EA045229B1 - COMBINATION OF HDAC AND PD-1 INHIBITORS AND ITS USE FOR THE TREATMENT OF COLON CANCER - Google Patents

Description

Field of technology

The present invention relates to combinations of HDACi and PD-1 inhibitors and the use of such combinations in the treatment of cancer.

State of the art

Cancer is a significant cause of morbidity and mortality worldwide. Although standards of care for many different types of cancer have improved significantly in recent years, current standards of care still cannot meet the need for effective therapies to improve cancer treatment. Clinical application of immuno-oncology agents targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death receptor-1 (PD-1) and its ligand PD-L1 have led to improvements in the treatment of many types of cancer. compared to the standard of care. Although these checkpoint inhibitors have resulted in improved clinical responses in these specific cancer types, durable clinical responses occur in only approximately 10% to 45% of patients. In addition, a significant number of tumors are either resistant or become refractory. Epigenetic modifiers such as histone deacetylase inhibitors (HDACi) have demonstrated successful results in the treatment of several hematologic malignancies, but despite preclinical data demonstrating activity against solid tumors, this finding has not translated into clinical use as monotherapy. Accordingly, there is a need in the art for new therapeutic options, including, for example, combination therapy options, for the treatment of cancer. This document provides solutions to these and other problems in the art.

Brief description of the invention

In a first aspect, the present invention provides a combination comprising a therapeutically effective amount of an anti-PD-1 antibody and a compound represented by the following structure:

ABOUT

or a pharmaceutically acceptable salt thereof, wherein said compound is present in an amount of at least 5 mg and wherein said combination is intended for administration to a patient suffering from colon cancer.

Preferably, said compound is present in an amount of 5 to 50 mg.

In one embodiment, the anti-PD-1 antibody is a monoclonal antibody, a human antibody, a murine antibody, a chimeric antibody, a humanized antibody or a chimeric humanized antibody, a peptibody, a diabody, a minibody, a single chain variable fragment (ScFv), or a fragment or variant thereof.

In a preferred embodiment, said humanized antibody includes nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680.

In another preferred embodiment, said anti-PD-1 antibody is present in an amount of from 0.1 to 10 mg/kg based on body weight.

In another preferred embodiment, said anti-PD-1 antibody is present in an amount of from 0.5 to 5 mg/kg based on body weight.

In another preferred embodiment, said anti-PD-1 antibody is present in an amount of: 1, 2, 3 or 5 mg/kg based on body weight.

In a second aspect, the present invention relates to a pharmaceutical composition containing the above combination and a pharmaceutically acceptable excipient.

In a third aspect, the present invention relates to a kit containing the above combination or the above pharmaceutical composition and further comprising one or more containers, instructions for use and/or medical devices for administration.

In a fourth aspect, the present invention relates to a method of treating colon cancer, comprising administering a therapeutically effective amount of the above combination or the above pharmaceutical composition to a patient in need thereof.

In one embodiment of the method, said cancer patient has not previously been treated.

In another embodiment of the method, said combination is administered to said cancer patient as first-line therapy.

In another embodiment of the method, said combination is administered to said cancer patient as second, third, fourth, fifth or sixth line therapy.

In another embodiment of the method, said combination is administered to said cancer patient after treatment with at least one anticancer therapy.

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Preferably, said anticancer therapy includes chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, or a combination thereof.

In one embodiment of the method, said cancer is resistant to at least one anticancer agent.

In another embodiment of the method, said compound of Formula I and said PD-1 inhibitor of said combination are administered simultaneously or sequentially.

In another embodiment of the method, the specified compound of formula I is administered 2-3 times a week.

In another embodiment of the method, the specified compound of formula I is administered daily.

In another embodiment of the method, the PD-1 inhibitor and the specified compound of formula I are administered simultaneously on day 1 of the administration regimen.

In another embodiment of the method, said anti-PD-1 antibody is a peptibody, diabody, minibody, single chain variable fragment (ScFv), or a variant thereof.

Preferably, said anti-PD-1 antibody includes nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680.

In another embodiment of the method, the specified combination is administered to the specified patient according to the scheme.

In another embodiment of the method, the specified regimen is repeated until the disease progresses or unacceptable toxicity occurs.

In another embodiment of the method, the said regimen includes a rest period of at least 1 day between successive periods of administration.

In another embodiment of the method, the specified compound of the specified combination is administered 2-3 times a week according to the specified schedule, and the specified antibody to PD-1 is administered every 2-3 weeks.

In another embodiment of the method, the specified compound of the specified combination is administered once a day for 21 days according to the specified schedule, and the specified antibody to PD-1 is administered every 2-3 weeks.

In a preferred embodiment, said method of treating cancer inhibits metastases of said cancer in said patient, reduces tumor volume or tumor burden in said patient, inhibits pre-existing metastases of said cancer in said patient, prolongs the time until said cancer progresses in said patient, prolongs the life of the patient, prolongs the survival of the specified patient without disease progression.

In a fifth aspect, the present invention provides a method of treating primary or secondary colon cancer in a subject, characterized in that said treatment results in one or more of the following: (i) a reduction in the number of cancer cells; (ii) reduction of tumor volume; (iii) increasing the rate of tumor regression; (iv) reducing or slowing the infiltration of cancer cells into peripheral organs; (v) reducing or slowing tumor metastasis; (vi) reducing or inhibiting tumor growth; (vii) preventing or delaying the onset and/or reappearance of cancer and/or prolonging disease- or tumor-free life; (viii) increase in total life time; (ix) reducing the frequency of treatment; (x) reducing the cancer burden; and (xi) relieving one or more symptoms associated with the cancer, wherein said treatment comprises administering a therapeutically effective amount of the combination according to any one of claims 1 to 7 to said subject in need of treatment.

Description of graphic materials

Fig. 1 illustrates tumor growth by group as median tumor volume (mm ³ , y-axis) over time (day, x-axis) for all groups in the study described in Example 1 herein.

Fig. 2 illustrates tumor growth by group as median tumor volume ( ^mm3 , y-axis) over time (day, x-axis) for mice treated with compound (HBI-8000) at a concentration of 50 mg/kg in the study described in the example. 1 of this document.

Fig. Figure 3 illustrates survival (Kaplan-Meier) for all groups studied in the study described in Example 1 of this document.

Fig. 4 illustrates survival (Kaplan-Meier) for mice treated with compound (HBI-8000) at a concentration of 50 mg/kg in the study described in Example 1 herein.

Fig. 5 illustrates tumor growth by group as median tumor volume (mm ³ , y-axis) over time (day, x-axis) for all groups in the study described in Example 2 herein.

