.

[0159] For example, the inhibitor antibody may be administered QW in an amount of about 0.1 mg / kg to about 30 mg / kg (e.g., including 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, and 30 mg / kg). For example, the inhibitor antibody may be administered Q2W in an amount of about 0.1 mg / kg to about 30 mg / kg (e.g., including 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, and 30 mg / kg). For example, the inhibitor antibody may be administered Q4W in an amount of about 0.1 mg / kg to about 30 mg / kg (e.g., including 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, and 30 mg / kg). For example, the inhibitor antibody may be administered B4W (twice every four weeks) in an amount of about 0.1 mg / kg to about 30 mg / kg (e.g., including 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, and 30 mg / kg). For example, the inhibitor antibody may be administered Q3W in an amount of about 0.1 mg / kg to about 30 mg / kg (e.g., including 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, and 30 mg / kg).For example, the inhibitor antibody may be administered Q2W in an amount of about 1000 mg to about 2000 mg (e.g., including 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, and 1600 mg). For example, the inhibitor antibody may be administered Q3W in an amount of about 1000 mg to about 2000 mg (e.g., including 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, and 1600 mg). For example, the inhibitor antibody may be administered Q4W in an amount of about 1000 mg to about 2000 mg (e.g., including 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, and 1600 mg). The administration of the inhibitor antibody may be continuous. The administration of the inhibitor antibody may be intermittent.

[0160] The inhibitor antibody may be administered as an intravenous infusion over about 10, 20, 30, 40, 50, or 60 minutes, or longer. The inhibitor antibody may be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5, or more weeks. The inhibitor antibody may be administered as an intravenous infusion over about 60 minutes once every two weeks. The inhibitor antibody may be administered as an intravenous infusion over about 60 minutes once every three weeks. The inhibitor antibody may be administered as an intravenous infusion over about 60 minutes once every four weeks. The inhibitor antibody may be administered as an intravenous infusion according to the package insert. The administration of the inhibitor antibody may be continuous. The administration of the inhibitor antibody may be intermittent.

[0161] The combinations described herein may be administered in a regimen. The regimen can be configured to provide a therapeutically effective amount of a compound of Formula I and an inhibitor, such as an inhibitor antibody, for a predetermined period (e.g., administration time). The regimen can be configured to limit or prevent side effects or undesirable complications of each of the components of the combination described herein. The regimen can be configured to provide increased efficacy (e.g., synergistic) of both therapies in the combination. A regimen useful for treating cancer may include any number of days of administration, which may be repeated as needed. The administration period may be interrupted by a rest period not including administration of at least one therapy. For example, the regimen may include an administration period of 2, 3, 5, 7, 10, 15, 21, 28, or more days. Such periods may be repeated. For example, the regimen may include a number of days set forth as previously described, in which the regimen is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more times.

[0162] The regimen may include a drug holiday of at least 1, 2, 3, 5, 7, 10 days or more, during which at least one therapy is no longer administered to the patient.The drug holiday can be determined, for example, by monitoring the patient's response to the drug or by measuring the effectiveness of treatment.The drug holiday may be applicable to a single therapy, and only one therapy of the combination described herein is discontinued during the drug holiday, while the other therapy continues to be administered.The drug holiday may also be applied to all the therapies administered to the subject, and the subject does not receive therapy for a certain period during the drug holiday.

[0163] The regimens described herein for treating cancer using the combinations described herein can be continued until disease progression or unacceptable toxicity.

[0164] The administration regimens for the combinations described herein include, for example, BIW or TIW administration of the compound of Formula I and the PD-L1 and / or PD-1 inhibitor, as well as the CTLA-4 inhibitor. For example, the compound of Formula I may be administered QD for about 21 days, and the inhibitor antibody described herein may be administered Q2W or Q4W. For example, the compound of Formula I may be administered BIW or TIW, and the inhibitor antibody described herein may be administered Q2W. In another exemplary regimen, the compound of Formula I may be administered BIW or TIW, and the inhibitor antibody may be administered BIW for 2 or 3 weeks. In yet another exemplary regimen, the compound of Formula I may be administered BIW or TIW, and the inhibitor antibody may be administered Q4W. In yet another exemplary regimen, the compound of Formula I may be administered BIW, and the inhibitor described herein may be administered Q2W, Q3W, or Q4W. In some cases, such regimens include administration of the inhibitor antibody administered Q2W, Q3W, or Q4W. In yet another exemplary regimen, the compound of Formula I may be administered T1W, and the inhibitor described herein may be administered Q2W, Q3W, or Q4W. In some cases, such regimens include administration of an inhibitor antibody administered Q2W, Q3W, or Q4W. In some cases, such regimens include administration of a compound of Formula I administered QD. In some cases, such regimens include administration of a compound of Formula I administered QD for at least 21 days. In yet another exemplary regimen, the compound of Formula I may be administered QD or QW, and the inhibitor (e.g., inhibitor antibody) is administered Q2W, Q3W, or Q4W.

