Methods and compositions comprising heart tolerant HDAC inhibitors

Abstract

Provided herein are methods including 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 the treatment of cancer.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application 63 / 441,131, filed January 25, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0003] This invention relates to compounds including HDAC inhibitors and the use of such compounds. The invention also relates to methods and uses of HDAC inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, and other checkpoint inhibitors. Background Technology

[0004] Many commonly used medications are known to disrupt cardiac rhythm and prolong the QT interval, leading to fatal ventricular arrhythmias and sudden cardiac death. For example, drugs such as antihistamines, antimicrobials, antidepressants, antibiotics, and anticancer drugs are known to affect cardiac rhythm.

[0005] Cancer is a leading cause of morbidity and mortality worldwide, and its standards of care have improved significantly over the years, including the use of known anticancer drugs, such as epigenetic modulators (e.g., histone deacetylase inhibitors (HDACi)), in combination with immuno-oncology agents targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell 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 prolongation. Predicting the risks involved with most drugs, especially anticancer drugs, is difficult because these drugs are often structurally and pharmacologically diverse. Therefore, there is a need in the art for novel anticancer therapies that cause zero to minimal disruption of cardiac rhythm. This article provides solutions to these and other problems in the art. Summary of the Invention

[0006] This document specifically provides methods comprising compounds including HDAC inhibitors (HDACi). The methods include administering an effective amount of HDACi to a subject such that the administration of HDACi does not cause an increase 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, PD-L1 inhibitor, and / or PD-1 inhibitor is an antibody. In some embodiments, the methods are used for the treatment of cancer.

[0007] In some embodiments of this disclosure, a method of treating a subject with a therapeutically effective amount of HDACi without causing an increase in QTc, QTcF, or heart rate (HR) is provided, wherein the HDACi comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, a stereoisomer, a prodrug, an enantiomer, a diastereomer, a hydrate, a cocrystal, or a polymorph thereof, wherein formula I is:

[0008]

[0009] In some embodiments, the compound of Formula I is N-(2-amino-4-fluorophenyl)-4-[[[(2E)-1-oxo-3-(3-pyridyl)-2-propen-1-yl]amino]methyl]benzamide or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, the method further includes administering a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.

[0010] Some other embodiments of this disclosure include a method for treating cancer, the method comprising administering a therapeutically effective amount of HDACi to a subject, wherein administering 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 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 HDACi to each subject at an increased dose results in a decrease in mean QTcF or median QTcF. In some embodiments, administering 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 includes administering a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.

[0011] Some other embodiments of this disclosure include a pharmaceutical composition comprising an effective amount of HDACi, wherein the effective amount is effective in treating cancer and does not cause an increase in QTc, QTcF, or heart rate (HR).

[0012] In some embodiments, HDACi inhibits Class I and Class IIb HDACs. In some embodiments, HDACi inhibits one or more of HDAC1, HDAC2, HDAC3, or HDAC10. In some embodiments, HDACi inhibits all of HDAC1, HDAC2, HDAC3, and HDAC10. In some embodiments, HDACi is tucidinostat (chidamide / HBI-8000).

[0013] In some embodiments, this document describes combinations (e.g., combination therapies, such as therapeutic methods and uses, kits, and compositions) for treating diseases including cancer. The kits comprise combinations of any of the embodiments described herein or pharmaceutical compositions of the embodiments described herein. In some embodiments, the kit further includes at least one administration device. In some embodiments, the components in the kit are sterilized. In some embodiments, the combinations described herein comprise HDAC inhibitors and anticancer agents, PD-L1 inhibitors, PD-1 inhibitors, and / or other CTLA-4 inhibitors. In some embodiments, the combinations described herein comprise HDAC inhibitors and anticancer agents.

[0014] In some implementations, the effective dose of HDACi is the dose that is effective in treating cancer. In some implementations, the cancer is an advanced solid tumor. In some implementations, the solid tumor is cancer, such as melanoma, renal cell carcinoma, or non-small cell lung cancer (NSCLC). In some implementations, the cancer may be a hematologic malignancy, such as lymphoma, non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, Reed-Sternberg disease, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), or chronic lymphocytic leukemia (CLL). In some implementations, the cancer is Hodgkin lymphoma or Reed-Sternberg disease. In some implementations, the cancer is relapsed or refractory peripheral T-cell lymphoma (“RR / PTCL”) or relapsed or refractory aggressive adult T-cell lymphoma (“RR / ATL”).

[0015] In some embodiments, the effective amount of the compound is from about 5 mg to about 80 mg daily. In some embodiments, HDACi is administered as an oral dose. In some embodiments, HDACi is administered once daily at a dose of about 20 mg, about 30 mg, or about 40 mg during a cycle. In some embodiments, the duration of the cycle is at least about two days. In some embodiments, the duration of the cycle is from about one week to about four weeks. In some embodiments, the method further includes administering a PD-1 inhibitor or a 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 every two (2) weeks. In some other embodiments, the anti-PD-1 antibody may be administered according to an established regimen, such as those provided in the package insert.

[0016] Some embodiments of this disclosure include a first pharmaceutical composition and a second pharmaceutical composition. The first pharmaceutical composition includes the HDACi and the second pharmaceutical composition includes 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.

[0017] In some embodiments, the anticancer agent, the PD-1 inhibitor, the PD-L1 inhibitor, and / or the CTLA-4 inhibitor are small molecule compounds, nucleic acids, peptides, proteins, antibodies, peptibody, diabody, minibody, single-chain variable fragment (ScFv), or fragments or variants thereof. In some embodiments, at least one of the CTLA-4 inhibitor, PD-L1 inhibitor, or PD-1 inhibitor is an antibody. In some embodiments, the inhibitor antibody is a monoclonal antibody. In some embodiments, the inhibitor antibody includes human antibodies, mouse antibodies, chimeric antibodies, humanized antibodies, or chimeric humanized antibodies. 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 from about 0.1 mg / kg to about 30 mg / kg. In some embodiments, the inhibitor antibody is present in an amount from about 0.5 mg / kg to about 15 mg / kg. In some embodiments, the inhibitor antibody is present in amounts of about: 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 5 mg / kg, 10 mg / kg, or 20 mg / kg. In some embodiments, the combination is suitable for parenteral administration to cancer patients. In some embodiments, the parenteral administration includes intravenous (IV) administration.

[0018] In other implementations, 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).

[0019] In other implementations, the PD-1 inhibitor is an antibody, such as nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR001, SHR-1210, or MEDI0680.

[0020] In other implementations, the CTLA-4 inhibitor is an antibody including ipilimumab.

[0021] In some embodiments, 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, 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 schwannoma (MPNST). In some embodiments, the cancer is non-small cell lung cancer (NSCLC), hepatocellular carcinoma, 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 lymphoma (NHL), Hodgkin lymphoma, Reed-Sternberg disease, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), or chronic lymphocytic leukemia (CLL).

[0022] In some implementations, the cancer patient is untreated. In some embodiments, the cancer patient is untreated for non-small cell lung cancer (NSCLC), hepatocellular carcinoma, 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 treatment. In some embodiments, the combination is administered to the cancer patient after treatment with at least one anticancer therapy. In some embodiments, the anticancer therapy includes chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, or combinations thereof. In some embodiments, the cancer is resistant to at least one anticancer agent.

[0023] In some embodiments, the compound of Formula I and the inhibitor in the combination are administered simultaneously or sequentially. In some embodiments, the compound of Formula I is administered 2 to 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 concomitantly on day 1 of the administration 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. In some embodiments, the regimen includes a rest period of at least 1 day between consecutive administration periods. In some embodiments, the compound of Formula I in the combination is administered 2 to 3 times per week in the regimen, and the PD-L1 inhibitor, PD-1 inhibitor, and / or CTLA-4 inhibitor is administered every 2 to 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 to 3 weeks.

[0024] 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 the subject's QTc, QTcF, or HR. In some embodiments, administration of HDACi to a subject in need at an increased dose results in a decrease in QTcF. In some embodiments, the method does not cause a change in HR or causes a decrease in HR.

[0025] In some embodiments, the method of treating cancer inhibits metastasis of the cancer in the patient. In some embodiments, the method of treating cancer reduces the tumor or tumor burden in the patient. In some embodiments, the method of treating cancer inhibits pre-existing metastasis of the cancer in the patient. In some embodiments, the method of treating cancer prolongs the time to disease progression of the cancer in the patient. In some embodiments, the method of treating cancer prolongs the survival of the patient. In some embodiments, the method of treating cancer increases the progression-free survival of the patient. Attached Figure Description

[0026] The novel features of the invention are particularly described in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description, along with the accompanying drawings, which illustrate illustrative embodiments utilizing the principles of the invention, in which:

[0027] Figures 1A and 1B show the mean HBI-8000 plasma concentrations in patient treatment groups comprising a combination of a compound of Formula I and a PD-1 inhibitory antibody. As seen in the legend, different colors are used to distinguish the dosage of each treatment.

[0028] Figure 2 shows a plot of log QTcF versus log RR for period 1, including the patient regression line and the overall regression line.

[0029] Figure 3 shows the change in QTcF from baseline relative to HBI-8000 concentration, with an overall regression line and a 90% confidence band. As seen in the legend, different colors are used to distinguish the dose of each treatment.

[0030] Figure 4 shows a waterfall plot of the maximum variation in target lesions according to tumor type.

[0031] Figure 5 shows a swimlane diagram of the tumor response during the study treatment process. Detailed Implementation

[0032] definition

[0033] All patents, applications, publications, and other publications cited herein are incorporated herein 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 pertains. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence known in the field of chemistry. If there is a difference between the described structure and the name given to that structure, the described structure will be given more weight. Where the stereochemistry of a structure or part thereof is not indicated in the described structure or part thereof, the described structure will be interpreted to encompass all its possible stereoisomers.

[0034] Any methods, apparatus, and materials similar to or equivalent to those described herein may be used in the practice of this invention. The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of this disclosure. Where multiple definitions exist for terms herein, the definitions in this section shall prevail unless otherwise stated. The headings used herein are for organizational purposes only and are in no way limiting of the invention described herein.

[0035] The QT interval is a measurement of the total time from ventricular depolarization to complete repolarization. This measurement begins at the start of the Q wave and ends at the end of the T wave, with QT expressed in milliseconds. The QT interval as described herein follows its plain and ordinary meaning as understood in the art.

[0036] “QTc” indicates the corrected QT interval. The corrected QT interval is an estimate of the QT at a heart rate of 60 bpm (heart beats per minute) to allow for comparison of values ​​at different heart rates. As described herein, “QTc” has its usual and common meaning as understood in the art.

[0037] Using Bazett's formula: QTc = QT / (RR) 1 / 2 Perform "QTc" correction, where RR is the interval between one R peak and the next R peak.

[0038] Using Fridericia: QT(Fri)=QT / (RR) 1 / 3 Perform "QTc" correction, where RR is the interval between one R peak and the next R peak.

[0039] "QTcF" indicates the cube root formula QTcF = QT / (RR) obtained through Fridricia. 1 / 3 The corrected QT interval. As described herein, "QTcF" refers to its usual and common meaning as understood in the art.

[0040] "Heart rate" (or "HR") indicates the number of heartbeats per minute or 60 / RR, where RR is the R-R interval per second.

[0041] The terms “P wave,” “Q wave,” “T wave,” “RR,” “QRS complex,” “PR interval,” “ST segment,” and “U wave” as described herein shall have their usual and common meanings as understood in the art.

[0042] The term "PD-L1 inhibitor" refers to any part (e.g., compound, nucleic acid, peptide, antibody) that reduces, inhibits, blocks, eliminates, or interferes with the activity, inhibition, binding of PD-L1 to its receptor PD-1, or expression of PD-L1 (e.g., programmed cell death 1 ligand; PD-L1 (CD274); GI: 30088843), including variants, isotypes, species homologs of human PD-L1 (e.g., mouse), and analogs that share at least one common epitope with PD-L1. PD-L1 inhibitors include molecules and macromolecules such as, for example, compounds (small molecule compounds), nucleic acids, peptides, antibodies, peptide bodies, biantibodies, mini-antibodies, single-chain variable fragments (ScFv), and fragments or variants thereof. Therefore, as used herein, a PD-L1 inhibitor refers to any part that antagonizes PD-L1 activity, its binding to PD-1, or its expression. The potency of a PD-L1 inhibitor can be measured, for example, by its inhibitor concentration at 50% (half-maximum inhibitory concentration or IC50). 50PD-L1 inhibitors include the exemplary compounds and compositions described herein. PD-L1 inhibitor antibodies refer to PD-L1 inhibitors as monoclonal or polyclonal antibodies as described herein.

[0043] The terms “dvalumab”, “avirumab”, “atezolizumab”, “BMS-936559”, “STI-A1010”, “STI-A1011”, “STI-A1012”, “STI-A1013”, “STI-A1014” and “STI-A1015” are used in accordance with their common and general meaning as understood in the art.

[0044] The term "PD-1 inhibitor" refers to a portion (e.g., compound, nucleic acid, peptide, antibody) that reduces, inhibits, blocks, eliminates, or interferes with the activity or expression of PD-1 (e.g., programmed cell death protein 1; PD-1 (CD279); GI: 145559515), including variants, isotypes, species homologs of human PD-1 (e.g., mouse), and analogs that share at least one common epitope with PD-1. PD-1 inhibitors include molecules and macromolecules such as, for example, compounds, nucleic acids, peptides, antibodies, peptide bodies, biantibodies, mini-antibodies, single-chain variable fragments (ScFv), and fragments or variants thereof. Therefore, as used herein, PD-1 inhibitor refers to any portion that antagonizes PD-1 activity or expression. The potency of a PD-1 inhibitor can be measured, for example, by its inhibitor concentration at 50% (half-maximum inhibitor concentration or IC50). 50 PD-1 inhibitors include the exemplary compounds and compositions described herein. PD-1 antibodies refer to PD-1 inhibitors as monoclonal or polyclonal antibodies as described herein.