Fig. Figure 6 illustrates survival (Kaplan-Meier) for all groups studied in the study described in Example 2 of this document.

Fig. 7 illustrates the individual time to study endpoint for each animal in Example 2 of this document.

Fig. Figure 8 illustrates the survival (Kaplan-Meier) of the study described in Example 3 of this document.

Fig. 9 illustrates the individual time to study endpoint for each animal in Example 3 of this document.

Fig. 10 illustrates the number of metastatic pulmonary lesions for the study described in

- 2 045229 example 4 of this document.

Fig. Figure 11 illustrates the median tumor growth curves for all study groups.

Detailed Description of the Invention

Definitions.

All patents, applications, published applications and other publications are incorporated by reference in their entirety. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which the invention pertains. The chemical structures and formulas given herein are compiled in accordance with the standard rules of chemical valence known in the field of chemistry. If there is a discrepancy between a given structure and the name given to that structure, the given structure should be taken as having greater weight. If the stereochemistry of a structure or part of a structure is not indicated in a given structure or part of a given structure, the given structure should be interpreted as including all possible stereoisomers.

Any methods, devices and materials similar or equivalent to those described herein can 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 the present invention. If there are multiple definitions for a given term, those given in this section take precedence unless otherwise noted. The headings used herein are for purposes of organization only and are not intended to limit in any way the invention described herein.

The term PD-1 inhibitor refers to a fragment (e.g., compound, nucleic acid, polypeptide, 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, isoforms, species homologues of human PD-1 (eg, murine) and analogues that share at least one epitope with PD-1. A PD-1 inhibitor includes molecules and macromolecules such as, for example, compounds, nucleic acids, polypeptides, antibodies, peptibodies, diabodies, minibodies, single chain variable fragments (ScFv) and fragments or variants thereof. Thus, as used herein, a PD-1 inhibitor refers to any moiety that antagonizes the activity or expression of PD-1. The effectiveness of a PD-1 inhibitor can be determined, for example, by the inhibitor concentration at 50% (the half-maximal inhibitor concentration or IC ₅₀ ). PD-1 inhibitors include exemplary compounds and compositions described herein. Anti-PD-1 antibody refers to a PD-1 inhibitor, which is a monoclonal or polyclonal antibody as described herein.

The terms nivolumab, pembrolizumab, pidilizumab, AMP-224, REGN2810, PDR 001, SHR-1210, SAR-439684 and MEDI0680 are used according to their obvious and generally accepted meaning as understood in the art.

The terms polypeptide and protein are used interchangeably herein and refer to any molecule that contains at least 2 or more amino acids.

The term effective amount refers to an amount of a therapeutic agent (eg, a combination provided herein or another active agent described herein, such as an anticancer agent described herein) that is sufficient to achieve the stated purpose or otherwise achieve the effect for which it is introduced. An effective amount may be sufficient to reduce and/or reduce the progression, development, reappearance, severity and/or duration of the disease, disorder or condition and/or symptom associated therewith, or may be sufficient to reduce the level of activity of the polypeptide (e.g., PD -1). An effective amount may be a therapeutically effective amount, which refers to an amount sufficient to provide a therapeutic benefit, such as, for example, reducing or reducing the prevalence or progression of a given disease, disorder or condition, reducing or reducing the reappearance, development or onset of a given disease, disorder or condition, and/or improving or enhancing the prophylactic or therapeutic effect(s) of another therapy option. A therapeutically effective amount of a composition described herein may enhance the therapeutic efficacy of another therapeutic agent.

The term regimen refers to a dosing protocol and schedule of administration of one or more therapeutic options (for example, combinations described herein or another active agent, such as, for example, an anticancer agent described herein) for the treatment of a disease, disorder or pathological described herein. condition. The regimen may include periods of active administration and periods of rest, as is known in the art. Active administration periods include administration of the combinations and compositions described herein and the length of time such combinations and compositions are effective. The rest periods of the regimens described herein include a period of time during which the active compound is not actively administered and, in some cases, include periods of time when the effectiveness of such compounds

- 3 045229 may be the minimum. The combination of active administration and rest in the regimens described herein may increase the effectiveness and/or duration of administration of the combinations and compositions described herein.

The terms therapeutic options and therapy refer to any protocols, methods and/or agents that can be used in the prevention, treatment, control and/or alleviation of a disease, disorder or condition, or one or more symptoms thereof. In some cases, the term refers to other active agents, such as the anticancer agents described herein. The terms therapeutic options and therapy may refer to antiviral therapy, antibacterial therapy, antifungal therapy, anticancer therapy, biological therapy, supportive care therapy and/or other therapy options used to treat, manage, prevent or alleviate a disease, disorder or condition or one or more symptoms thereof known to one skilled in the art, for example, a medical professional such as a physician.

The term patient or subject refers to a mammal such as a human, cattle, rat, mouse, dog, monkey, monkey, goat, sheep, cow or deer. Typically, in the context of this document, the patient is a human being.

The terms inhibition, inhibit refer to reducing the activity, binding or expression of a polypeptide or reducing or reducing a disease, disorder or pathological condition or symptom thereof. As used herein, inhibition may include partially or completely blocking stimulation, reducing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating protein or enzymatic activity.

The antibodies described herein may be polyclonal or monoclonal and include xenogeneic, allogeneic or syngeneic forms and modified versions thereof (eg, humanized or chimeric). Antibody is intended to mean a polypeptide product of B cells within the immunoglobulin class of polypeptides that is capable of binding to a specific molecular antigen and consists of two identical pairs of polypeptide chains, each pair having one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), and each amino-terminal portion of each chain includes a variable region of about 100 to about 130 or more amino acids, and each carboxy-terminal portion of each chain includes a constant region (see Borrebaeck (ed.) (1995) Antibody Engineering, Second Edition , Oxford University Press.; Kuby (1997) Immunology, Third Edition, W.H. Freeman and Company, New York). Specific molecular antigens that can be bound by the antibody described herein include PD-1 and its epitopes.

The term monoclonal antibody(ies) refers to a population of antibody molecules that contain a single type of antigen-binding site capable of immunoreaction with a specific epitope of an antigen, whereas the term polyclonal antibody(ies) refers to a population of antibody molecules that contain multiple types of antigen-binding sites that can interact with a specific antigen.