[0165] The regimen may also be a regimen for administering an inhibitor antibody together with a compound of Formula I described herein. In one exemplary regimen including an inhibitor antibody, the compound of Formula I may be administered BIW or TIW, with the inhibitor antibody being administered, for example, according to the prescribing information provided in the package insert. In another exemplary regimen, the inhibitor antibody is administered in an amount of about 1 mg / kg to about 20 mg / kg on day 1 of the regimen, then administered Q2W until disease progression or unacceptable toxicity, and the compound of Formula I is administered BIW or TIW over the same period. In another exemplary regimen, the inhibitor antibody is administered in an amount of about 1 mg / kg to about 20 mg / kg on day 1 of the regimen, then administered Q3W until disease progression or unacceptable toxicity, and the compound of Formula I is administered BIW or TIW over the same period. The inhibitor antibody may also be administered Q4W with the compound of Formula I, with the compound of Formula I being administered, for example, BIW or TIW during the course of such a regimen. The inhibitor antibody may be administered Q2W together with the compound of Formula I, with the compound of Formula I being administered, for example, BIW or TIW during the course of such a regimen. In yet another exemplary regimen, the inhibitor antibody may be administered Q2W or Q4W together with the compound of Formula I, with the compound of Formula I being administered, for example, QD or QW during the course of such a regimen. Such a regimen can be repeated as described above (e.g., 1, 2, 3, 4, 5, 6, 7, 8, and 9, 10, 11, 12, or more times).

[0166] In another exemplary regimen involving an inhibitor antibody, the compound of Formula I may be administered QD, with the inhibitor antibody being administered, for example, according to the prescribing information provided in the package insert. In another exemplary regimen, the inhibitor antibody is administered in an amount of about 1 mg / kg to about 20 mg / kg on day 1 of the regimen, then administered Q2W until disease progression or unacceptable toxicity, with the compound of Formula I being administered QD over the same period. In another exemplary regimen, the inhibitor antibody is administered in an amount of about 1 mg / kg to about 20 mg / kg on day 1 of the regimen, then administered Q3W until disease progression or unacceptable toxicity, with the compound of Formula I being administered QD over the same period. The inhibitor antibody may be administered Q4W together with the compound of Formula I, with the compound of Formula I being administered QD over the course of such a regimen. The inhibitor antibody may be administered Q2W together with the compound of Formula I, with the compound of Formula I being administered QD over the course of such a regimen. Such a regimen can be repeated (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more times) as described above.