[0045] The terms “nivolumab”, “pembrolizumab”, “pildizumab”, “AMP-224”, “REGN2810”, “PDR001”, “SHR-1210”, “SAR-439684” and “MEDI0680” are used in accordance with their usual and common meanings as understood in the art.

[0046] The term "CTLA-4 inhibitor" refers to a portion (e.g., compound, nucleic acid, peptide, antibody) that reduces, inhibits, blocks, eliminates, or interferes with the activity or expression of CTLA-4, including variants, isotypes, species homologs of human CTLA-4 (e.g., mouse), and analogs that share at least one common epitope with CTLA-4. CTLA-4 inhibitors include molecules and macromolecules such as, for example, compounds, nucleic acids, peptides, antibodies, peptide bodies, biantibodies, mini-antibodies, single-chain variable fragments (ScFv), and fragments or variants thereof. Therefore, as used herein, a CTLA-4 inhibitor refers to any portion that antagonizes the activity or expression of CTLA-4. The potency of a CTLA-4 inhibitor can be measured, for example, by its inhibitor concentration at 50% (half-maximum inhibitor concentration or IC50). 50 CTLA-4 inhibitors include the exemplary compounds and compositions described herein. CTLA-4 antibodies refer to CTLA-4 inhibitors as monoclonal or polyclonal antibodies as described herein.

[0047] The term "ipilimumab" is used in accordance with its usual and common meaning as understood in the art.

[0048] The terms “polypeptide” and “protein” are used interchangeably in this document and refer to any molecule that comprises at least two or more amino acids.

[0049] The term "inhibitor antibody" refers to a monoclonal or polyclonal antibody that binds to its substrate or target with sufficient strength to inhibit the activity of the substrate or target. As used herein, "inhibitor antibody" includes PD-L1 inhibitor antibodies, PD-1 inhibitor antibodies, and / or CTLA-4 inhibitor antibodies.

[0050] The term "effective amount" refers to an amount of a therapy (e.g., used in the methods provided herein) sufficient to achieve the stated purpose or otherwise achieve the effect of its administration. An "effective amount" may be sufficient to reduce and / or improve the progression, development, relapse, severity, and / or duration of a given disease, disorder, or condition and / or associated symptoms, or sufficient to reduce the activity or binding level of a peptide (e.g., PD-L1, PD-1, CTLA-4). An "effective amount" can also be a "therapeutic effective amount," which refers to an amount sufficient to provide a therapeutic benefit, such as, for example, reducing or improving the exacerbation or progression of a given disease, disorder, or condition, reducing or improving the relapse, development, or onset of a given disease, disorder, or condition, and / or improving or enhancing the preventive or therapeutic effect of another therapy. The "therapeutic effective amount" used in the methods described herein may enhance the therapeutic potency of another therapeutic agent.

[0051] The term "regimen" refers to a protocol for administering and timed application of one or more therapies (e.g., the methods described herein) to treat the disease, condition, or illness described herein. A regimen may include active application periods and rest periods as known in the art. An active application period includes the duration of administration of the combinations and compositions described herein and the potency of such combinations and compositions. A rest period of a regimen described herein includes periods during which compounds are not actively administered, and in some cases, includes periods during which the potency of such compounds can be minimized. Combinations of active application and rest periods in regimens described herein can increase the potency and / or duration of administration of the combinations and compositions described herein.

[0052] The term "therapies" refers to any regimen, method, and / or agent that can be used to prevent, treat, manage, or improve a disease, condition, or illness, or one or more symptoms thereof. In some cases, the term refers to an active agent, such as the anticancer agent described herein. The term "therapy" can also refer to antiviral therapy, antibacterial therapy, antifungal therapy, anticancer therapy, biological therapy, supportive therapy, and / or other therapies known to those skilled in the art (e.g., medical professionals, such as physicians) for the treatment, management, prevention, or improvement of a disease, condition, or illness, or one or more symptoms thereof.

[0053] The term "patient" or "subject" refers to a mammal, such as a human, cow, rat, mouse, dog, monkey, ape, goat, sheep, cow, or deer. Typically, as described in this article, a patient is a human.

[0054] The term “inhibition” (or “inhibit” or “inhibiting”) refers to a reduction in the activity, binding, or expression of a polypeptide, or a reduction or improvement in a disease, condition, or symptom thereof. As used herein, “inhibition” may include partially or completely blocking stimulation, reducing, preventing, or delaying activation or binding, or inactivating, desensitizing, or downregulating the activity or binding of a protein or enzyme.

[0055] The antibodies described herein can be polyclonal or monoclonal, and include xenogeneic, allogeneic, or syngeneic forms and their modified versions (e.g., humanized or chimeric). "Antibody" is intended to refer to a lymphocyte-derived polypeptide product within the immunoglobulin class of polypeptides capable of binding to a specific molecular antigen and consisting of two pairs of identical polypeptide chains, each pair having a heavy chain (approximately 50–70 kDa) and a light chain (approximately 25 kDa), with each amino-terminal portion of each chain comprising a variable region of approximately 100 to approximately 130 or more amino acids, and each carboxyl-terminal portion of each chain comprising a constant region. (See Borrebaeck (ed.) (1995) Antibody Engineering, 2nd ed., Oxford University Press; Kuby (1997) Immunology, 3rd ed., WH Freeman and Company, New York). Specific molecular antigens that can be bound by the antibodies described herein include PD-L1, PD-1, CTLA-4, and their epitopes.

[0056] The term "monoclonal antibody" refers to a group of antibody molecules that contain one antigen-binding site capable of responding to an immune response to a specific epitope of an antigen, while the term "polyclonal antibody" refers to a group of antibody molecules that contain multiple antigen-binding sites capable of interacting with a specific antigen. Monoclonal antibodies typically exhibit a single binding affinity for the specific antigen to which they respond to an immune response. For example, the monoclonal antibodies used according to the present invention can be made by a variety of techniques, including, for example, hybridoma methods (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 edition, 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA methods (see, for example, U.S. Patent No. 4,816,567), phage display technology (see, for example, Clackson et al., Nature, 352:624-628 (1991); Marks et al., J 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); and Lee et al., J.Immunol.Methods284(1-2):119-132(2004), and techniques for generating human or human-like antibodies in animals having partial or complete human immunoglobulin loci or genes encoding human immunoglobulin sequences (see, for example, WO 1998 / 24893; WO1996 / 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 lmmunol.7:33 (1993); US 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). .

[0057] The monoclonal antibodies described herein also include “chimeric” antibodies (immunoglobulins) in which a portion of the heavy and / or light chains are identical or homologous to the corresponding sequences in antibodies derived from a specific species or belonging to a specific antibody class or subclass, while the remainder of the chains are identical or homologous to the corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, provided they exhibit the desired biological activity (US Patent 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.

[0058] When used with respect to antibodies or functional fragments thereof (e.g., "humanized antibodies"), the term "human" refers to an antibody or functional fragment thereof having a human variable region or a portion thereof corresponding to a human germline immunoglobulin sequence. Such human germline immunoglobulin sequences are described in Kabat et al. (1991), Sequences of Proteins of Immunological Interest, 5th Edition, Department of Health and Human Services, NIH Publication No. 91-3242. In the context of this invention, human antibodies may include antibodies that bind to PD-L1 or variants thereof as described herein.

[0059] In some cases, human antibodies are antibodies having an amino acid sequence corresponding to that of antibodies produced by humans and / or antibodies produced using any techniques disclosed herein for manufacturing human antibodies. 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. Mal. Biol., 222:581 (1991). Furthermore, methods used to prepare human monoclonal antibodies include those described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boemer et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk and van deWinkel, Curr. Opin. Pharmacol., 2:368-74 (2001). Human antibodies can be prepared by administering antigens to transgenic animals that have been modified to produce such antibodies in response to antigen challenge, but whose endogenous loci have lost their ability, such as immunized xenomice (see, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 relating to XENOMOUSE technology). Also see, for example, Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006), relating to human antibodies generated via human B-cell hybridoma technology.

[0060] "Humanized antibody" refers to an antibody made from non-human cells having a variable region or a variable and constant region, wherein the variable region or the variable and constant region has been altered to more closely resemble antibodies made from human cells. For example, 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 this invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced through random or site-specific mutagenesis in vitro or through somatic mutations in vivo), such as in the CDR. Humanized antibodies may also include antibodies in which a germline CDR sequence derived from another mammalian species (such as a mouse) has been grafted onto a human frame sequence.

[0061] Humanized forms of non-human (e.g., mouse) antibodies are antibodies containing a minimal sequence derived from a non-human immunoglobulin. In some embodiments, the humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the hypervariable region of the receptor are replaced by residues from the hypervariable region of a non-human species (donor antibody) (such as a mouse, rat, rabbit, or non-human primate) having the desired specificity, affinity, and / or ability. In some cases, the framework (“FR”) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, the humanized antibody may include residues not found in the receptor antibody or the donor antibody. These modifications can be made to further improve antibody properties, such as binding affinity. Typically, humanized antibodies will include substantially all of at least one, usually two, variable domains, wherein all or substantially all of the hypervariable loops correspond to those of non-human immunoglobulin sequences, and all or substantially all of the FR regions are those of human immunoglobulin sequences, although the FR regions may include one or more individual FR residue substitutions that improve antibody properties such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FR is typically no more than 6 in the H chain and no more than 3 in the L chain. Humanized antibodies may optionally also include at least a portion of the immunoglobulin constant region (Fc), which may be a human immunoglobulin. Exemplary methods and humanized antibodies include those described by 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. Patent Nos. 6,982,321 and 7,087,409.

[0062] When discussing antibody use, the term "functional fragment" refers to a portion of an antibody, including heavy-chain or light-chain polypeptides, that retains some or all of the binding activity of the antibody from which it is derived as a fragment. Such functional fragments may include, for example, Fd, Fv, Fab, F(ab'), F(ab)2, F(ab')2, single-chain Fv (ScFv), biantibodies, triantibodies, tetraantibodies, and miniantibodies. Other functional fragments may include, for example, heavy-chain or light-chain polypeptides, variable-region polypeptides, or CDR polypeptides, or portions thereof, provided that such functional fragments retain binding activity. Such antibody-binding fragments can be found in, for example, Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York (1989); Myers (ed.), Molec. Biology and Biotechnology: A Comprehensive Desk Reference, New York: VCH Publisher, 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.

[0063] When referring to antibody use, the term "heavy chain" refers to a polypeptide chain of approximately 50-70 kDa, where the N-terminal portion includes a variable region of approximately 120 to 130 or more amino acids and the C-terminal portion includes a constant region. Based on the amino acid sequence of the heavy chain's constant region, the constant region can be one of five different types called alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ). The different heavy chains vary in size: α, δ, and γ contain approximately 450 amino acids, while μ and ε contain approximately 550 amino acids. When combined with light chains, these different types of heavy chains produce five well-known classes of antibodies: IgA, IgD, IgE, IgG, and IgM, including the four subclasses of IgG: IgG1, IgG2, IgG3, and IgG4. The heavy chain can be a human heavy chain.

[0064] When referring to antibody use, the term "light chain" refers to a polypeptide chain of approximately 25 kDa, wherein the N-terminal portion includes a variable region of approximately 100 to approximately 110 or more amino acids and the C-terminal portion includes 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, two distinct types exist, referred to as kappa (κ) or lambda (λ). The amino acid sequences of light chains are well known in the art. Light chains can be human light chains.

[0065] The term "variable domain" or "variable region" refers to a portion of the light or heavy chain of an antibody, typically located at the amino terminus of the light or heavy chain, with a length of approximately 120 to 130 amino acids in the heavy chain and approximately 100 to 110 amino acids in the light chain, and is responsible for the binding and specificity of each specific antibody to its specific antigen. Variable domains can vary widely in sequence between different antibodies. Sequence variability is concentrated in the CDR, while smaller variations within the variable domain are called frame regions (FRs). The CDRs of both the light and heavy chains are primarily responsible for antibody-antigen interactions. The amino acid position numbering used in this article is based on the EU index, such as Kabat et al. (1991). Sequences of proteins of immunological interest. (USD Department of Health and Human Services, Washington, DC) 5th edition. Variable regions can be human variable regions.

[0066] CDR refers to one of the three hypervariable regions (H1, H2, or H3) within the non-framework region of the VH β-sheet framework of an immunoglobulin (Ig or antibody), or one of the three hypervariable regions (L1, L2, or L3) within the non-framework region of the VL β-sheet framework of an antibody. Therefore, CDR is a variable region sequence scattered within the framework region sequence. CDR regions are well known to those skilled in the art and have been defined, for example, by Kabat as the region of highest variability 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 also been structurally defined by Chothia as those residues that do not belong to the conserved β-sheet framework and are therefore capable of adapting to different conformations (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). Both terms are generally accepted in the art. The position of the CDR within the canonical variable domain has 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 in the hypervariable region varies in different antibodies, the additional residues relative to the canonical position are usually adjacent to the residues in the canonical variable domain numbering scheme, which uses numbers such as a, b, and c (Al-Lazikani et al., as described above (1997)). Such nomenclature is also well known to those skilled in the art.

[0067] For example, CDRs defined according to the nomenclature of Kabat (high-variable), Chothia (structure), or MacCallum (J.Mol.Biol.262:732-745(1996)) are shown in Table 1 below:

[0068] Table 1: CDR Definition

[0069]

[0070] 1 The residue numbering follows the nomenclature of Kabat et al. mentioned above.

[0071] 2 Residue numbering follows the nomenclature of Chothia et al.