A monoclonal antibody typically exhibits a single binding affinity for the specific antigen with which it immunoreacts. For example, monoclonal antibodies for use in accordance with this invention can be produced by various methods, including, for example, the hybridoma method (for example, Kohler and Milstein., Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14 (3): 253-260 (1995), Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, ^2nd ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T -Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA techniques (see, for example, US Pat. No. 4,816,567), phage display technologies (see, for example, Clackson et al., Nature, 352: 624- 628 (1991); Marks et al., J Mol. Biol. 222: 581-597 (1992); Sidhuetal., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellowes, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004); and Lee et al., J. Immunol Methods 284(1-2): 119-132 (2004) and technologies for the production of human or human-like antibodies in animals that have parts or all of human immunoglobulin loci or genes encoding human immunoglobulin sequences (see, for example, WO 1998/ 24893; WO 1996/34096; WO 1996/33735; WO 1991/10741; Jakobovits et al., Proc. Natl. Acad. Sci. USA 90:2551 (1993); Jakobovits et al., Nature 362: 255-258 (1993); Bruggemann et al., Year in Immunol. 7:33 (1993); US Patents No. 5545807; 5545806; 5569825; 5625126; 5633425; and 5661016; Marks et al., Bio/Technology 10: 779-783 (1992); Lonberg et al., Nature 368: 856-859 (1994); Morrison, Nature 368: 812813 (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).

As used herein, monoclonal antibodies also include chimeric antibodies (immunoglobulins) in which part of the heavy and/or light chain is identical or homologous to the corresponding sequences in antibodies derived from a particular species or belonging to a particular class or subclass of antibodies, while the remaining chain ( i) identical or homologous to corresponding sequences in antibodies obtained from another species or belonging to another class or subclass of antibodies, as well as fragments of such antibodies, provided that they exhibit the necessary 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.

The term human(s), when used with respect to an antibody or functional fragment thereof (e.g., humanized antibody(s)), refers to an antibody or functional fragment thereof that has a human variable region or portion thereof corresponding to human germline immunoglobulin sequences . Such human germline immunoglobulin sequences are described by Rabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242. A human antibody in the context of this invention may include an antibody that binds to PD-1 or variants thereof, as described herein.

In some cases, a human antibody is an antibody that has an amino acid sequence corresponding to that of an antibody produced in a human and/or generated by any human antibody technology as described herein. Human antibodies can be produced using a variety of technologies known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Also available for the production of human monoclonal antibodies are the methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1,985); Boemer et al., J. Immunol., 147(1):86-95 (1991). Also see van Dijk and van de Winkel, Curr. Opin. Pharmacol., 2: 368-74 (2001). Human antibodies can be produced by administering an antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic stimulation, but whose endogenous loci have been disabled, for example, as in the case of the immunized xenomic mouse (see, for example, US Pat. Nos. 6075181 and 6150584 regarding XENOMOUSE technology). Also see, for example, Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies produced using human B-cell hybridoma technology.

Humanized antibody refers to antibodies produced by a non-human cell that have variable or variable and constant regions that have been altered to more closely resemble antibodies that would be produced by a human cell. For example, by changing the amino acid sequence of a non-human antibody so that it includes amino acids found in human germline immunoglobulin sequences. The humanized antibodies of the invention may contain amino acid residues not encoded by human germline immunoglobulin sequences (eg, mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example, in the CDR. Humanized antibodies may also include antibodies in which CDR sequences derived from the germ line of another mammalian species, such as mice, have been grafted into human framework sequences.

Humanized forms of non-human (eg, murine) antibodies are antibodies that contain a minimal sequence derived from a non-human immunoglobulin. In one embodiment, the humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the hypervariable region of the recipient are replaced by residues from the hypervariable region of a non-human species (donor antibody), for example, a mouse, rat, rabbit or non-human primate, having the necessary specificity, affinity and/or capacity. In some cases, framework (FR) residues of human immunoglobulin are replaced by corresponding non-human residues. In addition, humanized antibodies may contain residues that are not found in the recipient antibody or the donor antibody. These modifications can be made to further improve antibody characteristics such as binding affinity. In general, a humanized antibody will contain substantially all of at least one and typically two variable domains in which all or substantially all of the hypervariable loops correspond to non-human immunoglobulin sequence loops and all or substantially all of the FR regions correspond to human sequence regions. immunoglobulin, although FR regions may contain one or more substitutions of individual FR residues that improve the characteristics of the antibody, such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in FRs generally does not exceed 6 in H- chain, and in the L chain does not exceed 3. The humanized antibody may also optionally contain at least a portion of an 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.

The term functional fragment, as used in relation to an antibody, refers to a portion of the antibody, including heavy or light chain polypeptides, that retains some or all of the binding activity of the antibody from which the fragment was derived. Such functional moieties may include, for example, Fd, Fv, Fab, F(ab'), F(ab) ₂ , F(ab') ₂ , single chain Fv (ScFv), diabody, tribody, tetrabody and minibody. Other functional fragments may include, for example, heavy or light chain polypeptides, variable region polypeptides or CDR polypeptides or portions thereof, provided that such functional fragments retain binding activity. Descriptions of such antibody binding fragments can be found, for example, in 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); Pluckthun and Skerra, Meth. Enzymol., 178:497-515 (1989) and in Day, E. D., Advanced Immunochemistry, Second Ed., Wiley-Liss, Inc., New York, NY (1990). Antibody Engineering, Second Edition, Oxford University Press, 1995.

The term heavy chain, as used in relation to an antibody, refers to a polypeptide chain of about 50-70 kDa in length, in which the amino-terminal portion contains a variable region of about 120 to 130 or more amino acids in length, and the carboxy-terminal portion contains a constant region. The constant region can be one of five different types, called alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the heavy chain constant region. 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 the light chain, these different types of heavy chains result in the formation of five well-known classes of antibodies, IgA, IgD, IgE, IgG and IgM, respectively, including four subclasses of IgG, namely IgG1, IgG2, IgG3 and IgG4. The heavy chain may be a human heavy chain.

The term light chain, as used in connection with an antibody, refers to a polypeptide chain of about 25 kDa in length, in which the amino-terminal portion contains a variable region of about 100 to about 110 or more amino acids in length, and the carboxy-terminal portion contains a constant region. The approximate length of the light chain is 211 to 217 amino acids. There are two different types, called kappa (k) or lambda (λ) based on the amino acid sequence of the constant domains.

Light chain amino acid sequences are well known in the art. The light chain may be a human light chain.