[0167] The combinations described herein for treating cancer may be administered with other active agents (e.g., anticancer drugs) other than those present in the combinations described herein.The regimens for administering the combinations described herein, including the exemplary regimens shown above, can be modified to include the administration of such active agents, if necessary.The administration of such active agents, for example, anticancer drugs, can be carried out QD, QW, QM, BID, BIW, TIW, Q2W, Q3W, or Q4W, or according to the prescription information of the anticancer drug, for example, as shown in the package insert. Exemplary anticancer agents include, but are not limited to, Abraxane; Abiraterone; Ace-11; Aclarubicin; Acivicin; Acodazole hydrochloride; Acronine; Actinomycin; Acylfulvene; Adecipenol; Adozelesin; Adriamycin; Aldesleukin; All-trans-retinoic acid (ATRA); Altretamine; Ambamustine; Ambomycin; Amethantrone acetate; Amidox; Amifostine; Aminoglutethimide; Aminolevulinic acid; Amrubicin; Amsacrine; Anagrelide; Anastrozole; Andrographolide; Antarelix; Anthramycin; Aphidicolin glycinate; Apurinic acid; ara-CDP-DL-PTBA; Arginine deaminase; ARRY-162; ARRY-300; ARRY-142266; AS70302 6;Asparaginase;Asperlin;Aslaculin;Atamestane;Atrimustine;Axinastatin 1;Axinastatin 2;Axinastatin 3;Azasetron;Azatoxin;Azatyrosine;Azacitidine;AZD8330;Azetepa;Azotomycin;Balanol;Batimastat;BAY11-7082;BAY43-9006;BAY869766;Bendamustine;Benzochlorin;Benzo Depa; Benzoylstaurosporine; Beta-Arethin; Betaclamycin B; Betulinic acid; b-FGF inhibitors; Bicalutamide; Bisantrene; Bisaziridinylspermine; Visafide; Visafide dimesylate; Bistraten A; Bisantrene hydrochloride; Bleomycin; Bleomycin sulfate; Busulfan; Biceresin; Breflate; Bortezomib; Brequinar sodium; Bropirimine; Budotitane;Buthionine sulfoximine; bryostatin; cactinomycin; calsterone; calcipotriol; calphostin C; camptothecin derivatives; capecitabine; carboxamido-amino-triazole; carboxyamidotriazole; CaRestM3; CARN700; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; castanospermine; cecropin B; cedefingol; celecoxib; cetrorelix; chlorin; chloroquinoxaline sulfonamide; cicaprost; chlorambucil; clo Lofsin; Cilolemycin; Cisplatin; CI-1040; cis-Porphyrin; Cladribine; Clomiphene analogs; Clotrimazole; Collismycin A; Collismycin B; Combretastatin A4; Combretastatin analogs; Conagenin; Crambesidin 816; Crisnatol; Crisnatol mesylate; Cryptophycin 8; Cryptophycin A derivatives; Curacin A; Cyclopentanthraquinone; Cycloplatam; Sipemycin; Cyclophosphamide; Cytarabine; Cytarabine ocfosfate; Thin Cytolytic factor; Cytostatin; Dacarbazine; Dactinomycin; Daunorubicin; Daunorubicin hydrochloride; Decarbazine; Dacliximab; Dasatinib; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone; Dexifosfamide; Dexrazoxane; Dexverapamil; Dexormaplatin; Dezaguanine; Dezaguanine mesylate; Diaziquone; Didemnin B; Didox; Diethylnorspermine; Dihydro-5-azacytidine; Dihydrotaxin ol; 9-dioxamycin; diphenylspiromustine; docosanol; dolasetron; docetaxel; doxorubicin; doxorubicin hydrochloride; doxifluridine; droloxifene; droloxifene citrate; dromostanolone propionate; dronabinol; zuazomycin; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; edatrexate; eflornithine hydrochloride; eflornithine; elemene; emiteflu; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin;Epirubicin hydrochloride; Epristeride; Elbrozole; Eribulin; Esorubicin hydrochloride; Estramustine; Estramustine phosphate sodium; Etanidazole; Etoposide; Etoposide phosphate; Etoprine; Exemestane; Fadrozole; Fadrozole hydrochloride; Fazarabine; Fenretinide; Filgrastim; Finasteride; Flavopiridol; Fluzelastine; Fluasterone; Floxuridine; Fludarabine phosphate; Fludarabine; Fluorodaunorubicin hydrochloride; Forfenimex; Formestane; Fluorouracil; Flo Floxouridine; Flurocitabine; Foskidone; Fostriecin sodium; Fostriecin; Fotemustine; Gadolinium texaphyrin; Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitors; Gemcitabine; Geldanamycin; Gossyphol; GDC-0973; GSK1120212 / Trametinib; Herceptin; Hydroxyurea; Hepsulfam; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronate; Ibrutinib; Idarubicin; Idarubicin hydrochloride ;Ifosfamide;Canfosfamide;Ilmofosine;Iproplatin;Idoxifene;Idramanton;Ilmofosine;Ilomastat;Imidazoacridone;Imatinib (e.g., GLEEVEC);Imiquimod;Iobenguane;Iododoxorubicin;Ipomeanol;Irinotecan;Irinotecan hydrochloride;Irsogladine;Isobengazole;Isohomohalichondrin B;Itasetron;Imofosine;Interleukin Il (including recombinant interleukin IL-2; or r1L2);Interferon alfa-2a;Interferon Alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-la; interferon gamma-1b; jasplakinolide; kahalalide F; lamellarin N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leuprorelin; levamisole; liarozole; rissoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;Lysofylline; Lanreotide acetate; Lapatinib; Letrozole; Leucovorin; Leuprolide acetate; Liarozole hydrochloride; Lometrexol sodium; Lomustine; Lenalidomide; Lenvatinib; Rosoxantrone hydrochloride; LY294002; Pomalidomide; Maytansine; Mannostatin A; Marimastat; Masoprocol; Maspin; Matrilysin inhibitors; Menogaril; Melbarone; Meterelin; Methioninase; Metoclopramide; MIF inhibitors; Mifepristone; Miltefosine; Millimosti Pharmacist; Mitoguazone; Mitolactol; Mitonafide; Mitoxantrone; Mofalotene; Molgramostim; Mopidamol; Mycaperoxide B; Myriaporone; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocalcin; Mitochromin; Mitogillin; Mitomarcin; Mitomycin; Mitospel; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Nafarelin; Na Grestipene; napavin; nafterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modifiers; nitric oxide antioxidants; nitrullyn; nocodazole; nogalamycin; oblimersen (GENASENSE); octreotide; oxenon; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducers; ormaplatin; oxisuran; oxaloplatin; Osateron; Oxaliplatin; Oxaunomycin; Palauamine; Palmitoylrhizoxin; Pamidronate; Panaxytriol; Panomyphen; Parabactin; Pazeliptin; Pegaspargase; Perdecin; Pentosan polysulfate sodium; Pentostatin; Pentrozole; Perflubron; Perfosfamide; Perillyl alcohol; Phenazinomycin; Phenylacetate; Phosphatase inhibitors; Picibanil; Pilocarpine hydrochloride; Pirarubicin; Piritrexim; Placetin A;Placetin B; porfiromycin; prednisone; prostaglandin J2; pyrazoloacridine; paclitaxel; PD035901; PD184352; PD318026; PD98059; peliomycin; pentamstine; peplomycin sulfate; PKC412; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; promestane; podophyllotoxin; polyphenol E; porfimer sodium; porfiromycin; prednimustine; procarbazine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pirazofurin; raltitrexed; ramosetron; demethylated reterliptin demethylated); rhizoxin; rituximab; RII retinamide; rogletimide; rohitukin; romurtide; roquinimex; rubiginone B1; ruboxil; ribopurin; romidepsin; safingol; safingol hydrochloride; saintpin; sarcophytol A; sargramostim; semustine; sizofiran; sobuzoxane; borocaptate sodium; sodium phenylacetate; sorberol; sonermin; sorafenib; sunitinib; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; spongistatin 2; spongistatin 3; spongistatin 4; spongistatin 5; spongistatin 6; spongistatin 7; spongistatin 8; and spongistatin Gistatin 9; Squalamine; Stipiamide; Stromelysin inhibitors; Sulfinosine; Suradista; Suramin; Swainsonine; SB239063; Selumetinib / AZD6244; Simtrazene; SP600125; Sparfosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiroplatin; Streptonigrin; Streptozocin; Surofenur; Talimustine; Tamoxifen methiodide; Tauromustine; Tazarotene; Tecogalan sodium; Tegafur; Terlapyrylium; Temoporfin; Temozolomide; Teniposide; Tetrachlorodecaoxide; Tetrazomine; Taliblastine; Thiocoraline; Thrombopoietin; Thymalfasin; Thymopoietin receptor agonists; Thymotrin;Tirapazamine;Titanocene dichloride;Topsentin;Toremifene;Tretinoin;Triacetyluridine;Triciribine;Trimetrexate;Triptorelin;Tropisetron;Turosteride;Tyrphostin;Tallysomycin;TAK-733;Taxotere;Tegafur;Teroxantrone hydrochloride;Teroxil; phenanthrene; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trastuzumab; trestrone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubrozole hydrochloride; tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); UBC inhibitors; ubenimex; U0126; uracil mustard; uredepa; vapreotide; variolin B; veraresol; Veramine; verteporfin; vinorelbine; vinxartine; vitaxin; vinblastine; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglisinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrocidine sulfate; vinzolidine sulfate; vorozole; wortmannin; XL518; zanoteron; zeniplatin; zilascorub; zinostatin stimalamer; zinostatin; and zorubicin hydrochloride.