[0072] The term “cancer” refers to any physiological condition in mammals characterized by unregulated cell growth. The cancers described herein include solid tumors and hematological (blood) cancers. “Hematological cancers” refers to any blood-borne cancer and includes, for example, myeloma, lymphoma, and leukemia. “Solid tumor” or “tumor” refers to diseased and neoplastic cell growth and proliferation, whether malignant or benign, as well as all precancerous and cancerous cells and tissues that contribute to abnormal tissue growth. As used herein, “neoplastic” refers to any form of disordered or unregulated cell growth that contributes to abnormal tissue growth, whether malignant or benign.

[0073] The term “treating” refers to any successful or improved sign of the progression, severity, and / or duration of a disease, pathology, or condition, including any objective or subjective parameters such as elimination; relief; reduction of symptoms or making the patient more tolerant of the injury, pathology, or condition; slowing the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving the patient’s physical or mental health.

[0074] The term “enhancement” refers to an increase or improvement in the function or activity of a protein or cell after application or contact with the combination described herein, compared to the protein or cell before such application or contact.

[0075] The term "administration" refers to the act of delivering the combination or composition described herein to a subject via routes such as oral, mucosal, topical, suppository, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration. Parenteral administration includes intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Administration typically occurs after the onset of a disease, condition, or illness, or its symptoms; however, in some cases, it may occur before the onset of a disease, condition, or illness, or its symptoms (e.g., administration to a patient susceptible to such a disease, condition, or illness).

[0076] The term "co-administration" refers to the administration of two or more agents (e.g., the combination described herein and another active agent, such as the anticancer agent described herein). The timing of co-administration depends in part on the combination and composition administered and can include administration simultaneously, exactly before, or exactly after administration of one or more additional therapies (e.g., cancer therapies, such as chemotherapy, hormone therapy, radiotherapy, or immunotherapy). The compounds of the present invention can be administered to a patient alone or co-administered. Co-administration means the simultaneous or sequential administration of compounds (more than one compound or agent) alone or in combination. Thus, preparations can also be combined with other active substances (e.g., to reduce metabolic degradation) when needed. The compounds described herein can be used in combination with each other or with other active agents known for treating cancer.

[0077] The term "anticancer agent" is used in its usual, general sense and refers to a composition having the ability to inhibit vegetative growth or cell growth or proliferation. In some embodiments, the anticancer agent is a chemotherapeutic agent. In some embodiments, the anticancer agent is a pharmaceutical agent identified herein as having efficacy in methods of treating cancer. In some embodiments, the anticancer agent is a pharmaceutical agent approved by the FDA or a similar regulatory agency in a country outside the United States for the treatment of cancer.

[0078] The term "chemotherapeutic agent" is used in its usual, common sense sense and refers to a chemical composition or compound that has the ability to inhibit vegetative growth or cell growth or proliferation. "Chemotherapy" refers to a therapy or regimen that includes the administration of the chemotherapeutic agent or anticancer agent described herein.

[0079] combination

[0080] In some embodiments, combinations for treating cancer (e.g., combination therapies, such as treatment methods and uses, kits, and compositions) are described herein. In some embodiments, the combinations described herein include HDACi and anticancer agents, PD-1, PD-L1, and / or CTLA-4 inhibitors. In some embodiments, HDACi includes a generic benzamide structure belonging to subclass I (HDAC 1 / 2 / 3 and 8), class II (HDAC 4 / 5 / 6 / 7 / 9 / 10), or class IV (HDAC 11) 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 and second pharmaceutical compositions are co-packaged into a kit, which may further include instructions for co-administering the first and second pharmaceutical compositions. In some embodiments, the first and second compositions may be packaged separately for use in a clinical setting by administering them to a patient simultaneously from both the first and second pharmaceutical compositions within a timeframe during which the patient derives clinical benefit. In some embodiments, the combination comprises a unit dosage form of a pharmaceutical composition comprising HDACi and a PD-1 inhibitor. In some embodiments, the combination comprises a first pharmaceutical composition comprising HDACi for treating cancer, in combination with a second pharmaceutical composition comprising a PD-1 inhibitor. In some embodiments, the combination comprises the use of HDACi for preparing a first pharmaceutical composition for treating cancer, in combination with a second pharmaceutical composition comprising a PD-1 inhibitor.

[0081] Composition

[0082] This document provides combinations (e.g., combination therapies and compositions) for the treatment of a variety of diseases, conditions, and their symptoms, including, for example, cancer. Combinations described herein include HDAC inhibitors and PD-L1 inhibitors and / or PD-1 inhibitors, as well as further CTLA-4 inhibitors. Combinations described herein also include HDAC inhibitors and anticancer agents. 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 anticancer agents are described herein. In some embodiments, a combination is provided 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.

[0083]

[0084] Compounds of Formula I as described herein include pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, prodrugs, enantiomers, diastereomers, hydrates, eutectics, and polymorphs.

[0085] In some cases, the compound of formula I is present in amounts 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 amounts 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 amounts greater than about 5 mg or about 10 mg. The compound of Formula I may be present in amounts 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.

[0086] The combination may include compounds present in amounts 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 compounds of formula I present in amounts 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, compounds of formula I are present in amounts of at least about 5 mg or about 10 mg. The combination may include compounds of formula I present in amounts of at least 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.

[0087] The combination may include compounds of formula I present in amounts 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 compounds of formula I present in amounts 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, compounds of formula I are present in amounts of about 5 mg or about 10 mg. The combination may include compounds of formula I present in amounts 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.

[0088] Compounds 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, compounds of Formula I are present in amounts equivalent to 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. It is present in amounts of g / 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 amounts 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.

[0089] PD-L1 inhibitors

[0090] PD-L1 inhibitors used in the combinations described herein include any molecule capable of inhibiting, blocking, eliminating, or interfering with the binding of PD-L1 to PD-1, the activity of PD-L1, or the expression of PD-L1. In particular, PD-L1 inhibitors can be small molecule compounds, nucleic acids, peptides, antibodies, peptide bodies, biantibodies, mini-antibodies, single-chain variable fragments (ScFv), or functional fragments or variants thereof. In one instance, 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 instances, useful PD-L1 inhibitors in the combinations described herein include nucleic acids and peptides. PD-L1 inhibitors can be peptides (e.g., macrocyclic peptides) such as those exemplified in U.S. Patent Application Publication No. 2014 / 0294898, which is incorporated herein by reference in its entirety and for all purposes. In one instance, a PD-L1 inhibitor is an antibody, peptide, biantibody, mini-antibody, ScFv, or a functional fragment thereof. In another instance, a PD-L1 inhibitor is a PD-L1 inhibitor antibody. PD-L1 inhibitor antibodies can be monoclonal or polyclonal antibodies. In some embodiments, the PD-L1 inhibitor antibody is a monoclonal antibody.

[0091] PD-L1 antibodies include all known types of antibodies and their functional fragments, including but not limited to those exemplified herein, such as, for example, human antibodies, mouse antibodies, chimeric antibodies, humanized antibodies, or chimeric humanized antibodies.

[0092] In some embodiments, the PD-L1 inhibitor antibody is a human antibody. In another embodiment, the PD-L1 inhibitor antibody is a mouse 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 can be a human antibody or a humanized antibody. The PD-L1 inhibitor antibody can 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 as described herein.

[0093] PD-L1 inhibitor antibodies can be dvorumab. Dvorumab is a Fc-optimized monoclonal antibody targeting PD-L1 with potential immune checkpoint inhibition and anti-zombie activity. Without being bound by any particular theoretical constraint, dvorumab binds to PD-L1, thereby blocking its binding to and activation with its receptor PD-1 (which can be expressed on activated T cells). This can reverse T cell inactivation and activate the immune system to exert a cytotoxic T lymphocyte (CTL) response against PD-L1-expressing tumor cells. The Fc region of dvorumab is modified in a manner that does not induce antibody-dependent cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).

[0094] A PD-L1 inhibitor antibody could be avelumab. Avelumab is a monoclonal antibody against human immunoglobulin G1 (IgG1) targeting PD-L1, which has potential immune checkpoint inhibition and anti-sagmentation activity. Without being bound by any particular theory, avelumab binds to PD-L1 and prevents PD-L1 from interacting with its receptor PD-1. This inhibits the activation of PD-1 and its downstream signaling pathways. This can restore immune function by activating cytotoxic T lymphocytes (CTLs) targeting tumor cells overexpressing PD-L1. Avelumab appears to induce an antibody-dependent cellular cytotoxic (ADCC) response against PD-L1-expressing tumor cells.

[0095] PD-L1 inhibitor antibodies can be atecilizumab. Atezolizumab is a human Fc-optimized monoclonal antibody targeting the protein ligand PD-L1, possessing potential immune checkpoint inhibition and anti-neoplasm activity. Without being bound by any particular theory, atezolizumab binds to PD-L1, blocking its binding to and activation of its receptor PD-1 expressed on activated T cells. This enhances T-cell-mediated immune responses against neoplasms and reverses T-cell inactivation. Furthermore, by binding to PD-L1, atezolizumab also appears to prevent the binding of PD-L1 to B7.1 expressed on activated T cells, which could further enhance T-cell-mediated immune responses. The Fc region of atezolizumab is modified in a manner that does not induce antibody-dependent cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).

[0096] A PD-L1 inhibitor antibody could be BMS-936559. BMS-936559 is a fully human IgG4 monoclonal antibody against PD-L1 with potential immune checkpoint inhibitory activity. Without being bound by any specific theory, BMS-936559 binds to PD-L1 and inhibits its binding to both PD-1 and CD80.

[0097] 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 a fully human monoclonal antibody targeting PD-L1. In some other embodiments, the PD-L1 inhibitor may be administered according to established regimens, such as those provided in the packaging insert.

[0098] PD-1 inhibitors

[0099] PD-1 inhibitors used in the combinations described herein include any molecule capable of inhibiting, blocking, eliminating, or interfering with the activity or expression of PD-1. In particular, PD-1 inhibitors can be small molecule compounds, nucleic acids, peptides, antibodies, peptide bodies, biantibodies, mini-antibodies, single-chain variable fragments (ScFv), or functional fragments or variants thereof. In one instance, a PD-1 inhibitor is a small molecule compound (e.g., a compound having a molecular weight of less than about 1000 Da). In other instances, useful PD-1 inhibitors in the combinations described herein include nucleic acids and peptides. PD-1 inhibitors can be peptides (e.g., macrocyclic peptides), such as those exemplified in U.S. Patent Application Publication No. 2014 / 0294898, which is incorporated herein by reference in its entirety and for all purposes. In one example, a PD-1 inhibitor is an antibody, peptide body, biantibody, mini-antibody, ScFv, or a functional fragment thereof. In one example, a PD-1 inhibitor is AMP-224 (GSK).

[0100] AMP-224 is a recombinant fusion protein comprising the extracellular domain of PD-1 ligand programmed cell death ligand 2 (PD-L2) and the Fc region of human IgG. Certain cancers can partially evade and suppress the immune system through the interaction between PD-1 and B7-H1, without being bound by any particular theory. AMP-224 appears to block this interaction and therefore appears to overcome immunosuppression.

[0101] In another example, a PD-1 inhibitor is a PD-1 antibody. A PD-1 antibody can be a monoclonal or polyclonal antibody. In some implementations, the PD-1 antibody is a monoclonal antibody.

[0102] PD-1 antibodies include all known types of antibodies and their functional fragments, including but not limited to those exemplified herein, such as, for example, human antibodies, mouse antibodies, chimeric antibodies, humanized antibodies, or chimeric humanized antibodies.

[0103] In some embodiments, the PD-1 antibody is a human antibody. In some other embodiments, the PD-1 antibody is a mouse antibody. In some other embodiments, the PD-1 antibody is a chimeric antibody. In some other embodiments, the PD-1 antibody is a humanized antibody. In some embodiments, the PD-1 antibody is a chimeric humanized antibody. The PD-1 antibody can be a human antibody or a humanized antibody. The PD-1 antibody can be nivolumab, pembrolizumab, pildizumab, REGN2810, PDR 001, or MEDI0680. In some embodiments, two or more PD-1 antibodies are administered in combination with a compound of Formula I as described herein.

[0104] PD-1 antibodies can include nivolumab. Nivolumab (marketed as OPDIVO) is a fully human monoclonal antibody against PD-1 with immunopotentiation activity. Without being bound by any particular theory, nivolumab binds to PD-1 and blocks the activation of PD-1 through its homologous ligand, leading to T cell activation and a cell-mediated immune response against tumor cells or pathogens.

[0105] PD-1 antibodies can be pembrolizumab. Pembrolizumab (MK-3475, marketed as KEYTRUDA) is a humanized monoclonal IgG4 antibody targeting the human cell surface receptor PD-1, which has potential immunomodulatory activity. Without being bound by any particular theory, pembrolizumab binds to PD-1 (an inhibitory signaling receptor expressed on the surface of activated T cells) and blocks the binding and activation of PD-1 by its homologous ligands. This blockade of binding and activity leads to the activation of a T cell-mediated immune response against tumor cells.

[0106] PD-1 antibodies can include pidilimumab. Pidililimumab (CT-011) is a humanized monoclonal antibody against human PD-1, possessing immunomodulatory and antitumor activity. Without being bound by any specific theoretical constraints, pidilimumab blocks the interaction between the receptor PD-1 and its ligand, leading to a reduction in apoptosis in lymphocytes (primarily effector / memory T cells) and an enhancement of the antitumor activity of NK cells.

[0107] A PD-1 antibody could be REGN2810. REGN2810 is a human monoclonal antibody against PD-1 with potential immune checkpoint inhibition and anti-zombie activity. Without being bound by any particular theory, REGN2810 binds to PD-1, inhibits the binding of its homologous ligand, and prevents activation of its downstream signaling pathways. This can restore immune function by activating cytotoxic T cells.