The term variable domain or variable region refers to a portion of the light or heavy chain of an antibody that is generally located at the amino terminus of the light or heavy chain and has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, and determines the binding and specificity of each specific antibody for its specific antigen. Variable domains can vary greatly in sequence between different antibodies. Variation in the sequence is concentrated in the CDRs, while the less variable parts in the variable domain are called framework regions (FRs). The light and heavy chain CDRs are primarily responsible for the interaction of the antibody with the antigen. The numbering of amino acid positions used herein corresponds to the EU index as described in Rabat et al. (1991) Sequences of proteins of immunological interest. (US Department of Health and Human Services, Washington, DC) ^5th ed. The variable region may be a human variable region.

A CDR refers to one of three hypervariable regions (H1, H2 or H3) within the non-framework region of the VH β-sheet fold structure of an immunoglobulin (Ig or antibody) or one of three hypervariable regions (L1, L2 or L3) within the non-framework region of the VH fold structure βlayer of VL immunoglobulin. Accordingly, CDRs are variable region sequences interspersed with framework region sequences. CDR regions are well known to those skilled in the art and have been identified, for example, by Rabat, as regions of greatest hypervariability within the variable (V) domains of antibodies (Rabat et al., J. Biol. Chem. 252:66096616 (1977); Rabat, Adv. Prot. Chem. 32:1-75 (1978)). CDR region sequences have also been defined structurally by Chothia as residues that are not part of the conserved β-sheet fold structure and are thus capable of adopting different conformations (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)) . Both terminologies are well known in the art. CDR positions within the variable domain of a canonical antibody have been determined by comparison of 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 among antibodies, additional residues relative to canonical positions are traditionally numbered by adding a, b, c, etc. to the residue number in the canonical variable domain numbering scheme (AlLazikani et al., supra (1997)) . Likewise, such nomenclature is well known to those skilled in the art.

For example, CDRs defined according to the Rabat (hypervariable), Chothia (structural), or MacCallum designations (J. Mol. Biol. 262:732-745 (1996)) are shown in Table. 1 below:

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Kabat ¹ Table 1. CDR Definitions Chothia ² MacCallum ³ Loop location V _H CDR1 31-35 26-32 30-35 linking chains B and C V _H CDR2 50-65 53-55 47-58 binding of chains C' and C V _H CDR3 95-102 96-101 93-101 linking chains F and G V _L CDR1 24-34 26-32 30-36 linking chains B and C V _L CDR2 50-56 50-52 46-55 binding of chains C' and C V _L CDR3 89-97 91-96 89-96 linking chains F and G

¹ Residue numbering follows the nomenclature of Kabat et al., supra.

² Residue numbering follows the nomenclature of Chothia et al., supra.

The term cancer refers to any physiological condition in mammals characterized by unregulated cell growth. The cancers described herein include solid tumors and hematologic (blood-forming) cancers.

Hematological cancer refers to any cancer of the blood and includes, for example, myelomas, lymphomas and leukemias. Solid tumor or tumor refers to the involvement and growth and proliferation of neoplastic cells, malignant or benign, as well as all precancerous and cancerous cells and tissues, resulting in abnormal tissue growth. As used herein, neoplastic refers to any form of uncontrolled or unregulated cell growth, malignant or benign, that results in abnormal tissue growth.

The term treatment refers to any measure of success or reduction in the progression, severity and/or duration of a disease, pathology or condition, including any objective or subjective parameters such as mitigation; remission; reducing symptoms or improving the patient's tolerance to an injury, pathology or condition; slowing the rate of degeneration or decline in health; reducing the severity of the final phase of degeneration; or improving the patient's physical or mental well-being.

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

The term administration refers to the act of delivering a combination or composition described herein to a subject by routes such as oral, mucosal, topical, suppository, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous. Parenteral administration includes intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial administration. Administration typically occurs after the onset of the disease, disorder, or condition or symptoms thereof, but in some cases may occur before the onset of the disease, disorder, or condition, or symptoms thereof (eg, administration to patients susceptible to such disease, disorder, or condition).

The term co-administration refers to the administration of two or more agents (eg, a combination described herein and another active agent, such as an anti-cancer agent described herein). The co-administration schedule depends in part on the combinations and compositions administered and may include administration at the same time, shortly before or immediately after administration of one or more additional therapy options, for example, anticancer therapy such as chemotherapy, hormonal therapy, radiation therapy, or immunotherapy . The compound of the invention may be administered to a patient alone or may be administered together. Co-administration means simultaneous or sequential administration of a compound, alone or in combination (more than one compound or agent). Thus, the drugs can also be combined, when necessary, with other active substances (for example, to reduce metabolic degradation). The compounds described herein can be used in combination with each other, with other active agents that are known to be useful in the treatment of a disease associated with cells expressing a particular kinase described herein, or with additional agents that may not be effective in themselves, but may contribute to the effectiveness of the active agent.

The term anticancer agent is used in accordance with its apparent common meaning and refers to a composition having antineoplastic properties or the ability to inhibit cell growth or proliferation. In embodiments of the invention, the anticancer agent is a chemotherapeutic agent. In embodiments of the invention, the anticancer agent is an agent as defined herein that is useful in methods of treating cancer. In embodiments of the invention, the anticancer agent is an agent approved by the FDA or similar regulatory authority of a country other than the United States for the treatment of cancer.

The term chemotherapeutic agent or chemotherapeutic agent is used according to its apparent common meaning and refers to a chemical composition or chemical compound having antineoplastic properties or the ability to inhibit cell growth or proliferation. Chemotherapy refers to a therapy or regimen that includes the administration of a chemotherapeutic or anticancer agent described herein.

The terms halo, halogen and halide refer to -F, -Cl, -Br and -I.

The term alkyl, by itself or as part of another substituent, refers, unless otherwise indicated, to a linear (i.e. straight) or branched carbon chain (or carbon) or combination thereof, lacking unsaturation, and may include mono- , di- and multivalent radicals. As defined herein, alkyl may be designated by the number of carbon atoms (ie, C1-C10 means one to ten carbon atoms). Alkyls may include C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ and C1 -C4 lengths. Perfluoroalkyl refers to an alkyl in which all the hydrogen atoms in the alkyl chain are replaced by fluorine.

The term alkoxy refers to an alkyl group (eg, C1-C10, _C1 - _C8 , _C1 - _C6 and C1-C4 alkyl) attached to the rest of the molecule via an oxygen linker (-O-). Examples of alkoxy groups include groups having the formula -OR, where R represents a branched or linear alkyl. The perfluoroalkoxy moiety refers to an alkoxy in which all the hydrogen atoms in the alkyl chain are replaced by fluorine.

The term aminoalkyl refers to an alkyl group (eg, _C1 - _C10 , C1-C8, _C1 - _C6 and C1-C4 alkyl) in which one or more hydrogen atoms are replaced by an amino group.