[0168] Other exemplary anticancer agents include: elbrozole (e.g., R-55104); dolastatin 10 (e.g., DLS-10 and NSC-376128); mibobulin isethionate (e.g., CI-980); NSC-639829; discodermolide (e.g., NVP-XX-A-296); ABT-751 (Abbott; e.g., E-7010); altorhyrtin A; altorhyrtin C; cemadotin hydrochloride (e.g., LU-103793 and NSC-D-669356); epothilone A; epothilone B; epothilone C; epothilone D; epothilone E; epothilone F; epothilone B N-oxide; epothilone A N-oxides; 16-aza-epothilone B; 21-aminoepothilone B; 21-hydroxyepothilone D; 26-fluoroepothilone; auristatin PE (e.g., NSC-654663); sobridotin (e.g., TZT-1027); LS-4559-P (Pharmacia; e.g., LS-4577); LS-4578 (Pharmacia; e.g., LS-477-P); LS-4477 (Pharmacia); LS-4559 (Pharmacia); RPR-112378 (Aventis); DZ-3358 (Daiichi); FR-182877 (Fujisawa; e.g., WS-9265B); GS-164 (Takeda); GS-198 (Takeda); KAR-2 (Hungarian Academy of Sciences); B SF-223651 (BASF; e.g., ILX-651 and LU-223651); SAH-49960 (Lilly / Novartis); SDZ-268970 (Lilly / Novartis); AM-97 (Armad / Kyowa Hakko); AM-132 (Armad); AM-138 (Armad / Kyowa Hakko); IDN-5005 (Indena); cryptophycin 52 (e.g., LY-355703); AC-7739 (Ajinomoto; e.g., AVE-8063A and CS-39.HC1); AC-7700 (Ajinomoto; e.g., AVE-8062; AVE-8062A; CS-39-L-Ser.HC1;and RPR-258062A); Vitilevuamide; Tubulysin A; Canadensol; CA-170 (Curis, Inc.); Centaureydin (e.g., NSC-106969); T-138067 (Tularik; e.g., T-67; TL-138067 and TI-138067); COBRA-1 (Parker-Hughes Institute; e.g., DDE-261 and WHI-261); H10 (Kansas State University); H16 (Kansas State University); Oncocidin Al (e.g., BTO-956 and DIME); DDE-313 (Parker-Hughes Institute); physianolide B; laulimalide; SPA-2 (Parker-Hughes Institute); SPA-1 (Parker-Hughes Institute; e.g., SPIKET-P); 3-IAABU (Cytoskeleton / Mount Sinai School of Medicine; e.g., MF-569); narcosine (e.g., NSC-5366); nascapine; D-24851 (Asta Medica; A-105972 (Abbott); hemiasterlin; 3-BAABU (Cytoskeleton / Mount Sinai School of Medicine; e.g., MF-191); TMPN (Arizona State University); vanadocene acetylacetonate; T-138026 (Tularik); Monsatrol; indanocine (i.e., NSC-698666); 3-IAABE (Cytoskeleton / Mount Sinai School of Medicine; e.g., MF-191); ToSinai School of Medicine; A-204197 (Abbott); T-607 (Tuiarik; e.g., T-900607); RPR-115781 (Aventis); eleutherobin (e.g., desmethyleleutherobin; desaetyleleutherobin; isoeleutherobin A; and Z-eleutherobin); caribeoside; caribeolin; halichondrin B; D-64131 (Asta Medica); D-68144 (Asta Medica); diazonamide A; A-293620 (Abbott); NPI-2350 (Nereus); Taccalonolide A; TUB-245 (Aventis); A-259754 (Abbott); diozostatin;(-)-Phenirahistine (e.g., NSCL-96F037); D-62638 (Asta Medica); D-62636 (Asta Medica); Myoseverin B; D-43411 (Zentaris; e.g., D-81862); A-289099 (Abbott); A-318315 (Abbott); HTI-286 (e.g., SPA-110; trifluoroacetate salt) (Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI); Resverastatin phosphate sodium sodium); BPR-OY-007 (National Institutes of Health); and SSR-250411 (Sanofi); goserelin; leuprolide; triptolide; homoharringtonine; topotecan; itraconazole; deoxyadenosine; sertraline; pitavastatin; clofazimine; 5-nonyloxytryptamine; vemurafenib; dabrafenib; gefitinib (IRESSA); erlotinib (TARCEVA); cetuximab (ERBITUX); lapatinib (TYKERB); panitumumab (VECTIBIX); vandetanib (CAPRELSA); afatinib / BIBW2992; CI-1033 / canertinib; neratinib / HKI-272; CP-724714; TAK-285; AST-1306; ARRY334543; ARRY-380; AG-1478; dacomitinib / PF299804; OSI-420 / desmethylerlotinib; AZD8931; AEE726; pelitinib / EKB-569; CUDC-101; WZ8040; WZ4002; WZ3146; AG-490; XL647; PD153035; 5-azathioprine; 5-aza-2'-deoxycytidine; 17-N-allylamino-17-demethoxygeldanamycin (17-AAG); 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; and BMS-599626.