[0108] A PD-1 antibody could be PDR 001. PDR 001 is a fully humanized monoclonal antibody against PD-1 with immune checkpoint inhibition and anti-zombie activity. Without being bound by any particular theory, PDR 001 binds to PD-1 expressed on activated T cells and blocks the interaction between PD-1 and its homologous ligand. Inhibition of ligand binding prevents PD-1-mediated signaling and leads to both T cell activation and the induction of a T cell-mediated immune response against tumor cells.

[0109] The PD-1 antibody could be MEDI0680 (AMP-514), a monoclonal antibody against PD-1 with potential immunomodulatory and anti-zombie activity. Without being bound by any particular theory, MEDI0680 appears to inhibit the activation of PD-1 and its downstream signaling pathways. This inhibition could restore immune function by activating both T cells and cell-mediated immune responses against tumor cells overexpressing PD-1. In some other embodiments, the PD-1 inhibitor can be administered according to established regimens, such as those provided in the packaging insert.

[0110] CTLA-4 inhibitors

[0111] The CTLA-4 inhibitors used in the combinations described herein include any molecule capable of inhibiting, blocking, eliminating, or interfering with the activity or expression of CTLA-4. In particular, CTLA-4 inhibitors can be small molecule compounds, nucleic acids, peptides, antibodies, peptide bodies, biantibodies, mini-antibodies, single-chain variable fragments (ScFv), or functional fragments or variants thereof. In one instance, 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 instances, useful CTLA-4 inhibitors in the combinations described herein include nucleic acids and peptides. CTLA-4 inhibitors can be peptides (e.g., macrocyclic peptides). In one example, the CTLA-4 inhibitor is an antibody, peptide body, biantibody, mini-antibody, ScFv, or a functional fragment thereof. In one example, the CTLA-4 inhibitor is ipilimumab.

[0112] In another example, a CTLA-4 inhibitor is a CTLA-4 antibody. CTLA-4 antibodies can be monoclonal or polyclonal. In some implementations, the CTLA-4 antibody is a monoclonal antibody.

[0113] CTLA-4 antibodies include all known types of antibodies and their functional fragments, including but not limited to those exemplified herein, such as, for example, human antibodies, mouse antibodies, chimeric antibodies, humanized antibodies, or chimeric humanized antibodies.

[0114] In some embodiments, the CTLA-4 antibody is a human antibody. In other embodiments, the CTLA-4 antibody is a mouse 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 can be a human antibody or a humanized antibody. The CTLA-4 antibody can be administered in combination with a compound of Formula I as described herein. In some other embodiments, the CTLA-4 inhibitor can be administered according to established regimens, such as those provided in the packaging insert.

[0115] CD276 inhibitors

[0116] CD276 (B7-H3) is a relatively new but important member of the immune checkpoint family. CD276 is expressed on antigen-presenting cells in the active / inflammatory “hot” tumor microenvironment (“TME”) and inhibits CD8. + Cytotoxic T cells. CD276 expression is upregulated by administration of a compound of formula I as described herein. CD276 inhibitors used in the combinations described herein comprise any molecule capable of inhibiting, blocking, eliminating, or interfering with the activity or expression of CD276. In particular, CD276 inhibitors can be small molecule compounds, nucleic acids, peptides, antibodies, peptide bodies, biantibodies, mini-antibodies, single-chain variable fragments (ScFv), or functional fragments or variants thereof. In one instance, a CD276 inhibitor is a small molecule compound (e.g., a compound having a molecular weight of less than about 1000 Da). In other instances, useful CD276 inhibitors in the combinations described herein include nucleic acids and peptides. A CD276 inhibitor can be a peptide (e.g., a macrocyclic peptide). In one example, a CD276 inhibitor is an antibody, peptide body, biantibody, mini-antibody, ScFv, or a functional fragment thereof.

[0117] In another example, the CD276 inhibitor is a CD276 antibody. The CD276 antibody can be a monoclonal or polyclonal antibody. In some embodiments, the CD276 antibody is a monoclonal antibody.

[0118] CD276 antibodies include all known types of antibodies and their functional fragments, including but not limited to those exemplified herein, such as, for example, human antibodies, mouse antibodies, chimeric antibodies, humanized antibodies, or chimeric humanized antibodies.

[0119] In some embodiments, the CD276 antibody is a human antibody. In some embodiments, the CD276 antibody is a mouse 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 can be a human antibody or a humanized antibody. The CD276 antibody can be administered in combination with a compound of Formula I as described herein or with any other composition described herein. In some other embodiments, the CD276 antibody can be administered according to established protocols, such as those provided in the packaging insert.

[0120] PD-L1 inhibitor antibodies, PD-1 inhibitor antibodies, CTLA-4 inhibitor antibodies, and / or CD276 inhibitor antibodies (any of which is referred to herein as an “inhibitor antibody”) can be any antibody isotype. The term isotype refers to an antibody class encoded by a heavy chain constant region gene. The heavy chain of a given antibody or functional fragment determines the class of the antibody or functional fragment: IgM, IgG, IgA, IgD, or IgE. Each class may have a κ or λ light chain. The term subclass refers to a minor difference in the amino acid sequence of the heavy chain that distinguishes the subclass. In humans, IgA has two subclasses (subclasses IgA1 and IgA2), and IgG has four subclasses (subclasses IgG1, IgG2, IgG3, and IgG4). Such classes and subclasses are well known to those skilled in the art.

[0121] Useful inhibitory antibodies bind to their substrates with sufficient strength to inhibit the activity of the substrates (e.g., PD-L1, PD-1, CTLA-4, and / or CD276). As used herein, the term "binding" refers to an interaction between molecules to form a complex. Interactions can be, for example, non-covalent interactions, including hydrogen bonds, ionic bonds, hydrophobic interactions, and / or van der Waals interactions. A complex can 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 a functional fragment thereof can be detected using, for example, enzyme-linked immunosorbent assay (ELISA) or any of a variety of methods well known to those skilled in the art.

[0122] The strength of the total non-covalent interaction between a single antigen-binding site on an inhibitor antibody or functional fragment and a single epitope of a target molecule is the affinity of the antibody or functional fragment for that epitope. The association (k1) and dissociation (k2) between the antibody or its functional fragment and a monovalent antigen are also considered. -1 The ratio of (k1 / k) -1 K is the association constant, which is a measure of affinity. The value of K varies for different complexes of the antibody or functional fragment with the antigen, and depends on k1 and k2. -1Both. The association constant K of the antibody or functional fragment of the present invention can be determined using any of the methods provided herein or any other methods well known to those skilled in the art.

[0123] Affinity at a single binding site does not always 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 a reaction at a second site. The strength of this multiple interaction between a multivalent antibody and an antigen is called affinity. The affinity of an antibody or functional fragment can be a better measure of its binding ability than the affinity at its individual binding sites. For example, high affinity can compensate for low affinity, as sometimes found with pentamer IgM antibodies, which can have lower affinity than IgG, but the high affinity of IgM resulting from its multivalent nature enables it to bind antigens effectively.

[0124] The specificity of an inhibitor antibody or its functional fragment refers to the ability of a single antibody or its functional fragment to react with only one antigen (e.g., a single epitope of PD-L1, PD-1, and CTLA-4). An antibody or functional fragment is considered specific when it can distinguish between the primary, secondary, or tertiary structures of an antigen or differences in isomers of the antigen.

[0125] The inhibitor antibody can be present in amounts measured relative to the body weight of the patient in need. For example, the inhibitor antibody can be present in amounts of 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 amounts 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 amounts 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 amounts of about 0.1 mg / kg to about 20 mg / kg or about 0.1 mg / kg to about 30 mg / kg.

[0126] In some other embodiments, the inhibitor antibody may be present in amounts 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 amounts 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 amounts of about: 3 mg / kg, 10 mg / kg, 20 mg / kg, or 30 mg / kg.

[0127] Inhibitor antibodies may be present in the combination in amounts of approximately: 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. Inhibitor antibodies may be present in the combination in amounts of approximately: 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. Inhibitor antibodies may be present in the combination in amounts of approximately 1000 mg to approximately 2000 mg. The inhibitor antibody may be present in combination in amounts 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 mg to about 2000 mg.

[0128] Inhibitor antibodies may be present in combination in amounts of approximately: 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 amounts 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.

[0129] In some cases, the therapeutically effective amount of an inhibitor antibody is determined to be the amount provided in the insert package accompanying the inhibitor antibody. The term "inser package" refers to a package insert typically included in the packaging of a commercially available drug approved by the FDA or a similar regulatory agency outside the United States, containing information such as use, dosage, administration, contraindications, and / or warnings regarding the use of such drugs.

[0130] Compounds of Formula I as described herein may be provided in synergistic amounts with PD-L1 and / or PD-1 inhibitors and CTLA-4 inhibitors. The term synergistic refers to combinations or regimens (such as those described herein) that are more effective than the additive effect of the individual therapies or regimens.

[0131] The synergistic effects of the combinations described herein may allow for the use of lower doses of one or more 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 effects may allow for less frequent administration of at least one of the administered 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 anticancer agent) to subjects having the diseases, conditions, or ailments described herein. Such lower doses and reduced administration frequency may reduce toxicities associated with administering at least one therapy (e.g., a compound of Formula I, or a PD-L1 inhibitor, or a PD-1 inhibitor, or a CTLA-4 inhibitor, or an anticancer agent) to subjects without reducing therapeutic efficacy. The synergistic effects described herein avoid or reduce adverse or unwanted side effects associated with the use of any therapy.

[0132] Pharmaceutical Composition

[0133] The combinations described herein can be provided as pharmaceutical compositions suitable for administration to patients described herein via any route, including but not limited to: oral, mucosal (e.g., nasal, inhalation, pulmonary, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus, intramuscular, or intra-arterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal, or transcutaneous administration to patients.

[0134] Exemplary dosage forms include: tablets; caplets; capsules (e.g., gelatin capsules); cachets; lozenges; suppositories; powders; gels; liquid dosage forms suitable for parenteral administration to patients; and sterile solids (e.g., crystalline or amorphous solids) that can be reconfigured to provide liquid dosage forms suitable for parenteral administration to patients.

[0135] The pharmaceutical compositions and dosage forms described herein typically include one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy. Whether a particular excipient is suitable for inclusion in a pharmaceutical composition or dosage form depends on a variety of factors, such as, for example, the intended route of administration to the patient. The pharmaceutical compositions described herein may include other agents, such as stabilizers, lubricants, buffers, and disintegrants, which can reduce the rate at which the active ingredient decomposes in a particular formulation.

[0136] The pharmaceutical compositions described herein may, in some cases, include other active agents (e.g., anticancer agents, such as those described herein) in amounts provided herein.

[0137] In some embodiments, the compounds of Formula I are provided in oral dosage forms such as tablets or capsules. In some embodiments, the compounds of Formula I are supplied as powders (e.g., lyophilized powders) that can be resuspended in a liquid suitable for parenteral administration.

[0138] The PD-L1 inhibitors, PD-1 inhibitors, and CTLA-4 inhibitors described herein may be provided in forms that facilitate or promote their administration to patients. For example, in the case where the inhibitor is an inhibitor antibody as described herein, the inhibitor may be formulated as a ready-to-use solution for parenteral administration. In other instances, the inhibitor (including, for example, an inhibitor antibody) may 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.

[0139] The combinations described herein can be offered as controlled-release drug products with the aim of improving drug therapy compared to its non-controlled counterpart. Controlled-release formulations can prolong drug activity, reduce dosing frequency, and increase subject compliance. Additionally, controlled-release formulations can be used to influence the timing of action or other characteristics, such as drug blood levels, and may thus affect the occurrence of side effects (e.g., adverse effects).

[0140] Reagent test kit

[0141] The combination 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 of administration of the combination or ease of preparation. The kit includes compounds of Formula I, wherein the compounds are supplied in formulations as described herein.

[0142] The kits of the present invention may include combinations of the formulations described herein, having the same or different formulations. Each component of the combinations described herein in the kit may be supplied in a separate container. Optionally or additionally, the components of the combinations described herein may be supplied in a single container. In such cases, the container may be a container ready for administration to a patient in need, such as, for example, an IV bag, ampoule, or syringe. In some embodiments, the compounds of formula I in the kit are formulated for oral administration (e.g., tablets, capsules, or sachets).

[0143] The contents of the kits described herein can be provided in a sterile form. The kits and their contents can be provided in a form ready for administration to a subject in need. In such cases, the components of the kit combination are supplied as a formulation and optionally in an administration device, such that administration requires minimal further action from the user. Where the kit includes an administration device, such devices include those known and understood by those skilled in the art for use with the administration routes described herein, such as, but not limited to, syringes, pumps, bags, cups, inhalers, droppers, patches, creams, or injectors.

[0144] method

[0145] The combinations, pharmaceutical compositions, and kits described herein are for the treatment of diseases, conditions, or to alleviate or eliminate symptoms of diseases and conditions, such as, for example, cancer. It should be understood that the methods described herein involve administering the combinations and pharmaceutical compositions described herein, and such combinations and pharmaceutical compositions may be provided in the form of kits as described herein. This document provides a method for treating cancer by administering a therapeutically effective amount of the combinations described herein to a patient in need. This document also provides a method for managing cancer by administering a therapeutically effective amount of the combinations described herein to a patient in need.

[0146] In some implementations, the combination is used to treat cancer. In some implementations, the cancer is the cancer described herein.

[0147] 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 anticancer agent.

[0148] Combinations used for the methods described herein include compounds of formula I:

[0149]

[0150] The PD-L1 inhibitors, PD-1 inhibitors, and CTLA-4 inhibitors used in the methods described herein are those inhibitors described herein. For example, PD-L1 inhibitors, PD-1 inhibitors, and CTLA-4 inhibitors can be small molecule compounds, nucleic acids, peptides, antibodies, peptide bodies, biantibodies, mini-antibodies, single-chain variable fragments (ScFv), or functional fragments or variants thereof. In other instances, the inhibitor can be an inhibitor antibody as described above.