The term alkylamino refers to an alkyl group (eg, C1-C10, C1-C8, C1-C6 and C1-C4 alkyl) attached to the rest of the molecule via a nitrogen linker (-NR-).

Examples of alkylamino groups include N-methylamino, N-ethylamino, N-isopropylamino and the like.

The term acyl refers to a moiety having the formula -C(O)R, where R represents a substituted or unsubstituted alkyl, haloalkyl or amino group. The term acylamino refers to an acyl moiety having an attached amino group and includes, for example, moieties such as acetylamino, propionylamino, butyrylamino, isobutyrylamino, and others.

The term alkikthyo refers to an alkyl group (eg, _C1 - _C10 , C1-C8, Q-C6 and C1-C4 alkyl) attached to the rest of the molecule via a sulfur linker (-S-).

Examples of alkylthio groups include methylthio, ethylthio, propylthio and others.

The term heterocycle or heterocyclyl refers to a stable 3-15 membered monocyclic group that is saturated or unsaturated and contains one or more heteroatoms (eg, N, O or S). Exemplary heterocycles include, but are not limited to, morpholinyl, piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, oxetanyl, azetidinyl, and others.

Compositions.

Proposed herein is a combination comprising a therapeutically effective amount of an anti-PD-1 antibody and a compound having the following structure:

or a pharmaceutically acceptable salt thereof, wherein said compound is present in an amount of at least 5 mg, and wherein said combination is for administration to a patient suffering from colon cancer.

In some cases, the combination contains a compound of the above structure present in an amount greater than about: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 85, 90, 100, 125 , 150, 175 or 200 mg. The combination may contain a compound of the above structure present in an amount greater than about: 6, 7, 8, 9 or 10 mg. In some cases, a compound of the above structure is present in an amount greater than about 5 mg or about 10 mg. The combination may contain a compound of the above structure present in an amount greater than: 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, from 50 mg to about 100 mg, or from 100 mg to about 200 mg.

The combination may contain a compound of the above structure present in an amount of at least about: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 85, 90, 100, 125, 150, 175 or 200 mg. The combination may contain a compound of the above structure present in an amount of at least about 5, 6, 7, 8, 9 or 10 mg. In some cases, a compound of the above structure is present in an amount of at least about 5 mg or about 10 mg. The combination may contain a compound of the above structure present in an amount of at least: 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 from

- 8 045229

100 mg to about 200 mg.

The combination may contain a compound of the above structure present in an amount of about: 5, 10, 15, 20, 25, 30, 35, 40, 45, 0, 60, 70, 80, 85, 90, 100, 125, 150 , 175 or 200 mg. The combination may contain a compound of the above structure present in an amount of about 5, 6, 7, 8, 9 or 10 mg. In some cases, a compound of the above structure is present in an amount of about 5 mg or about 10 mg. The combination may contain a compound of the above structure present in an amount of: 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, from 50 mg to about 100 mg, or from 100 mg to about 200 mg.

A compound of the above structure may be present in the combinations described herein in an amount relative to the patient's weight (ie, mg/kg). In some cases, the compound of formula I is present in an amount equivalent to: from about 0.0001 mg/kg to about 200 mg/kg, from 0.001 mg/kg to about 200 mg/kg, from 0.01 mg/kg to about 200 mg /kg, from 0.01 to about 150 mg/kg, from 0.01 to 100 mg/kg, from 0.01 to 50 mg/kg, from 0.01 to 25 mg/kg, 0.01 mg/kg up to about 10 mg/kg or from 0.01 mg/kg to about 5 mg/kg, from 0.05 to about 200 mg/kg, from 0.05 to 150 mg/kg, from 0.05 mg/kg to about 100 mg/kg, from 0.05 to 50 mg/kg, from 0.05 to about 25 mg/kg, from 0.05 to 10 mg/kg or from 0.05 to 5 mg/kg, 0.5 mg/kg to about 200 mg/kg, from 0.5 mg/kg to about 150 mg/kg, from 0.5 mg/kg to about 100 mg/kg, from 0.5 mg/kg to about 50 mg/ kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg. In other cases, the compound of formula I is present in an amount equivalent to: from about 1 mg/kg to about 200 mg/kg, from 1 mg/kg to about 150 mg/kg, from 1 mg/kg to about 100 mg/kg, from 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.

PD-1 inhibitors useful in the combination described herein include any molecule capable of inhibiting, blocking, eliminating or interfering with the activity or expression of PD-1. In particular, the PD-1 inhibitor may be a small molecule, nucleic acid, polypeptide, antibody, peptide, diabody, minibody, single chain variable fragment (ScFv), or a functional fragment or variant thereof. In one case, the PD-1 inhibitor is a small molecule compound (eg, a compound having a molecular weight of less than about 1000 Da). In other cases, PD-1 inhibitors useful in the combinations described herein include nucleic acids and polypeptides. The PD-1 inhibitor may be a polypeptide (eg, a macrocyclic polypeptide) such as those set forth in US Patent Application No. 2014/0294898, which is incorporated herein by reference in its entirety and in all respects. In one example, the PD-1 inhibitor is an antibody, peptibody, diabody, minibody, ScFv, or a functional fragment thereof. In one example, the PD1 inhibitor is AMP-224 (GSK).

AMP-224 is a recombinant fusion protein containing the extracellular domain of programmed cell death ligand 2 (PD-L2) PD-1 ligand and the Fc region of human IgG. Some cancers may bypass and suppress the immune system, in part and not limited to any particular theory, through the interaction between PD-1 and B7-H1. AMP-224 blocks this interaction and therefore overcomes immune suppression.

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

Anti-PD-1 antibodies include all known types of antibodies and functional fragments thereof, including, but not limited to, those described herein, such as, for example, human antibodies, mouse antibodies, chimeric antibodies, humanized antibodies, or chimeric humanized antibodies.

In one embodiment, the anti-PD-1 antibody is a human antibody. In another embodiment, the anti-PD-1 antibody is a murine antibody. In another embodiment, the anti-PD-1 antibody is a chimeric antibody. In another embodiment, the anti-PD-1 antibody is a humanized antibody. In another embodiment, the anti-PD-1 antibody is a chimeric humanized antibody. The anti-PD-1 antibody may be a human antibody or a humanized antibody. The anti-PD-1 antibody may be nivolumab, pembrolizumab, pidilizumab, REGN2810, PDR 001, or MEDI0680. In some embodiments, two or more anti-PD-1 antibodies are administered in combination with a compound of Formula I, as described herein.