[0169] In some embodiments, the combinations described herein are co-administered with an anti-cancer agent described above, where the anti-cancer agent has known activity against a particular cancer (e.g., gemcitabine is co-administered with the combinations described herein for the treatment of pancreatic cancer). The anti-cancer agent may be approved for use in treating a particular indication (e.g., a particular cancer) at concentrations, amounts, and using treatment regimens known in the art.

[0170] It is understood that modifications that do not substantially affect the activity of the various embodiments of this invention are also included within the definition of the invention provided herein. Although the invention has been described with reference to embodiments of the present disclosure, those skilled in the art will readily appreciate that the specific examples and studies detailed above are merely illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. [Example]

[0171] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

[0172] This example is a Phase 1b / 2 open-label, dose-ranging study of HBI-8000 (also known in the art as "chidamide" or "tucidinostat," and also referred to herein as the compound of Formula I) in combination with nivolumab in patients with advanced solid tumors, including melanoma, renal cell carcinoma (RCC), and non-small cell lung cancer (NSCLC). The study was endorsed / approved by the U.S. Department of Health and Human Services and conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki, and the protocol was approved by the institutional review boards or ethics committees of all participating centers. All patients provided written informed consent to participate prior to enrollment.

[0173] One objective of Phase 1b was to evaluate the safety and tolerability of HBI-8000 in combination with standard doses and regimens of nivolumab, determine the maximum tolerated dose (MTD) and / or recommended Phase 2 dose (RP2D) of HBI-8000, and assess the frequency and severity of toxicities of the combination as assessed by NCI CTC version 4.03. Additional objectives included assessing the pharmacokinetics (PK) of HBI-8000 and, if applicable, the effect of HBI-8000 on the electrocardiogram (ECG) QT interval (QTc interval) corrected for heart rate.

[0174] Three dose levels of HBI-8000 (20 mg, 30 mg, and 40 mg) administered orally twice weekly (BIW) were evaluated. Doses were taken approximately 30 minutes after a meal. The starting dose (20 mg) was selected based on its established pharmacokinetic profile in monotherapy in Japanese patients with T-cell lymphoma. Doses up to 40 mg BIW administered as a single agent in heavily pretreated lymphoma patients were safe, with manageable toxicity. In combination with nivolumab, the monoclonal antibody is unlikely to interfere with HBI-8000 metabolism, so we anticipated a safe starting dose of 20 mg when combined with standard-dose nivolumab.

[0175] Dose escalation decisions were based on a traditional 3 + 3 design and the observed incidence of dose-limiting toxicities (DLTs). Each treatment cycle was defined as 28 days. To be eligible for DLT evaluation, subjects had to have either experienced a DLT or received at least 75% of the planned HBI-8000 dose within the 28-day DLT evaluation period without a toxicity-related treatment delay. Subjects who experienced a DLT within the first 2 weeks after receiving 100% of the designated HBI-8000 dose were also eligible for DLT evaluation. Unacceptable toxicity was defined as grade 3 or higher non-hematologic and hematologic toxicity accompanied by clinical complications. Unacceptable toxicity observed within the first 28 days of HBI-8000 administration was considered a DLT. The RP2D was identified as the highest dose at which the DLT rate was less than 33.3%. HBI-8000 administration was continued until disease progression or unacceptable toxicity was observed. The efficacy of this combination was further evaluated at RP2D in an expansion cohort of selected patients based on objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, progression-free survival, and duration of response.

[0176] Patient Selection Adults aged 18 years or older with histopathologically or cytologically confirmed advanced nonuveal melanoma, RCC, or NSCLC eligible for nivolumab were eligible for screening, provided they were eligible for nivolumab. Patients were required to have ≥1 measurable target lesion as defined by RECIST v.1.1 (Eisenhauer 2009), an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (Oken 1982), and a life expectancy of at least 12 weeks. Key exclusion criteria included hypersensitivity to monoclonal antibodies, cardiovascular disease, uncontrolled hypertension, active brain metastases, leptomeningeal disease, severe gastrointestinal disease, autoimmune disease, severe infection, human immunodeficiency virus (HIV), and active hepatitis B.