[0151] Target cancer

[0152] Cancer can be a solid tumor. Cancer can be a blood cancer. In some cases, cancer is a solid tumor, such as squamous cell carcinoma, non-squamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, 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 schwannoma (MPNST).

[0153] In some implementations, cancer is a solid tumor, such as non-small cell lung cancer (NSCLC), hepatocellular carcinoma, melanoma, ovarian cancer, breast cancer, pancreatic cancer, renal cell carcinoma, or colorectal cancer. Cancer can be non-small cell lung cancer (NSCLC). Cancer can be hepatocellular carcinoma. Cancer can be melanoma. Cancer can be ovarian cancer. Cancer can be breast cancer. Cancer can be pancreatic cancer. Cancer can be renal cell carcinoma. Cancer can be colorectal cancer.

[0154] This document provides a method for treating NSCLC by administering a therapeutically effective amount of the 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 IIB. NSCLC may be stage IIIA or IIIB cancer. NSCLC may be stage IV cancer. The staging of cancers as described herein is described by cancer staging symbols such as the American Joint Committee on Cancer (AJCC) Malignant Tumor TNM staging system, which are well known in the art. Those skilled in the art will readily understand that other staging classification systems may be used and are applicable to the methods described herein. In some cases, the method is a method for treating stage IIIA or IIIB NSCLC by administering the combination described herein comprising a compound of Formula I and an inhibitor antibody.

[0155] This document further provides a method for treating melanoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and an inhibitor antibody. In some embodiments, the melanoma is stage IIA, IIB, or IIC cancer. In some embodiments, the melanoma is stage IIIA, IIIB, or IIIC cancer. In some other embodiments, the melanoma is stage IV cancer. In some embodiments, the method is a method for treating stage II (e.g., stage IIA, IIB, or IIC) melanoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and an inhibitor antibody.

[0156] This document also provides a method for treating breast cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and an inhibitor antibody. Breast cancer may be HER2-negative breast cancer. Breast cancer may be HER2-positive breast cancer. Breast cancer may be triple-negative breast cancer. In some embodiments, breast cancer is stage IA or D3 cancer. In some embodiments, breast cancer is stage IIA or IIB cancer. In some embodiments, breast cancer is stage IIIA, IIIB, or IIIC cancer. In some embodiments, breast cancer is stage IV cancer.

[0157] In other implementations, the cancer is a blood cancer, such as lymphoma, non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, Reed-Sternberg disease, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), or chronic lymphocytic leukemia (CLL). In some implementations, the cancer is Hodgkin lymphoma or Reed-Sternberg disease.

[0158] The combinations described herein can be administered to cancer patients at any time after diagnosis. For example, the cancer patient may be untreated (e.g., not receiving cancer therapy for the diagnosed cancer). The cancer patient may be untreated for one type of cancer but may be diagnosed with one or more other cancers caused by, for example, metastases or malignancies. The cancer patient may be immune checkpoint naive for one or more types of cancer. The cancer patient may have refractory cancer. In some cases, the combinations described herein are administered as first-line therapy (e.g., as a first-line treatment for untreated cancer patients) to patients in need.

[0159] However, cancer incidence and mortality are often associated with cancers that are ineffective with treatment or have acquired resistance to one or more cancer therapies, or cancers that have become difficult to treat with one or more cancer therapies. Therefore, the combinations described herein can be administered as second-, third-, fourth-, fifth-, sixth-, or more-line treatments to patients in need. The combinations described herein can be administered to cancer patients who have already been treated with at least one anticancer therapy or anticancer agent. In some cases, the patient has already received at least one anticancer therapy, including, for example, chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, or combinations thereof. The patient may have cancer that is resistant / refractory to treatment with at least one anticancer agent.

[0160] The cancer treatment methods described in this article include treating subjects who have been treated with checkpoint inhibitors and experienced no response, partial response, or stable disease but subsequently developed resistance and disease progression, or subjects who experienced a complete response to treatment but subsequently developed resistance and disease progression (as defined by RECIST or other criteria). Resistance is defined as disease progression or lack of response to treatment during treatment. Failure to such inhibitor antibody therapy can be treated with a combination of the inhibitor antibody and an HDAC inhibitor, such as, but not limited to, HBI-8000, or an HDAC inhibitor that inhibits one or more cancer-associated class I HDACs selected from HDAC1, HDAC2, or HDAC3. In some cases, the HDAC inhibitor also inhibits class IIb HDAC1.

[0161] Reaction evaluation criteria

[0162] RECIST:

[0163] RECIST is a set of established criteria or standards internationally recognized for assessing patient response, stability, and progression in clinical trials and clinical practice. Originally published in 2000 and 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 has traditionally been used to assess response to chemotherapy as a collaborative effort between 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.

[0164] Assessment of target lesions:

[0165] Complete Response (CR): All target lesions disappear; Partial Response (PR): The sum of the longest diameters (LDs) of the target lesions is reduced by at least 30%, with the baseline sum LD as a reference; Stable Disease (SD): There is not enough shrinkage to qualify for PR, nor enough increase to qualify for PD, with the minimum sum LD recorded since the start of treatment as a reference; Progressive Disease (PD): The sum of the LDs of the target lesions is increased by at least 20%, with the minimum sum LD recorded since the start of treatment or the appearance of one or more new lesions as a reference.

[0166] Assessment of non-target lesions:

[0167] 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 tumor marker levels remaining above normal limits; Disease progression (PD): appearance of one or more new lesions and / or clear progression of existing non-target lesions.

[0168] Other reaction evaluation criteria:

[0169] Other response evaluation criteria include the immune-related response evaluation criteria or iRECIST, such as those defined by Wolchok et al. in 2009 (Wolchok JD, et al.; Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria. Clin. Cancer Res 2009; 15(23):7412-20) and the revised response criteria of the International Working Group (Cheson BD et al.; Revised response criteria for malignant lymphoma. J. Clin. Oncol. 2007; 25:579-586).

[0170] Assessment of the effect of HDACi on heart rate:

[0171] Combined with pharmacokinetic analysis, Holter monitors were used to record 12-lead continuous digital ECGs (under controlled conditions to minimize digital noise) on baseline day (1–7 days prior to C1D1) and on C1D1 (Phase 1b only). Triple 10-second ECGs were retrieved from the Holter flash card at matched time points on baseline day and on C1D1, before administration (0.5 hours before breakfast) and up to 4 hours after administration. PR, QRS, RR, and QT intervals were analyzed by a central ECG laboratory. Meal times (breakfast) were normalized over two days. Heart rate correction was applied to the measured QT data using Fridricia correction (QTcF).

[0172] Calculate QTcF using the following formula:

[0173] Fridericia: QTcFri = QT / (RR) 1 / 3 (Fridericia LS. Die systolendauer imelektrokardiogramm bei normalenmenschen und bei herzkranken. Acta MedScand. 1920; 53:469-486).

[0174] The cancer treatment methods described in this article include treating subjects with HDACi such that the administration of HDACi does not cause an increase in QTc, QTcF, or heart rate (HR).

[0175] Methods of treating cancer include inhibiting cell growth by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of formula I described herein and a PD-L1 inhibitor and / or a PD-1 inhibitor, plus a CTLA-4 inhibitor.

[0176] This article also provides a method for inhibiting cancer metastasis in patients in need by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I described herein and a PD-L1 inhibitor and / or a PD-1 inhibitor, plus a CTLA-4 inhibitor. In some embodiments, metastasis is inhibited by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0177] In some embodiments, a method of reducing pre-existing tumor metastases in cancer patients in need is described by administering a therapeutically effective amount of the combination described herein, wherein said combination comprises a compound of formula I described herein and a PD-L1 inhibitor and / or a PD-1 inhibitor, plus a CTLA-4 inhibitor. In some embodiments, pre-existing tumor metastases are reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0178] In some other embodiments, the method of treating cancer also provides a method of reducing the tumor burden in an individual by administering a therapeutically effective amount of the combination described herein, wherein said combination comprises a compound of formula I described herein and a PD-L1 inhibitor and / or a PD-1 inhibitor, plus a CTLA-4 inhibitor. In some embodiments, the tumor burden is reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0179] In some embodiments, the method of treating cancer also provides a method for reducing the tumor burden in an individual by administering a therapeutically effective amount of the combination described herein, wherein said combination comprises a compound of formula I described herein and a PD-L1 inhibitor and / or a PD-1 inhibitor, plus a CTLA-4 inhibitor. In some embodiments, the tumor burden is reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0180] The methods for treating cancer described herein also provide methods for increasing or otherwise prolonging the time to disease progression (TTP) in certain stages, including advanced stages of cancer, such as stages III and IV cancers described herein. TTP can be prolonged in a patient by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I described herein and a PD-L1 inhibitor and / or a PD-1 inhibitor, plus a CTLA-4 inhibitor. In some embodiments, the increase is a comparison between the time to disease progression without treatment and treatment with the combination described herein. In some embodiments, the methods described herein prolong the time to disease progression for 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, including values ​​therein.

[0181] The methods for treating cancer described herein also provide methods for increasing or otherwise prolonging the survival (including overall survival) of patients diagnosed with cancer as described herein. Patient survival can be prolonged by administering a therapeutically effective amount of the combination described herein, wherein said combination comprises a compound of formula I described herein and a PD-L1 inhibitor and / or a PD-1 inhibitor, plus a CTLA-4 inhibitor. In some embodiments, the increase is a comparison between survival without treatment and survival with the combination described herein. In some embodiments, the methods described herein prolong survival for 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, including values ​​therein.

[0182] The methods for treating cancer described herein also provide methods for increasing progression-free survival in patients diagnosed with cancer as described herein. Patient progression-free survival can be prolonged by administering a therapeutically effective amount of the combination described herein, said combination comprising a compound of formula I described herein and a PD-L1 inhibitor and / or a PD-1 inhibitor, plus a CTLA-4 inhibitor. In some embodiments, the increase is a comparison between progression-free survival without treatment and treatment with the 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, including values ​​therein.

[0183] This article also provides a method for reducing the level of myeloid-derived suppressor cells (MDSCs) in patients in need by administering an effective amount of the combination described herein, wherein the combination comprises a compound of formula I described herein and a PD-L1 inhibitor and / or a PD-1 inhibitor, plus a CTLA-4 inhibitor. A reduction in MDSCs may be beneficial for the treatment of the cancers described herein. MDSC levels in human patients can be measured before, during, and after administration of the combination described herein. In some embodiments, comparing the amount of MDSCs in a patient before and after administration may be useful. A reduction in the amount, level, or number of MDSCs after administration may indicate the effectiveness of the combination, for example, in the treatment of the cancers described herein. MDSC levels can be monitored during the treatment or regimen described herein using the combination described herein. In such cases, determining MDSC levels at various points during administration may indicate the effectiveness of the regimen.

[0184] This article also provides methods for reducing the percentage or level of Treg cells in patients in need. Such methods include administering an effective amount of the combination described herein, wherein the combination comprises a compound of formula I described herein and a PD-L1 inhibitor and / or a PD-1 inhibitor, plus a CTLA-4 inhibitor. A reduction in Treg cells may be beneficial for the treatment of the cancers described herein. Treg cell levels in human patients can be measured before, during, and after administration of the combination described herein. In some embodiments, comparing the amount of Treg cells in a patient before and after administration may be useful. A reduction in the amount, level, or number of Treg cells after administration may indicate the effectiveness of the combination, for example, in the treatment of the cancers described herein. Treg cell levels can be monitored during the treatment or regimen described herein using the combination described herein. In such cases, determining Treg cell levels at various points during administration may indicate the effectiveness of the regimen.

[0185] The combinations described herein can be used in methods to enhance the activity of natural killer (NK) cells. The combinations described herein can also be used in methods to enhance the activity of cytotoxic T cells. The enhancement methods include contacting NK cells or cytotoxic T cells with the combinations described herein, wherein the combinations enhance the activity of the NK cells or cytotoxic T cells relative to their activity prior to contact. In some embodiments, the enhanced activity of NK cells or cytotoxic T cells is observed in cancer patients who have been treated with combinations as described herein.

[0186] The combinations described herein can also enhance antibody-dependent cell-mediated cytotoxicity in cancer patients when administered with combinations as described herein.

[0187] The combinations described herein may include administration of each therapy (e.g., a compound of Formula I and a PD-L1 inhibitor and / or a PD-1 inhibitor, plus a CTLA-4 inhibitor), wherein said administration is performed simultaneously or sequentially (in either order). In some embodiments, the compound of Formula I and the PD-L1 inhibitor and / or a PD-1 inhibitor, plus a CTLA-4 inhibitor, are administered simultaneously (e.g., within at least 1 to 5 minutes of each other). In some embodiments, the compound of Formula I and the PD-L1 inhibitor and / or a 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).

[0188] Compounds of Formula I can be administered regularly, for example, on a continuous or intermittent basis, once daily (QD), twice daily (BID), once weekly (QW), twice weekly (BIW), three times weekly (TIW), or monthly (QM), such as BIW for 3 months followed by a one-month resuscitation. For example, compounds of Formula I can be administered by BID. Compounds of Formula I can be administered by TIW. In some cases, compounds of Formula I are administered 2 to 3 times per week. In some embodiments, compounds of Formula I are administered by QD. The compound can be administered by QD for approximately: 1 day to about 7 days, 1 day to about 14 days, 1 day to about 21 days, 1 day to about 28 days, or daily until disease progression or unacceptable toxicity. The administration of compounds of Formula I can be partly dependent on patient tolerability, where greater tolerability may allow for larger or more frequent administrations. Alternatively, in cases where patients show poor tolerance to compounds of Formula I, smaller amounts of the compound or less frequent administrations may be given. Compounds of Formula I can be administered in any of the regimens described herein.