The anti-PD-1 antibody may be nivolumab. Nivolumab (marketed as OPDIVO) is a fully human monoclonal antibody directed against PD-1 with immunopotentiating activity. Without being limited to any particular theory, nivolumab binds to and blocks activation of PD-1 by its cognate ligands, resulting in activation of T cells and cell-mediated immune responses against tumor cells or pathogens.

The anti-PD-1 antibody may be pembrolizumab. Pembrolizumab (MK-3475, marketed as KEYTRUDA) is a humanized monoclonal antibody

- 9 045229

IgG4 directed against the human cell surface receptor PD-1 with potential immunopotentiating activity. Without being limited to 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 cognate ligands. Blocking binding and activity results in activation of T cell-mediated immune responses against tumor cells.

The anti-PD-1 antibody may be pidilizumab. Pidilizumab (CT-011) is a humanized monoclonal antibody directed against human PD-1 with immunomodulatory and antitumor activity. Without being limited to any particular theory, pidilizumab blocks the interaction of the PD-1 receptor with its ligands, which leads to attenuation of apoptotic processes in lymphocytes, mainly in effector cells/memory T cells, and increased antitumor activity of NK cells.

The anti-PD-1 antibody may be REGN2810. REGN2810 is a human monoclonal antibody directed against PD-1 with potential immune checkpoint inhibitory and antineoplastic activity. Without being limited to any particular theory, REGN2810 binds to PD-1, inhibits binding to its cognate ligand, and prevents activation of its downstream signaling pathways. This may restore immune function through activation of cytotoxic T cells.

The anti-PD-1 antibody may be PDR 001. PDR 001 is a fully humanized monoclonal antibody directed against PD-1 with immune checkpoint inhibitory and antineoplastic activity. Without being limited to any particular theory, PDR 001 binds to PD-1 expressed on activated T cells and blocks interaction with its cognate ligands. Inhibition of ligand binding prevents PD-1-mediated signaling and leads to activation of both T cells and the induction of T cell-mediated immune responses against tumor cells.

The anti-PD-1 antibody may be MEDI0680. MEDI0680 (AMP-514) is a monoclonal antibody directed against PD-1 with potential immunomodulatory and antineoplastic activity. Without being limited to any particular theory, MEDI0680 inhibits the activation of PD-1 and its downstream signaling pathways. This inhibition may restore immune function by activating both T cells and cell-mediated immune responses against PD-1 overexpressing tumor cells.

The anti-PD-L1 antibody can be of any antibody isotype. The term isotype refers to the class of antibody encoded by the heavy chain constant region genes. The heavy chains of a given antibody or functional fragment determine the class of that antibody or functional fragment: IgM, IgG, IgA, IgD, or IgE. Each class can have either k or X light chains. The term subclass refers to minor differences in the amino acid sequences of the heavy chains that define subclasses. In humans, there are two subclasses of IgA (subclasses IgA1 and IgA2) and four subclasses of IgG (subclasses IgG1, IgG2, IgG3, and IgG4). Such classes and subclasses are well known to those skilled in the art.

Useful anti-PD-1 antibodies bind to PD-1 with sufficient strength to inhibit PD-1 activity. In the context of this document, binding refers to the interaction between molecules to form a complex. The interactions may be, for example, non-covalent interactions, including hydrogen bonds, ionic bonds, hydrophobic interactions and/or van der Waals interactions. A complex may also involve the linking 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, an enzyme-linked immunosorbent assay or any of a variety of methods that are well known to those skilled in the art.

The strength of the overall non-covalent interaction between one antigen-binding site of a PD-1 antibody or functional fragment and one epitope of a target molecule, such as PD-1, represents the affinity of the antibody or functional fragment for that epitope. The ratio of association (k1) to dissociation (k_1) of an antibody or its functional fragment with respect to a monovalent antigen (k1/k.1) represents the association constant K, which is a measure of affinity. The value of K varies for different antibody complexes or functional fragments and antigens and depends on both k1 and k_1. The association constant K for an antibody or functional fragment of the invention can be determined using any method provided herein or any other method well known to those skilled in the art.

Affinity at one binding site does not always reflect the true strength of the interaction between the antibody or functional fragment and the antigen. When complex antigens containing a number of repeated antigenic determinants are contacted by antibodies containing a number of 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. Force

- 10 045229 such multiple interactions between a multivalent antibody and an antigen are called avidity. The avidity of an antibody or functional fragment may be a better measure of its binding ability than the affinity of its individual binding sites. For example, high avidity can compensate for the low affinity that is sometimes found in pentameric IgM antibodies, which may have lower affinity than IgG, but the high avidity of IgM due to its multivalency allows it to bind antigen efficiently.

The specificity of an anti-PD-1 antibody or functional fragment thereof refers to the ability of a single antibody or functional fragment thereof to interact with only one antigen (eg, one PD-1 epitope). An antibody or functional fragment can be considered specific when it can recognize differences in the primary, secondary or tertiary structure of the antigen or isomeric forms of the antigen.

The anti-PD-1 antibody may be present in an amount determined based on the weight of the patient requiring it. For example, the anti-PD-1 antibody may be present in an amount of: 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, from 0.1 mg/kg to about 15 mg/kg, from 0.1 mg/kg to about 10 mg/kg, from 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 anti-PD-1 antibody may be present in an amount of: 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, from 0.5 mg/kg to about 15 mg/kg, from 0.5 mg/kg to about 10 mg/kg, from 0.5 mg/kg to about 7.5 mg/kg, from 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 anti-PD-1 antibody may be present in an amount ranging from about 0.5 mg/kg to about 5 mg/kg or from about 0.1 mg/kg to about 10 mg/kg. The anti-PD-1 antibody may be present in an amount ranging from about 0.5 mg/kg to about 15 mg/kg, or from about 0.1 mg/kg to about 20 mg/kg.

In other embodiments, the anti-PD-1 antibody may be present in an amount of about: 0.1, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, or 30 mg/kg. The anti-PD-1 antibody may be present in an amount of about: 1, 2, 3 or 5 mg/kg.

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

Anti-PD-1 antibody may be present in combination in an amount of about: 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 , 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400 or 500 mg/ml. In one embodiment, the anti-PD-1 antibody is present in combination in an amount of: 1 mg/ml to about 10 mg/ml, 5 mg/ml to about 10 mg/ml, 5 mg/ml to about 15 mg/ml, from 10 mg/ml to about 25 mg/ml; from 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.