[0177] evaluation Safety assessments included physical examination, vital signs, electrocardiogram, ECOG performance status, and laboratory tests. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 and classified using the Medical Dictionary for Regulatory Affairs (MedDRA) classification system version 18.0 or later.

[0178] Tumor assessments were performed every 8 weeks until treatment discontinuation, and then every 12 (±1) weeks in subjects in whom disease progression had not yet been observed, according to guidelines set forth in RECIST v.1.1 and Immune-Related Response Evaluation Criteria in Solid Tumors (iRECIST).

[0179] statistical analysis Statistical analyses of safety, tolerability, and antitumor activity were primarily descriptive. Toxicity was tabulated by type and grade. The safety population included all patients who received ≥1 dose of HBI-8000 and nivolumab. Continuous variables were summarized using descriptive statistics, and categorical variables were summarized using the number and percentage of each category. Pharmacokinetic parameters were derived using noncompartmental methods with Phoenix® WinNonlin® version 6.4 (Certara, LP, Princeton, NJ, USA).

[0180] Non-compartmental PK analysis Noncompartmental PK analysis of HBI-8000 was performed in Phase 1b using continuous plasma concentration data collected up to 24 hours after the first dose of HBI-8000 (Day 1 of Cycle 1, C1D1) and up to 7 hours after the ninth dose (C2D1). In conjunction with PK analysis, 12-lead continuous digital ECGs were recorded (in a controlled environment to minimize digital noise) using a Holter monitor on baseline (within 1–7 days before C1D1 administration) and on C1D1 (Phase 1b only). Triple-duplicate 10-second ECGs were extracted from Holter flashcards on baseline and at matching time points on C1D1 up to 4 hours after dosing, and PR, QRS, RR, and QT intervals were analyzed in a central ECG laboratory. Meal times (breakfast) were standardized on both days and were taken after or ≥1 hour before the scheduled extraction time of the triple-duplicate ECG. The measured QT data were heart rate corrected using Fridericia correction (QTcF).

[0181] result Seventeen patients were enrolled in Phase 1b from August 2016 to August 2017: three at the 20 mg, seven at the 30 mg, and seven at the 40 mg dose levels. Patient characteristics are summarized in Table 1. Other than the underlying cancer diagnosis, there were no apparent differences in baseline characteristics that would affect safety assessments.

[0182] patient Demographic and other baseline characteristics

[0183] [Table 2]

[0184] exposure: Overall, the median (min, max) duration of study drug exposure was 2.8 months (0.6, 28.3) for HBI8000 and 2.3 months (0.5, 22.5) for nivolumab. The median (min, max) total number of completed cycles was 3.0 cycles (1, 31) for HBI-8000 and 2.5 cycles (1, 24) for nivolumab.

[0185] safety Dose-limiting toxicity (DLT) A total of 17 patients were enrolled in the study. Two patients were not evaluable for DLTs. One patient in the 30 mg BIW dose cohort prematurely withdrew consent, and one patient in the 40 mg BIW dose cohort discontinued treatment prematurely because a higher dose of steroids than permitted by the protocol was required to manage their underlying pulmonary disease. Neither patient received at least 75% of the HBI-8000 dose within the 28-day DLT evaluation period. These patients were included in the overall safety analysis but were deemed not evaluable for DLTs.

[0186] Of the 15 DLT-evaluable patients, the first three were in the 20 mg dose cohort, followed by three in the 30 mg dose cohort. None experienced DLTs. Of the six patients in the 40 mg cohort, one patient with melanoma experienced grade 3 headache 24–48 hours after receiving the first dose and grade 3 diarrhea after the third dose, and one patient with RCC experienced grade 3 fatigue on the day of HBI-8000 administration. These were considered DLTs. Therefore, 40 mg was deemed to have exceeded the MTD. Three additional patients were evaluated at the 30 mg B1W dose level. No DLTs were observed. The RP2D for further evaluation of the safety and efficacy of HBI-8000 in combination with nivolumab was determined to be 30 mg B1W.

[0187] Treatment-emergent adverse events (TEAEs) All 17 patients who received HBI-8000 also received nivolumab. These patients were included in the safety analysis. The mean duration of HBI-8000 treatment was 6.2 months. A detailed summary of TEAEs and treatment modifications attributable to HBI-8000 alone, nivolumab alone, or both is provided in Table 2.

[0188] [Table 3]

[0189] All 17 patients experienced TEAEs, although not all TEAEs were related to HBI-8000, nivolumab, or both. TEAEs related to the combination of both HBI-8000 and nivolumab were observed in 11 (64.7%) subjects, and TEAEs related to HBI-8000 alone or nivolumab alone were observed in 10 (58.8%) subjects. Six subjects experienced TEAEs attributable to the combination and TEAEs related to HBI-8000 alone. The incidence of TEAEs related to HBI-8000 alone appeared to increase with increasing HBI-8000 dose. However, no similar trend was observed for TEAEs associated with the combination or nivolumab alone. Regardless of any differences in incidence, TEAEs leading to discontinuation appeared to be similar across the three dose levels.