[0189] For example, compounds of formula I can be administered in amounts 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 QD. For example, compounds of formula I can be administered in amounts 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 BIW. For example, compounds of formula I can be administered in amounts 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 TIW. For example, compounds of formula I can be administered in amounts 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 QW. For example, a compound of formula I may be administered in amounts 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 Q2W. For example, a compound of formula I may be administered in amounts of about 5 mg or about 10 mg QD. For example, a compound of formula I may be administered in amounts of about 5 mg or about 10 mg BIW. For example, a compound of formula I may be administered in amounts of about 5 mg or about 10 mg TIW. For example, a compound of formula I may be administered in amounts of about 5 mg or about 10 mg QW. For example, a compound of formula I may be administered in amounts of about 5 mg or about 10 mg Q2W. The administration of a compound of formula I may be continuous. The administration of a compound of formula I may be intermittent.

[0190] For example, a compound of formula I may be administered in amounts 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 QD. For example, a compound of formula I may be administered in amounts 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 BIW. For example, a compound of formula I may be administered in amounts 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 QW. For example, a compound of formula I may be administered in amounts 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 QW. For example, compounds of Formula I can be administered in amounts 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 Q2W. The administration of compounds of Formula I can be continuous. The administration of compounds of Formula I can be intermittent.

[0191] For example, compounds of formula I can be expressed in amounts 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. Administer at a dose of g / 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 QD. For example, the compound of formula I can be administered in amounts 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 BIW. For example, the compound of formula I can be administered in amounts 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 TIW.For example, the compound of formula I can be applied in amounts 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 QW. For example, the compound of formula I can be administered in amounts 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 Q2W. In one example, the compound of formula I can be administered in amounts of about 15 mg / kg to about 75 mg / kg QD. In another example, the compound of formula I can be administered in amounts of about 20 mg / kg to about 50 mg / kg. In yet another example, the compound of formula I may be administered in amounts 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 or intermittent.

[0192] For example, compounds of formula I may be administered in amounts 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 QD. For example, compounds of formula I may be administered in amounts 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 BIW. For example, compounds of formula I can be administered in amounts 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 QW. For example, the compound of formula I can be administered in amounts 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 Q2W. In one example, the compound of formula I can be administered in amounts of about 15 mg / kg to about 75 mg / kg QD. In another example, the compound of formula I can be administered in amounts of about 20 mg / kg to about 50 mg / kg.In yet another example, the compound of formula I may be administered in amounts 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 or intermittent.

[0193] As used herein, the term daily is intended to mean once or more daily administration of the therapeutic compounds of the combinations described herein (such as compounds of formula I) for a period of time. The term continuous is intended to mean daily administration of the therapeutic compounds of the combinations described herein (such as compounds of formula I) for an uninterrupted period of at least 10 days to 52 weeks. As used herein, the terms intermittent or intermittently are intended to mean stopping and starting at regular or irregular intervals. For example, intermittent administration of the therapeutic compounds of the combinations described herein (such as compounds of formula I) includes administration 1 to 6 days per week (e.g., 2 to 3 times per week or QD), periodic administration (e.g., daily administration for two to eight consecutive weeks, followed by a rest period of at least one day without administration), or, for example, administration every other day.

[0194] When the inhibitor is an inhibitor antibody, it can be administered according to an established regimen (such as those provided in the packaging insert). The inhibitor antibody can be administered in the amounts described herein and can be administered QW, once every 2 weeks (Q2W), once every 3 weeks (Q3W), or once every 4 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 BIW for at least 3 weeks. In some embodiments, the inhibitor antibody is administered Q4W.

[0195] For example, inhibitor antibodies can be administered at doses of about 0.1 mg / kg to about 30 mg / kg (including, for example, 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, 30 mg / kg), QW. For example, inhibitor antibodies can be administered at doses of about 0.1 mg / kg to about 30 mg / kg (including, for example, 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, 30 mg / kg), Q2W. For example, inhibitor antibodies can be administered at doses of about 0.1 mg / kg to about 30 mg / kg (including, for example, 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, 30 mg / kg), Q4W. For example, inhibitor antibodies can be administered at a dose of about 0.1 mg / kg to about 30 mg / kg (including, for example, 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, 30 mg / kg), B4W (twice every 4 weeks). For example, inhibitor antibodies can be administered at doses of about 0.1 mg / kg to about 30 mg / kg (including, for example, 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, 30 mg / kg), Q3W.For example, inhibitory antibodies can be administered in doses of about 1000 mg to about 2000 mg (including, for example, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg), Q2W. For example, inhibitory antibodies can be administered in doses of about 1000 mg to about 2000 mg (including, for example, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg), Q3W. For example, inhibitory antibodies can be administered in doses of about 1000 mg to about 2000 mg (including, for example, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg), Q4W. The administration of inhibitory antibodies can be continuous. The administration of inhibitory antibodies can be intermittent.

[0196] Inhibitor antibodies can be administered as an intravenous infusion over approximately 10, 20, 30, 40, 50, or 60 minutes or more. Inhibitor antibodies can be administered as an intravenous infusion over approximately 60 minutes every 1, 2, 3, 4, 5 weeks or more. Inhibitor antibodies can be administered as an intravenous infusion over approximately 60 minutes every two weeks. Inhibitor antibodies can be administered as an intravenous infusion over approximately 60 minutes every three weeks. Inhibitor antibodies can be administered as an intravenous infusion over approximately 60 minutes every four weeks. Inhibitor antibodies can be administered as an intravenous infusion according to the packaging insert. Inhibitor antibody administration can be continuous. Inhibitor antibody administration can be intermittent.

[0197] The combinations described herein can be administered in a regimen. A regimen can be constructed to provide a therapeutically effective amount of a compound of Formula I and an inhibitor (such as an inhibitor antibody) over a predetermined time period (e.g., administration time). A regimen can be constructed to limit or prevent side effects or undesirable complications of each component of the combination described herein. A regimen can be constructed in a manner that results in an increased effect (e.g., synergistic) of the two therapies in the combination. A regimen for treating cancer can include any number of administration days that can be repeated as needed. Administration periods can include rest periods during which at least one therapy is not administered. For example, a regimen can include administration periods comprising 2, 3, 5, 7, 10, 15, 21, 28 days or more. These periods can be repeated. For example, a regimen can include a set number of days as described above, wherein the regimen is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more times.

[0198] The protocol may include rest periods 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. Rest periods can be determined, for example, by monitoring the patient's response to the medication or by measuring the efficacy of the treatment. Rest periods may be applied to a single therapy, such that only one therapy in the combination described herein is discontinued during the rest period, while other therapies continue to be administered. Rest periods may be applied to all therapies administered to the subject, such that the subject is not receiving any therapy for a defined period during the rest period.

[0199] The regimens described in this article for the use of combination therapy for cancer can be continued until disease progression or unacceptable toxicity.

[0200] Regimes for administering the combinations described herein include, for example, BIW or TIW administration of a compound of Formula I and administration of a PD-L1 and / or PD-1 inhibitor, plus a CTLA-4 inhibitor. For example, the compound of Formula I may be administered QD for approximately 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 embodiment, the compound of Formula I may be administered TIW, and the inhibitor described herein may be administered Q2W, Q3W, or Q4W. In some cases, such embodiments include administration of an inhibitor antibody administered Q2W, Q3W, or Q4W. In some cases, such embodiments include administration of the compound of Formula I administered QD. In some cases, such embodiments include administration of the compound of Formula I administered QD for at least 21 days. In yet another exemplary embodiment, the compound of Formula I may be administered QD or QW, and the inhibitor (e.g., an inhibitor antibody) may be administered Q2W, Q3W, or Q4W.

[0201] The regimen may be a regimen of administering an inhibitor antibody with a compound of Formula I as described herein. In one exemplary regimen including an inhibitor antibody, the compound of Formula I may be administered by first-time (BIW) or second-time (TIW), and the inhibitor antibody is administered according to prescribing information provided, for example, in a packaging insert. In another exemplary regimen, the inhibitor antibody is administered on day 1 of the regimen at an amount of about 1 mg / kg to about 20 mg / kg, and thereafter administered Q2W until disease progression or unacceptable toxicity, and the compound of Formula I is administered by BIW or TIW during the same time period. In another exemplary regimen, the inhibitor antibody is administered on day 1 of the regimen at an amount of about 1 mg / kg to about 20 mg / kg, and thereafter administered Q3W until disease progression or unacceptable toxicity, and the compound of Formula I is administered by BIW or TIW during the same time period. The inhibitor antibody may be administered together with the compound of Formula I Q4W, wherein the compound of Formula I is administered, for example, by BIW or TIW during the course of such a regimen. The inhibitor antibody may be administered together with the compound of Formula I Q2W, wherein the compound of Formula I is administered, for example, by BIW or TIW during the course of such a regimen. In yet another exemplary embodiment, the inhibitor antibody may be administered together with a compound of Formula I via Q2W or Q4W, wherein the compound of Formula I is administered, for example, via QD or QW, during the course of such an embodiment. Such embodiments may be repeated as described above (e.g., 1, 2, 3, 4, 5, 6, 7, 8 and 9, 10, 11, 12 or more times).

[0202] In another exemplary regimen including an inhibitor antibody, the compound of Formula I may be administered QD, and the inhibitor antibody may be administered according to prescribing information provided, for example, in a packaging insert. In another exemplary regimen, the inhibitor antibody may be administered on day 1 of the regimen at an amount of about 1 mg / kg to about 20 mg / kg, and thereafter Q2W until disease progression or unacceptable toxicity, and the compound of Formula I may be administered QD during the same time period. In another exemplary regimen, the inhibitor antibody may be administered on day 1 of the regimen at an amount of about 1 mg / kg to about 20 mg / kg, and thereafter Q3W until disease progression or unacceptable toxicity, and the compound of Formula I may be administered QD during the same time period. The inhibitor antibody may be administered Q4W together with the compound of Formula I, wherein the compound of Formula I may be administered QD during the course of such a regimen. The inhibitor antibody may be administered Q2W together with the compound of Formula I, wherein the compound of Formula I may be administered QD during the course of such a regimen. Such regimens may be repeated as described above (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more times).