In some cases, the therapeutically effective amount of the anti-PD-1 antibody is defined as the amount indicated on the package insert supplied with the anti-PD-1 antibody. The term package insert refers to instructions typically included in the commercial packaging of drugs approved by the FDA or equivalent regulatory authority in a country other than the United States, which contains information, for example, about the use, dosage, administration, contraindications and/or warnings regarding the use of such drugs.

A compound of the structure described herein may be provided in amounts that are synergistic with the amount of the PD-1 inhibitor. The term synergistic refers to a combination described herein (e.g., a compound of Formula I and a PD-1 inhibitor, including coadministration with another active agent, such as an anticancer agent described herein) or a combination of regimens, such as those described herein, that are more effective than the additive effect of each individual therapy option or regimen.

The synergistic effect of the combination described herein may allow the use of lower dosages of one or more components of the combination (eg, a compound of Formula I or a PD-1 inhibitor). The synergistic effect may allow for less frequent administration of at least one therapeutic option (eg, a compound of Formula I or a PD-1 inhibitor) to a subject with a disease, disorder, or condition described herein. Such lower dosages and reduced frequency of administration may reduce the toxicity associated with the use of at least one therapy option (eg, a compound of Formula I or a PD-1 inhibitor) in a subject without compromising the effectiveness of the treatment. The synergistic effect described herein avoids or reduces adverse or undesirable side effects associated with the use of any therapy option.

Pharmaceutical compositions.

The combinations described herein may be provided in pharmaceutical form.

- 11 045229 a composition suitable for administration to a patient described herein by any route, including, but not limited to: oral, mucosal (e.g., nasal, inhalation, pulmonary, sublingual, vaginal, buccal or rectal), parenteral (e.g., subcutaneous, intravenous, by bolus injection, intramuscular or intraarterial), topical (eg, eye drops or other ophthalmic medications), transdermal, or percutaneous administration to the patient.

Examples of dosage forms include: tablets; caplets; capsules (eg gelatin capsules); starch capsules; lozenges; suppositories; powders; gels; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (eg, crystalline or amorphous solids), which can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

The pharmaceutical compositions and dosage forms described herein typically contain one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy. Whether a particular excipient is suitable for 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 contain other agents, such as stabilizers, lubricants, buffers and disintegrants, which may reduce the rate at which the active ingredient may degrade in a particular composition.

The pharmaceutical compositions described herein may, in some cases, contain additional active agents other than those present in the combinations described herein (eg, an anticancer agent, such as those described herein), in the amounts provided herein.

In one embodiment of the invention, a compound of formula I is provided in an oral dosage form, such as a tablet or capsule. In another embodiment of the invention, the compound of formula I is provided in the form of a powder (eg, a lyophilized powder) that can be resuspended in a liquid suitable for parenteral administration.

The PD-1 inhibitors described herein may be provided in forms convenient or easy to administer to a patient. For example, when the PD-1 inhibitor is an anti-PD1 antibody, as described herein, the PD-1 inhibitor can be formulated as a ready-to-use solution for parenteral administration. In other examples, a PD-1 inhibitor, including, for example, an anti-PD-1 antibody, can be formulated as a powder (eg, a lyophilized powder) that can be resuspended in a liquid suitable for parenteral administration. In one embodiment, the combination contains an anti-PD-1 antibody formulated for intravenous administration. In another embodiment, the combination comprises a compound of Formula I formulated in an oral dosage form (eg, a tablet or capsule) and a PD-1 inhibitor formulated in an intravenous dosage form.

The combinations described herein may be provided as controlled-release pharmaceutical products, the purpose of which is to improve drug therapy compared to the results achieved with their uncontrolled-release counterparts. Controlled-release formulations may prolong the activity of the drug, reduce the frequency of dosing, and increase subject compliance with the treatment regimen. In addition, controlled release formulations can be used to influence the time of onset of action or other characteristics, such as blood drug levels, and thus influence the occurrence of side (eg, adverse) events.

Sets.

The combinations and pharmaceutical compositions described herein may be provided as part of a kit. Such kits may, for example, improve patient compliance with a treatment regimen or increase the accuracy or ease of preparation for administering the combination. The kit contains a compound of Formula I, wherein the compound is provided in the formulated form described herein. The kit also contains a PD-1 inhibitor described herein. The kit may contain AMP-224. In some embodiments, the kit contains an anti-PD-1 antibody described herein, such as, for example, nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. The kit may contain a package insert or other information (eg, prescribing information) useful for administering the combination to a patient in need thereof, such as the cancer patient described herein.

Kits of the invention may contain combinations described herein (eg, compounds of Formula I and anti-PD-1 antibodies), having the same or different compositions. Each component of the combination described herein in the kit may be provided in a separate, individual container. Alternatively or additionally, the components of the combinations described herein may be provided in a single container. In such cases, the container

- 12 045229 may be a container ready for administration to a patient in need, such as, for example, an IV bag, ampoule or syringe. In one embodiment of the invention, the compound of formula I in the kit is formulated for oral administration (eg, tablet, capsule or sachet). The PD-1 inhibitor may be provided, for example, as a powder (eg, lyophilized powder) or as a solution for parenteral administration. In some cases, the PD-1 inhibitor is an anti-PD-1 antibody described herein, formulated for parenteral administration, such as intravenous administration.

The contents of the kits described herein may be provided in sterile form. The kit and its contents may be provided in a form that is ready for administration to a subject in need thereof. In such cases, the components of the kit combination are provided as a formulation and, optionally, in an administration device such that administration requires little or no additional action on the part of the user. Where kits contain delivery devices, such devices include devices known and understood by those skilled in the art for the routes of administration described herein, such as, without limitation, syringes, pumps, bags, cups, inhalers, droppers, patches, creams or injectors.

Ways.

The combinations, pharmaceutical compositions and kits described herein are useful for treating diseases, disorders or alleviating or eliminating symptoms of diseases and disorders, such as, for example, colon cancer. It should be understood that the methods described herein relate to the administration of combinations and pharmaceutical compositions described herein, and such combinations and pharmaceutical compositions may be provided in kit form as described herein. Provided herein are methods of treating colon cancer by administering a therapeutically effective amount of a combination described herein to a patient in need thereof.

The combination useful in the methods described herein includes a compound represented by the following structure:

or a pharmaceutically acceptable salt thereof.

PD-1 inhibitors for use in the methods described herein are the PD-1 inhibitors described herein. For example, a PD-1 inhibitor may be a small molecule, nucleic acid, polypeptide, antibody, peptide, diabody, minibody, single chain variable fragment (ScFv), or a functional fragment or variant thereof. In one example, the PD-1 inhibitor is AMP-224. In other examples, the PD-1 inhibitor may be an anti-PD-1 inhibitory antibody as described above. In one instance, an anti-PD-1 antibody for use in the methods described herein is nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680.