[0190] Two patients experienced only grade 1 and 2 TEAEs, and 15 experienced grade 3 or higher TEAEs. Note that TEAEs related to HBI-8000 or nivolumab, either alone or in combination, were rare. Furthermore, grade ≥3 TEAEs were rare, regardless of causality (Tables 3A–3C).

[0191] TEAEs observed in ≥40% of all subjects were fatigue, decreased appetite, dyspnea, decreased platelet count, anemia, weight loss, nausea, diarrhea, and peripheral edema. More TEAEs were reported with HBI-8000 at 30 mg and 40 mg compared with 20 mg, but there was no clear increase in grade ≥3 events at 40 mg. When examining TEAEs associated with HBI-8000, regardless of severity, there appeared to be a slight trend toward an increase at higher doses. However, when examining TEAEs associated with the combination of HBI-8000 and nivolumab, this trend was not detected.

[0192] Grade ≥3 TEAEs observed in ≥15% of patients were fatigue, hypophosphatemia, decreased lymphocyte count, increased lipase level, and hypoxia. These were asymptomatic except for fatigue and hypoxia. Grade ≥3 TEAEs occurred in all HBI8000 dose cohorts.

[0193] SAEs were observed in 11 patients, with four experiencing SAEs related to nivolumab alone. No SAEs were attributed to HBI-8000 alone or the combination of HBI-8000 and nivolumab. TEAEs leading to discontinuation of both HBI-8000 and nivolumab were observed in three patients (17.6%). One patient died from a TEAE unrelated to either HBI-8000 or nivolumab. No clear differences in the incidence, severity, causality, or seriousness of TEAEs were detected among the dose levels tested.

[0194] [Table 4]

[0195] [Table 5]

[0196] [Table 6]

[0197] Pharmacokinetics HBI-8000 concentration After administration of a single dose of HBI-8000 alone on Day 1 (C1D1) of Cycle 1, mean plasma concentrations of HBI-8000 were generally similar for the 20 mg and 30 mg doses. Mean HBI-8000 concentrations were higher for the 40 mg dose compared with the 30 mg dose at all sampling time points up to 24 hours post-dose. Following 4 weeks of continuous dosing on a BIW schedule in Cycle 1, a similar trend was observed for HBI-8000 concentrations up to 7 hours post-dose on C2D1. Of note, plasma collections were performed to determine the PK of HBI-8000 for the first and ninth doses of HBI-8000 before administration of nivolumab. See Figures 1A-1B.

[0198] HBI-8000 Pharmacokinetic Parameters In the 20 mg, 30 mg, and 40 mg BIW cohorts, the median time to peak plasma concentration (tmax) was 5 to 7 hours after dosing (Table 4). Exposure parameters [Cmax, AUC 0~24 , and / or AUC 0~7 ] was generally similar between the 20 mg and 30 mg doses on C1D1. HBI-8000 exposure was observed to be increased with the 40 mg dose compared to the 30 mg dose at both the first dose (C1D1) and the ninth dose (C2D1).

[0199] Comparison of pharmacokinetic parameters between the first and ninth doses showed no significant accumulation of HBI-8000. The geometric mean ratios of HBI-8000 exposure parameters (C2D1:C1D1) were 1.08-1.18 for Cmax and 1.08-1.18 for AUC across the 30 mg and 40 mg BIW regimens. 0~7 The range was 1.36 to 1.37.

[0200] [Table 7]

[0201] Analysis of QTcF by time-matched plasma concentrations of HBI-8000 12-lead Holter electrocardiogram measurement All patients in the pharmacodynamics cohort (N = 16) had baseline QTcF or QT interval values ​​below 450 ms on Holter ECG. After administration of a single dose of 20, 30, or 40 mg of HBI-8000 on C1D1, the change (Δ) from baseline ventricular heart rate remained essentially stable across doses evaluated over the 0-4 hour observation interval. This indicates that the heart rate-corrected QT interval (QTcF; QTc corrected using the Fridericia correction formula) was unlikely to be affected by changes in heart rate. This result was supported by a scatterplot of log QTcF versus log RR values ​​for individual patients. No statistically significant (p = 0.1588) unidirectional trend was observed between ECG intervals (see Figure 2). Therefore, this observation ruled out the possibility of heart rate being a confounding factor when assessing the effect of HBI-8000 plasma concentrations on QTcF.

[0202] At the 30 mg dose, mean and median ΔQTcF values ​​showed no discernible change between time points (median 0 to -1.5 ms), whereas at the 40 mg dose, decreases were observed (median -3.0 to -11.5 ms), with the highest median decrease observed 4 hours post-dose (i.e., -11.5 ms), the final time point being C max Two patients receiving the 20 mg BIW dose of HBI-8000 demonstrated left or right bundle branch block, which precluded estimation of QT intervals. As a result, QTcF assessment was possible in only one of three patients in the 20 mg dose cohort.

[0203] Relationship between HBI-8000 concentration / exposure and ECG QT interval An inverse correlation was observed between ΔQTcF and HBI-8000 concentrations, with QTcF decreasing with increasing HBI-8000 exposure. Concentration-QT modeling revealed a negative slope between ΔQTcF and HBI-8000 concentrations (slope estimate [95% CI]: -0.02154 [-0.03426, -0.008814]). This inverse correlation between plasma concentrations and ΔQTcF revealed by concentration-QT modeling was consistent with the trend observed at the 40 mg dose, although a similar inverse correlation was not detected at the 30 mg dose. Examination of model residuals versus time ruled out the possibility of time as a potential confounding factor affecting the statistical results, and no positive hysteresis was found.