[0203] The combinations for treating cancer described herein can be co-administered with other active agents (e.g., anticancer agents) besides those present in the combinations described herein. Regimens for administering the combinations described herein (including the exemplary regimens described above) may be modified as needed to include the administration of such active agents. Administration of such active agents (e.g., anticancer agents) may be performed QD, QW, QM, BID, BIW, TIW, Q2W, Q3W, or Q4W, or according to the prescribing information for such anticancer agents as described, for example, in a packaging insert. Exemplary anticancer agents include, but are not limited to: ABRAXANE; abiraterone; ace-11; aclarubicin; acivicin; acodazole hydrochloride; acronine; actinomycin; acylfulvene; adenypenol; adozelesin; adriamycin; aldesleukin; all-trans-retinoic acid (ATRA); altretamine; ambamustine; ambomycin; and ametantrone acetate. acetate); Amidox; Amifostine; Aminoglutethimide; Aminolevulinic acid; Amrubicin; Amsacrine; Anagrelide; Anastrozole; Andrographolide; Antalepix; Anthramycin; Aphidicolin glycinate; Apurinic acid Arginine deaminase; ARRY-162; ARRY-300; ARRY-142266; AS703026; Asparaginase; Asperlin; Asulacrine; Atamestane; Atrimustine; Axinastatin 1; Axinastatin 2; Axinastatin 3; Azasetron; Azatoxin; Azatyrosine;Azacitidine; AZD8330; Azatepa; Azotomycin; Balanol; Batimastat; BAY 11-7082; BAY 43-9006; BAY869766; Bendamustine; Benzochlorin; Benzodepa; Bendostolin; β-alethine; Beta-aclamycin B; Betulinic acid; β-FGF inhibitor; Bicalutamide; Bisantrene; Bisaziridinylspermine; Bisnafide; Bisnafide dimethylsulfonate; Bistratene A A); Bismuth subsalicylate; Bleomycin; Bleomycin sulfate; Busulfan; Bizelesin; Breflate; Bortezomib; Brequinar sodium; Bropirimine; Budotiane; Butthionine sulfoximine; Bryostatin; Cactinomycin; Calusterone; Calcipotriol; Calphostin C; Camptothecin derivatives; Capecitabine; Carboxamide-amino-triazole; Carboxyamidotriazole; CaRest M3; CARN 700; caracemide; carbetimer; carboplatin; carmustine; carrubicin hydrochloride; carzelesin; castanospermine; cecropin B; cedefingol; celecoxib; cetrorelix; chlorin;Chloroquinoxaline sulfonamide; cicaprost; chlorambucil; chlorofusin; cirolemycin; cisplatin; CI-1040; cisporphyrin; cladribine; clomifene analogs; clotrimazole; colismycin A; colismycin B; compretastatin A4; colretastatin analogs; conagenin; crambescidin 816; cristatol; cristatol mesylate; cryptophycin 8; cryptophycin A derivatives; curacin A; Cyclopentanthraquinones; Cycloplatam; Cypemycin; Cyclophosphamide; Cytarabine; Cytarabine phosphoside; Cytolysin; Cytostatin; Dacarbazine; Dactinomycin; Daunorubicin; Daunorubicin Hydrochloride; Dacarbazine; Dacliximab; Dasatinib; Decitabine; Dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; didox; diethylnorspermine; dihydro5azacytidine; dihydrotaxol; 9-dioxamycin; diphenylspiromonasine spiromustine; docetaxel; doxorubicin; doxorubicin hydrochloride; doxifluridine;Droloxifen; Droloxifen Citrate; Dronadanolone Propionate; Dronabinol; Duazomycin; Duocarmycin SA; Ebselen; Ecomustine; Edelfosine; Edrecolomab; Edatraxate; Eflornithine Hydrochloride hydrochloride; efornithine; elemene; emitefur; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin; epirubicin hydrochloride; epristeride; erbulozole; eribulin; esorubicin hydrochloride hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprine; exemestane; fadrozole; fadrozole hydrochloride; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fluxuridine; fludarabine phosphate; fludarabine; fluorodaunorubicin hydrochloride hydrochloride; forfenimex; formestane; fluorouracil; floxouridine; flurocitabine; fosquidone; fostriecin sodium; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine;Ganirelix; gelatinase inhibitor; gemcitabine; geldanamycin; gossyphol; GDC-0973; GSK1120212 / trametinib; herceptin; hydroxyurea; hepsulfam; heregulin; hexamethylenediacetamide; hypericin; ibandronic acid acid); ibrutinib; idarubicin; idarubicin hydrochloride; ifosfamide; canfosfamide; ilmofosine; iproplatin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridone; imatinib (e.g., GLEEVEC); imiquimod; iobenguane; iododoxorubicin; ipomeanol; irinotecan; irinotecan hydrochloride; irsogladine; isobengazole; isohomohalicondrin B; itasetron; iimofosine; interleukin Il (including recombinant interleukin IL-2; or r1L2); interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon β-la; interferon γ-1b; jasplakinolide; kahalalide F; lamellarin Ntriacetate; lanreotide; leinamycin; lenograstim; lentolstatin sulfate; letrozole; leuprorelin; levamisole; liarozole; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;Lovastatin; Loxoribine; Lurtotecan; Luttium texaphyrin; Lysofylline; Lanreotide acetate; Lapatinib; Letrozole; Leucovorin; Leuprolide acetate; Liarozole hydrochloride; Lometrexol sodium; Lomustine; Lenalidomide; Lenvatinib; Loxoanthraquinone hydrochloride; LY294002; Pomalidomide; Maitansine; Mannostatin A; Marimastat; Masoprocol; Maspin; Matrix dissolving factor inhibitor; Menogaril; Merbarone; Meterelin; Methioninase; Metoclopramide; MIF inhibitor; Mifepristone; Miltefosine; Mirimostim; Mitoguazone; Mitolactalol; Mitonafide; Mitoxantrone; Mofarotene; Molgramostim; Mopidamol; Mycaperoxide B; Myriaporone; Maytansine; Mechlorethamine hydrochloride; Megestrol Acetate); Melengestrol acetate; Melphalan; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocoromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxanthraquinone hydrochloride; Mycophenolic acid;Nafarelin; Nagrestip; Napavin; Naphterpin; Nartograstim; Nedaplatin; Nemorubicin; Neridonic acid; Nilutamide; Nisamycin; Nitric oxide regulator; Nitrooxide antioxidant; Nitrullyn; Nocodazole; Nogalamycin; Oblimersen (GENASENSE); Octreotide; Ocidenone; Oligonucleotide; Onapristone Ondansetron; Ondansetron; Oracin; Oral cytokine inducer; Ormaplatin; Oxisuran; Oxaloplatin; Osaterone; Oxaliplatin; Oxaunomycin; Palauamine; Palmitoylrhizoxin; Pamidronate; Panomifene; Parabactin; Pazelliptine; Pegaspargase; Peldesine; Pentosan sulfate sodium polysulfate sodium); pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitor; picibanil; pilocarpine hydrochloride; pirarubicin; piritraxim; placetin A; placetin B; porfiromycin; prednisone; prostaglandin J2; pyrazoloacridine; paclitaxel; PD035901; PD184352; PD318026; PD98059; peliomycin;Pentamustine; Peplomycin sulfate; PKC412; Pipobroman; Piposulfan; Piroxantrone hydrochloride; plicamycin; Plomestane; Podophyllotoxin; Polyphenol E; Porphyromycin; Prednimustine; Procarbazine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazofurin; Raltitrexed; Ramosetron; Demethylated Retelliptine (demethylated); rhizoxin; rituximab; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; riboprine; romidepsin; safingol; safingol hydrochloride; saintopin; sarcophytol A A); Sargramostim; Semustine; Sizofiran; Sobuzoxane; Sodium Borocaptate; Sodium Phenylacetate; Solvent; Sonermin; Sorafenib; Sunitinib; Sparfosic acid; Spiramycin D; Spiramustine; Splenopentin; Spongistatin 1); Spongistatin 2; Spongistatin 3; Spongistatin 4; Spongistatin 5; Spongistatin 6; Spongistatin 7; Spongistatin 8; and Spongistatin 9; Squalamine; Stipiamide; Stromelysin inhibitor; Suradista; Suramin; Swainsonine; SB239063;Selumetinib / AZD6244; Simtrazene; SP600125; Sparfosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiroplatin; Streptonigrin; Streptozocin; Sulofenur; Talimustine; Tamoxifen methiodide; Tauromustine; Tazarotene; Tecogalan sodium sodium); tegafur; tellurapyrylium; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thymalfasin; thymopoietin receptor agonist; thymotrinan; tirapazamine; titanocene bichloride; topsentin; toremifene; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrphostin; talisomycin; TAK-733; taxotere; tegafur; teloxantrone hydrochloride; teroxirone; testolactone; thiotepa; tiazofurin; tirapazamine; toremifene citrate citrate); trastuzumab; trestolone acetate;Triciribine phosphate; Trimetrexate; Trimetrexate glucuronate; Triptorelin; Tubulozole hydrochloride; Tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL); UBC inhibitor; Ubenimex; U0126; Uracil mustard; Uredepa; Vapreotide; Varian B; velaresol; veramine; verteporfin; vinorelbine; vinxaltine; vitaxin; vinblastine; vinblastine sulfate; vinblastine sulfate; vindesine; vindesine sulfate; vinpidin sulfate; vinblastine sulfate; vinblastine sulfate; vinorelbine tartrate; vindrodine sulfate; vinorelbine sulfate; vorozole; wortmannin; XL518; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer; zinostatin; and zorubicin hydrochloride.

[0204] Other exemplary anticancer agents include irbuprozole (e.g., R-55104); dolastatin 10 (e.g., DLS-10 and NSC-376128); mivobulin 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); cimedotin 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 AN-oxide; 16-aza-epothilone B; 21-aminoepothilone B; 21-hydroxyepothilone D; 26-fluoroepothilone; Reoxetine PE (Auristatin PE) (e.g., NSC-654663); Soblidotin (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); BSF-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); Vitivalamide; Tubulysin A; Canadensol; CA-170 (Curis, Inc.); Centaureidin (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); Fijianolide B; Laulimalide; SPA-2 (Parker Hughes Institute); SPA-1 (Parker Hughes Institute); Institute; e.g., SPIKET-P); 3-IAABU (cytoskeleton / Mt. 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 / Mt. 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 / Mt. Sinai School of Medicine); Medicine); A-204197 (Abbott); T-607 (Tuiarik; e.g., T-900607); RPR-115781 (Aventis); Eleutherobin (e.g., Desmethyleleutherobin; Desaetyleleutherobin; Isoeleutherobin A; and Z-Eleutherobin); Caribaeolin;Halichondrin B; D-64131 (Asta Medica); D-68144 (Asta Medica); Diazotamide A; A-293620 (Abbott); NPI-2350 (Nereus); Taccalonolide A; TUB-245 (Aventis); A-259754 (Abbott); Diozostatin; (-)-Phenylahistin (e.g., NSCL-96F037); D-62638 (Asta Medica); D-62636 (Asta Medica); Myoseverin B B); D-43411 (Zentaris; e.g., D-81862); A-289099 (Abbott); A-318315 (Abbott); HTI-286 (e.g., SPA-110; trifluoroacetate) (Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI); Resverastatin phosphate sodium; BPR-OY-007 (National Health Research) Institutes); and SSR-250411 (Sanofi); goserelin; leuprolide; triptolide; homoharringtonine; topotecan; itraconazole; deoxyadenosine; sertraline; pitavastatin; clofazimine; 5-nonyloxytryptamine mine); 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 (desmethyl erlotinib) erlotinib; AZD8931; AEE726; pelitinib / EKB-569; CUDC-101; WZ8040; WZ4002; WZ3146; AG-490; XL647; PD153035; 5-azathioprine; 5-aza-2'-deoxycytidine; 17-N-allylamino-17-demethoxygerdin (17-AAG); 20-epim-1,25-dihydroxyvitamin D3; 5-ethynyluracil; and BMS-599626.

[0205] In some embodiments, the combinations described herein are co-administered with the aforementioned anticancer agents, wherein the anticancer agents have known activity against a specific cancer (e.g., gemcitabine co-administered with the combinations described herein for the treatment of pancreatic cancer). The aforementioned anticancer agents may be approved for use in treating certain indications (e.g., certain cancers) at concentrations, amounts, and treatment regimens known in the art.

[0206] It should be understood that modifications that do not substantially affect the activity of various embodiments of the invention are also included within the definition of the invention provided herein. Although the invention has been described with reference to the disclosed embodiments, those skilled in the art will readily understand 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.

[0207] Example

[0208] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

[0209] This embodiment is an open-label dose-finding Phase Ib / 2 study of the combination of HBI-8000 (also known in the art as “chidamide” or “tucitabine”, and a compound of formula I, referred to herein as such) and nivolumab in patients with advanced solid tumors, including melanoma, RCC (renal cell carcinoma), and NSCLC (non-small cell lung cancer). The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki, and with the assurance / approval of the U.S. Department of Health and Human Services; the protocol was approved by the institutional review committees or ethics committees of all participating sites. All patients provided written informed consent prior to enrollment.

[0210] One objective of Phase Ib 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 the Phase II recommended dose (RP2D) of HBI-8000, and assess the frequency and severity of toxicities of the combination as evaluated by NCI CTC version 4.03. Another objective included evaluating the pharmacokinetics of HBI-8000 and its effect on heart rate-corrected electrocardiogram (ECG) QT interval (QTc interval), if present.

[0211] HBI-8000 was evaluated for oral administration at three dose levels (20 mg, 30 mg, and 40 mg) twice weekly (BIW). The medication is taken approximately 30 minutes after a meal. The starting dose (20 mg) was selected based on pharmacokinetic characteristics established as a monotherapy in Japanese patients with T-cell lymphoma. Continuous administration of up to 40 mg BIW as a single agent in heavily pre-treated lymphoma patients has been safe and toxicities have been manageable. In combination with nivolumab, 20 mg as a starting dose is expected to be safe in combination with a standard dose of nivolumab because the monoclonal antibody is unlikely to interfere with the metabolism of HBI-8000.

[0212] The decision to gradually increase the dose is based on the standard 3+3 design and the observed incidence of dose-limiting toxicities (DLTs). Each treatment cycle is defined as 28 days. To assess DLT, a subject must have already experienced a DLT, or have received at least 75% of the planned HBI-8000 dose during the 28-day DLT assessment period without treatment delay due to toxicity. Subjects experiencing a DLT within the first two weeks after receiving 100% of the specified dose of HBI-8000 may also be assessed for DLT. Unacceptable toxicity is defined as grade 3 or higher non-hematologic and hematologic toxicity with clinical complications. Unacceptable toxicity observed within the first 28 days after HBI-8000 administration is considered a DLT. RP2D is identified as the highest dose in which the incidence of DLT is less than 33.3%. HBI-8000 administration continues until disease progression or unacceptable toxicity is observed. Based on the evaluation criteria of Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1, progression-free survival, and duration of response, and based on objective response rate, the potency of the combination was further evaluated in an expanded cohort of the selected patient population under RP2D.

[0213] Patient selection

[0214] Adults 18 years of age or older with histopathologically or cytologically confirmed advanced non-uveal melanoma, RCC, or NSCLC who are instructed to use nivolumab are eligible for screening, provided they are instructed to use nivolumab. Patients must have ≥1 measurable target lesion (as defined by RECIST v.1.1 (Eisenhauer 2009)), Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (Oken 1982), and a life expectancy of at least 12 weeks. The primary exclusion criteria include hypersensitivity to monoclonal antibodies, cardiovascular disease, uncontrolled hypertension, active brain metastases, meningeal disease, severe gastrointestinal disease, autoimmune disease, severe infection, human immunodeficiency virus, and active hepatitis B.

[0215] evaluate

[0216] Safety assessments included physical examination, vital signs, ECG, ECOG status, and laboratory tests. Adverse events (AEs) were classified according to the National Cancer Institute Criteria for Commonly Used Adverse Event Terminology (NCI CTCAE) version 4.03 and categorized using the Medication for Regulatory Activities Medical Dictionary (MedDRA) classification system version 18.0 or later.

[0217] Tumor evaluation was performed every 8 weeks until treatment was discontinued, and then every 12 (±1) weeks in subjects in whom no disease progression was observed, following the guidelines specified by RECIST v.1.1 and the criteria for evaluating immune-related responses in solid tumors (iRECIST).

[0218] Statistical analysis

[0219] Statistical analyses of safety, tolerability, and antitumor activity were primarily descriptive. Toxicity was tabulated by type and grade. The safety population included all patients receiving ≥1 dose of HBI-8000 and nivolumab. Continuous variables were summarized using descriptive statistics, and categorical variables were summarized by the number and percentage of each category. Pharmacokinetic parameters were analyzed using a non-compartmental method. Derived from version 6.4 (Certara, LP, Princeton, NJ, USA).

[0220] Non-room PK analysis

[0221] Non-atrioventricular PK analysis of HBI-8000 was performed in Phase 1b using continuous plasma concentration data collected up to 24 hours after the first (Cycle 1, Day 1; C1D1) dose and up to 7 hours after the ninth (C2D1) dose. In conjunction with PK, a Holter monitor was used to record 12-lead continuous digital ECGs (under controlled conditions to minimize digital noise) on baseline day (1–7 days prior to C1D1) and on C1D1 (Phase 1b only). Triple 10-second ECGs were extracted from the Holter flash card at matched time points up to 4 hours post-dose on baseline day and on C1D1. PR, QRS, RR, and QT intervals were analyzed by a central ECG laboratory. Meal times (breakfast) were normalized over two days and occurred ≥1 hour after the planned extraction time of the triplicate ECGs. Heart rate correction (QTcF) was performed on the measured QT data using Fridricia.

[0222] result

[0223] Phase 1b enrolled 17 patients: from August 2016 to August 2017, 3 at a 20 mg dose level, 7 at a 30 mg dose level, and 7 at a 40 mg dose level. Patient characteristics are summarized in Table 1. Apart from potential cancer diagnoses, there were no significant differences in baseline characteristics affecting safety assessment.

[0224] patient

[0225] Demographic and other baseline characteristics

[0226] Table 1. Patient characteristics based on dose groups

[0227]

[0228] Abbreviations: RCC = Renal Cell Carcinoma; NSCLC = Non-Small Cell Lung Cancer.

[0229] 1 Targeted therapies and immunotherapies do not include anti-PD-1, anti-PD-L1, and ipilimumab. 2

[0230] 2 Tumor-infiltrating lymphocyte therapy

[0231] Exposure:

[0232] Overall, the median (min, maximum) duration of study drug exposure was 2.8 (0.6, 28.3) months for HBI-8000 and 2.3 (0.5, 22.5) months for nivolumab. The median (min, maximum) total number of completed cycles was 3.0 (1, 31) cycles for HBI-8000 and 2.5 (1, 24) cycles for nivolumab.

[0233] Security

[0234] Dose-limiting toxicities (DLT)

[0235] The study enrolled a total of 17 patients; two patients were not evaluable for DLT; one patient in the 30 mg BIW dose group withdrew consent early, and one patient in the 40 mg BIW dose group discontinued early due to the need for a steroid dose higher than that permitted for managing underlying lung disease. Neither of these patients received the minimum 75% dose of HBI-8000 during the 28-day DLT assessment period. They were considered not evaluable for DLT but were included in the overall safety analysis.

[0236] Of the 15 patients evaluable for DLT, the first 3 were in the 20 mg dose group, followed by 3 in the 30 mg dose group. No patients experienced DLT. In the 40 mg group, 6 patients, including one with melanoma, experienced grade 3 headache 24–48 hours after the first dose and grade 3 diarrhea after the third dose, and one with RCC, experienced grade 3 fatigue on the day of HBI-8000 administration; these were considered DLT. Therefore, 40 mg was considered to exceed the MTD. Three additional patients were evaluated at a 30 mg BIW dose level. No DLT was observed. The RP2D for further evaluation of the safety and efficacy of the combination of HBI-8000 and nivolumab was determined to be 30 mg BIW.

[0237] Treatment-Emergent Adverse Event (TEAE)

[0238] All 17 patients who received HBI-8000 also received nivolumab. They were included in the safety analysis. The mean duration of HBI-8000 treatment was 6.2 months. Table 2 provides a detailed overview of TEAEs and treatment modifications attributable to HBI-8000 alone, nivolumab alone, or both.

[0239] Table 2: Summary of the number of subjects who experienced treatment-emergent adverse events (TEAEs) based on dose level

[0240]

[0241]

[0242] *DLT cannot be evaluated by 1 subject.

[0243] All 17 patients experienced treatment-associated adverse events (TEAEs); not all TEAEs were associated with HBI-8000, nivolumab, or both. TEAEs associated with the HBI-8000 and nivolumab combination were observed in 11 (64.7%) subjects, while those associated with HBI-8000 or nivolumab alone were observed in 10 (58.8%) subjects. Six subjects experienced TEAEs attributable to the combination and those associated with HBI-8000 alone. The incidence of TEAEs associated with HBI-8000 alone appeared to increase with progressively increasing HBI-8000 doses. However, no similar trend was observed with TEAEs associated with either the combination or nivolumab alone. Despite any differences in incidence, the number of TEAEs leading to treatment discontinuation appeared similar across the three dose levels.

[0244] Two patients experienced only grade 1 and 2 TEAEs, while 15 patients experienced grade 3 or higher TEAEs. It should also be noted that TEAEs associated with HBI-8000 and nivolumab (alone or in combination) were rare. Furthermore, grade ≥3 TEAEs were uncommon regardless of causality (Tables 3A-C).

[0245] TEAEs observed in ≥40% of all subjects were fatigue, decreased appetite, dyspnea, decreased platelet count, anemia, weight loss, nausea, diarrhea, and peripheral edema. Although more TEAEs appeared to be reported at HBI-8000 30 mg and 40 mg compared to 20 mg, there was no significant increase in grade ≥3 events at 40 mg. When examining HBI-8000-related TEAEs (regardless of severity), a slight increasing trend appeared at higher doses. However, this trend was not detected when examining TEAEs associated with the combination of HBI-8000 and nivolumab.

[0246] Grade ≥3 TEAEs observed in ≥15% of patients were fatigue, hypophosphatemia, decreased lymphocyte count, elevated lipase levels, and hypoxia. Aside from fatigue and hypoxia, they were asymptomatic. Grade ≥3 TEAEs occurred in all HBI-8000 dose groups.

[0247] SAEs were observed in 11 patients, with 4 experiencing SAEs associated with 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 3 patients (17.6%). One patient died from a TEAE unrelated to either HBI-8000 or nivolumab. No significant differences in the incidence, severity, causality, or severity of TEAEs were detected at the tested dose levels.

[0248] Table 3A. Description of adverse events observed in ≥4 patients who received 20 mg of HBI-8000

[0249]

[0250]

[0251] Table 3B. Description of adverse events observed in ≥4 patients who received 30 mg of HBI-8000

[0252]

[0253]

[0254] Table 3C describes adverse events observed in ≥4 patients who received 40 mg of HBI-8000. Table 3C also records adverse events observed in a total number of patients who received 20 mg, 30 mg, and 40 mg of HBI-8000.

[0255]

[0256]

[0257]

[0258] *One subject could not evaluate DLT.

[0259] Pharmacokinetics

[0260] HBI-8000 concentration

[0261] Following a single dose of HBI-8000 on Day 1 of Cycle 1 (C1D1), mean plasma concentrations of HBI-8000 were generally comparable between the 20 mg and 30 mg doses. At each sampling time point up to 24 hours post-dose, mean HBI-8000 concentrations were higher at the 40 mg dose compared to the 30 mg dose. A similar trend in HBI-8000 concentrations was observed for C2D1 up to 7 hours post-dose after 4 weeks of continuous administration according to the BIW schedule in Cycle 1. Notably, nivolumab was administered after plasma collection determined by the HBI-8000PK of the first and ninth doses of HBI-8000. See Figures 1A-B.

[0262] HBI-8000 Pharmacokinetic Parameters

[0263] In the 20, 30, and 40 mg BIW dose groups, the median time to peak plasma concentration (tmax) ranged from 5 to 7 hours post-dose (Table 4). Under C1D1, exposure parameters [Cmax, AUC]... 0-24 and / or AUC 0-7 The levels are generally comparable between 20 and 30 mg doses. For the first dose (C1D1) and the ninth dose (C2D1), an increase in HBI-8000 exposure was observed at the 40 mg dose relative to the 30 mg dose.

[0264] No significant accumulation of HBI-8000 was observed when pharmacokinetic parameters were compared between the first and ninth doses. In the 30 mg BIW and 40 mg BIW dosing regimens, the geometric mean ratio (C2D1:C1D1) of the HBI-8000 exposure parameters ranged from 1.08 to 1.18 for Cmax and for AUC. 0-7 It ranges from 1.36 to 1.37.

[0265] Table 4. Geometric mean (geometric CV%) of HBI-8000 pharmacokinetic parameters on day 1 of cycles 1 and 2

[0266] Abbreviation: AUC 0-7=Area under the concentration-time curve (AUC) from 0 to 7 hours after administration; AUC 0-24 =AUC from 0 to 24 hours after administration; C max = Maximum observed concentration; C Pre = Pre-dose (valence) concentration; CV% = Percentage coefficient of variation; / D = Dose normalization parameter; n = Number of valid observations for each parameter, unless otherwise stated; n / a: Not applicable; t max = Arrive at C max The time.

[0267] a The data presented for this parameter is the median (minimum, maximum).

[0268] b Since n=2, it presents a single value.

[0269] c n = 6

[0270] d n = 3.

[0271] Analysis of time-matched plasma concentrations of QTcF using HBI-8000

[0272] 12-lead Holter electrocardiogram measurement

[0273] All patients in the pharmacodynamic cohort (N=16) had baseline QTcF or QT interval values ​​below 450 ms on Holter ECG. Following single-dose administration of HBI-8000 at C1D1 at 20, 30, or 40 mg, changes in baseline (Δ) ventricular heart rate remained substantially stable across the assessed doses within the 0- to 4-hour observation interval, suggesting that the heart rate-corrected QT interval (QTcF; QTc corrected using the Fridericia correction formula) was unlikely to be affected by heart rate variations. This was supported by scatter plots of individual patient log QTcF versus log RR values, which showed no statistically significant (p=0.1588) unidirectional trend across these ECG intervals (see Figure 2). Therefore, this observation excludes the possibility of heart rate as a confounding factor in assessing the effect of HBI-8000 plasma concentration on QTcF.

[0274] The mean and median ΔQTcF showed indistinguishable changes at time points at the 30 mg dose (median values ​​of 0 to -1.5 ms), but a decrease was observed at the 40 mg dose (median values ​​of -3.0 to -11.5 ms), with the highest median decrease (i.e., -11.5 ms) observed at 4 hours post-dose, which was at C maxThe last time point for nearby assessment. Two patients receiving the 20 mg BIW dose of HBI-8000 had left or right bundle branch block, which ruled out the estimation of QT values. Therefore, QTcF evaluation was only applicable to one of the three patients in the 20 mg dose group.

[0275] Relationship between HBI-8000 concentration / exposure and ECG QT interval

[0276] An inverse relationship was observed between ΔQTcF and HBI-8000 concentration, with QTcF decreasing with increasing HBI-8000 exposure. Concentration-QT modeling indicated a negative slope between ΔQTcF and HBI-8000 concentration (slope estimate [95% CI] -0.02154 [-0.03426, -0.008814]). The inverse relationship between plasma concentration and ΔQTcF revealed by concentration-QT modeling is consistent with the trend observed at a 40 mg dose, although a similar inverse relationship was not detected at a 30 mg dose. The model residual versus time check ruled out the possibility of time as a confounding factor that could affect the statistical results, and no positive hysteresis was found.

[0277] The model predicts the geometric mean C for 20, 30, and 40 mg HBI-8000 doses. max The average ΔQTcF values ​​were -2.3, -2.5, and -5.6 ms (Table 5), with the average upper 90% confidence limits ranging from -1.1 to -2.8 ms, which are far below the 10 ms threshold for significant effects (Table 5).

[0278] Table 5: Statistical estimation of QTcF changes from baseline at maximum plasma drug concentrations of HBI-8000

[0279]

[0280] This substudy was designed to investigate whether HBI-8000 at maximum plasma concentrations would prolong QTcF. Holter ECGs were collected up to 4 hours after administration, but the tmax in this study was greater than the 4-hour prediction from a previous single-dose PK study of HBI-8000 in Japan. Therefore, the median plasma concentration at 4 hours was 17%, 19%, and 15% lower than the Cmax values ​​for 20, 30, and 40-mg doses, respectively. Because no hysteresis effect was observed and because ΔQTcF showed an inverse relationship with HBI-8000 concentration, where QTcF decreases more significantly at higher concentration and dose levels, this discrepancy with tmax was not expected to affect the conclusion that there was no significant effect on QTcF within this dose range. In this study, there were no QTcF values ​​>450 ms and no ΔQTcF values ​​>30 ms. The conclusion is that HBI-8000 at the administered dose and regimen does not prolong QTcF.

[0281] Preliminary anti-tumor effect

[0282] Of the 17 enrolled subjects, 15 underwent tumor evaluation after receiving HBI-8000 and nivolumab. Signals of antitumor activity were evident in melanoma, RCC, and NSCLC (Figure 3). When tumor response was evaluated by RECIST v.1.1, all 5 melanoma patients responded as follows: 1 achieved a complete response (CR) and 4 achieved a partial response (PR). In the 3 NSCLC patients, 1 had a PR and 2 had stable disease without disease progression. In the RCC patients, 2 out of 7 had a PR, 1 had stable disease, and 4 had disease progression. Tumor responses were observed at all dose levels (Figure 3).

[0283] The time course of clinical response was also analyzed (Figure 4). Observation of antitumor effects began early and became clinically apparent with subsequent follow-up. The earliest objective response was observed at the end of Cycle 2, 8 weeks after treatment, via imaging studies during the initial tumor evaluation of the first program. The longest time from treatment initiation to response in one patient was 32 months, although a partial response (PR) was observed 16 months after discontinuation of nivolumab and HBI-8000 in that patient.

[0284] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in the practice of the invention. The appended claims are intended to define the scope of the invention and thereby cover the methods and structures within the scope of these claims and their equivalents.

Claims

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

2. The method of claim 1, wherein the administration of HDACi causes a reduction in the subject's QTc, QTcF, or HR.

3. The method of claim 1 or claim 2, wherein administering the HDACi to the subject at an increased dose results in a decrease in QTcF.

4. The method according to any one of claims 1-3, wherein administering the HDACi to the subject does not result in a change in HR or a decrease in HR.

5. The method according to any one of claims 1-4, wherein the HDACi suppresses Class I and Class IIb HDACs.

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

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

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

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

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

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

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

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

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

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

16. The method of claim 15, wherein the duration of the period is from about one week to about ten weeks.

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

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

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

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

21. The method of claim 20, wherein nivolumab is administered to the subject at a dose of 240 mg every two (2) weeks.

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