[0204] The model calculates the geometric mean C for 20, 30, and 40 mg HBI-8000 doses. max We predicted that the mean ΔQTcF at 10 ms was -2.3, -2.5, and -5.6 ms, respectively (Table 5), with an average upper 90% confidence limit of -1.1 to -2.8 ms, well below the 10 ms threshold indicating a significant effect (Table 5).

[0205] [Table 8]

[0206] This substudy was designed to investigate whether maximum plasma concentrations of HBI-8000 would prolong QTcF. Holter ECGs were collected up to 4 hours after dosing, but the tmax in this study was longer than the 4 hours predicted from a previous single-agent pharmacokinetic study of HBI-8000 conducted in Japan. Thus, the median plasma concentrations at 4 hours were 17%, 19%, and 15% lower than the Cmax values ​​for the 20, 30, and 40 mg doses, respectively. Because no hysteresis effect was observed, and ΔQTcF showed an inverse correlation with HBI-8000 concentration, with greater decreases in QTcF at higher concentrations and dose levels, this discrepancy with tmax is not expected to affect the conclusion that there is a lack of significant effect on QTcF in this dose range. No QTcF values ​​in this study were >450 ms, and no ΔQTcF values ​​were >30 ms. It was concluded that HBI-8000, at the dose and regimen administered, did not prolong QTcF.

[0207] Preliminary antitumor effects Of the 17 enrolled subjects, 15 underwent tumor evaluation after receiving HBI-8000 and nivolumab. Signs of antitumor activity were clearly demonstrated in melanoma, RCC, and NSCLC (Figure 3). Tumor response was assessed by RECIST v.1.1. All five melanoma patients responded, with one complete response (CR) and four partial responses (PR). Of the three NSCLC patients, one achieved PR, two stable disease, and no disease progression was observed. Of the seven RCC patients, two achieved PR, one stable disease, and four progressed. Tumor responses were observed at all dose levels (Figure 3).

[0208] The time course of clinical response was also analyzed (Figure 4). Antitumor effects were observed early and became clinically evident during subsequent follow-up. The earliest objective response was observed at the first scheduled tumor assessment by imaging 8 weeks after treatment at the end of cycle 2. The longest time to response was 32 months after the start of treatment in one patient; however, nivolumab and HBI-8000 were discontinued in this patient 16 months after a PR was observed.

[0209] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It is to be understood that various alternatives to the embodiments of the invention described herein can be employed in practicing the invention. The scope of the invention is defined by the following claims, and it is intended that methods and structures within the scope of such claims and their equivalents be covered thereby.

Claims

1. A method for treating a subject with an HDAC inhibitor (HDACi), comprising administering to the subject an effective amount of HDACi that does not cause an increase in QTc, QTcF, or heart rate (HR).

2. 2. The method of claim 1, wherein administering the HDACi causes a decrease in QTc, QTcF, or HR in the subject.

3. 3. The method of claim 1 or claim 2, wherein the HDACi is administered to a subject in increasing doses, resulting in a reduction in QTcF.

4. The method of any one of claims 1 to 3, wherein administering said HDACi to said subject results in no change in HR or in a decrease in HR.

5. The method of any one of claims 1 to 4, wherein said HDACi inhibits class I and class IIb HDACs.

6. The method of claim 5, wherein the HDACi inhibits one or more of HDAC1, HDAC2, HDAC3, or HDAC10.

7. The method of claim 6, wherein the HDACi inhibits all of HDAC1, HDAC2, HDAC3, and HDAC10.

8. The method of any one of claims 1 to 7, wherein the HDACi is tucidinostat (chidamide).

9. The method according to any one of claims 1 to 8, wherein the effective amount is an amount effective for treating cancer.

10. The method of any one of claims 1 to 9, wherein the cancer is an advanced solid tumor or a blood cancer.

11. 11. The method of claim 10, wherein the cancer is one or more of malignant melanoma, renal cell carcinoma, or non-small cell lung cancer (NSCLC).

12. 12. The method of any one of claims 1 to 11, wherein the effective amount is from about 5 mg to about 80 mg per day.

13. 13. The method of claim 12, wherein the HDACi is administered as an oral dose.

14. 14. The method of claim 13, wherein the HDACi is administered at a dose of about 20 mg, about 30 mg, or about 40 mg once daily during a cycle.

15. 15. The method of claim 14, wherein the cycle is at least about two days in duration.

16. 16. The method of claim 15, wherein the cycle is from about 1 week to about 10 weeks in duration.

17. 17. The method of claim 16, further comprising administering an anti-cancer agent, a PD-1 inhibitor, or a PD-L1 inhibitor.

18. 18. The method of claim 17, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered on day 2 of the cycle.

19. 19. The method of claim 18, wherein the PD-1 inhibitor is an anti-PD-1 antibody.

20. 20. The method of claim 19, wherein the anti-PD-1 antibody is nivolumab.

21. 21. The method of claim 20, wherein nivolumab is administered to the subject at a dose of 240 mg per administration every two weeks.

Images