It should be understood that the compound of the above structure and the PD-1 inhibitor forming a combination for use in such methods include each therapeutic agent in the amounts described herein and are administered as described herein. For example, a compound of the above structure may be present in the combination administered to a patient in need thereof in an amount ranging from about 5 mg to about 50 mg or from about 5 mg to about 100 mg. As another example, a PD-1 inhibitor may be an anti-PD-1 antibody present in an amount of from about 0.1 mg/kg to about 10 mg/kg or from about 0.1 mg/kg to about 20 mg /kg. These amounts are merely illustrative and in no way limit the amount of each therapeutic agent that may be present in the combination described herein.

It is also understood that a combination for use in the methods described herein may be provided as a kit as described above. Such kits contain each component of the combination described herein and, optionally, additional components of the kit, including, for example, containers and administration devices such as those described above.

The combinations described herein can be administered to a patient with cancer at any time after diagnosis. For example, a patient with cancer may have been treatment-naïve (ie, not receiving anti-cancer therapy for the diagnosed cancer). A patient with cancer may not have previously been treated for one type of cancer, but may be diagnosed with one or more other types of cancer, caused, for example, by metastases or malignancies. A patient with cancer may be naïve to the immune checkpoints of one or more types of cancer. A cancer patient may have cancer that is refractory. In some cases

- 13 045229 the combinations described herein are administered as first-line therapy (eg, the first treatment option administered to a patient who has not previously been treated) to a patient in need thereof.

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

Methods for treating cancers herein include treating subjects who have been treated with a PD-L1 checkpoint inhibitor and have not demonstrated any response to treatment, or have demonstrated a partial response or stable disease but then have developed resistance to treatment with disease progression, or have demonstrated complete response to treatment but then developed treatment resistance with disease progression (as defined by RECIST or other criteria). Resistance is defined as disease progression during treatment or lack of response to treatment. Such failure of treatment with a PD-L1 inhibitory antibody may be compensated for by treatment with PD-1 in combination with an HDAC inhibitor, such as, without limitation, HBI-8000 or an HDAC inhibitor that inhibits a cancer-associated class I HDAC selected from one or more of HDAC1 , HDAC2 or HDAC3. In some cases, an HDAC inhibitor also inhibits class IIb HDAC10. HBI-8000 has been reported to inhibit HDACs at 1, 2, 3 and 10 low nanomolar concentrations (see Zhi-Qiang Ning et al., Cancer Chemother Pharmacol (2012) 69:901-909). It also has activity against HDACs 8 and 11. Ning et al. also report that HBI-8000 is more active than Entinostat against HDACs 1, 2, 3, 8, 10 and 11. In addition, HBI-8000 has a favorable pharmacokinetic and safety profile that allows for continuous oral dosing pK (t1/ ₂ about 17 hours).

Response criteria.

RECIST.

RECIST is a set of established criteria or internationally recognized standards for assessing response, stability and progression in patients 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) by the joint efforts of the European Organization Cancer Research and Treatment, United States National Cancer Institute and National Cancer Institute of Canada Clinical Research Group, RECIST has traditionally been used in assessing response to chemotherapy.

Assessment of target lesions.

Complete response (CR): disappearance of all target lesions; partial response (PR): at least 30% reduction in the total ND (largest diameter) of the target lesions, using the initial total ND as the reference point; stable disease (SD): absence of both a significant decrease to be considered PR and a sufficient increase to be considered PD, taking as the reference point the smallest total ND since the start of treatment; Progressive disease (PD): at least a 20% increase in the cumulative DI of target lesions, taking as the reference point the lowest cumulative DI recorded since the start of treatment, or the appearance of one or more new lesions.

Evaluation of non-target lesions.

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 persistence of tumor marker levels above normal limits; Progressive disease (PD): the appearance of one or more new lesions and/or unambiguous progression of existing non-target lesions.

Other response criteria.

Other response criteria include the immune-related response criteria or iRECIST defined by Wolchok et al., in 2009 (Wolchok J.D., 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 B.D. et al., Revised response criteria for malignant lymphoma. J. Clin. Oncol. 2007; 25:579-586).

Methods of treating cancer include methods of inhibiting cell growth by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of formula I and a PD-1 inhibitor described herein. In one example, the PD-1 inhibitor is AMP-224. Another example provides a method of inhibiting cell growth by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of formula I and an anti-PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684) , PDR 001, SHR1210 or MEDI0680.

Also provided herein are methods of inhibiting cancer metastasis in a patient in need thereof by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 inhibitor described herein. In one example, the PD-1 inhibitor is AMP-224. Another example provides a method of inhibiting cancer metastasis in a patient in need thereof by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of formula I and an anti-PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In some embodiments, metastasis is inhibited by at least about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%.

In another aspect, a method is provided for reducing pre-existing tumor metastases in a cancer patient in need thereof by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of formula I and a PD-1 inhibitor described herein. In one example, the PD-1 inhibitor is AMP-224. Another example provides a method of reducing pre-existing tumor metastases in a cancer patient in need thereof by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and an anti-PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In some embodiments, pre-existing tumor metastases are reduced by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%.

In another aspect, methods of treating cancer also provide methods of reducing tumor burden in an individual by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 inhibitor described herein. In one example, the PD-1 inhibitor is AMP-224. In another example, a method of reducing tumor burden in an individual is provided by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and an anti-PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-1). 439684), PDR 001, SHR-1210 or MEDI0680. In some embodiments, the tumor burden is reduced by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%.

In another aspect, methods of treating cancer also provide methods of reducing a tumor burden in a subject by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 inhibitor described herein. In one example, the PD-1 inhibitor is AMP-224. In another example, a method of reducing tumor burden in an individual is provided by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and an anti-PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-1). 439684), PDR 001, SHR-1210 or MEDI0680. In some embodiments, the tumor burden is reduced by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%.

The methods of treating cancer described herein also provide methods for increasing or otherwise prolonging the time until disease progression at certain stages (including advanced stages of cancer, such as stage III and IV cancers described herein). The time to disease progression in a patient can be prolonged by administering a therapeutically effective amount of a combination described herein, wherein the combination contains a compound of formula I and a PD-1 inhibitor described herein. In one example, the PD-1 inhibitor is AMP-224. Another example provides a method of increasing the time to disease progression in a patient by administering a therapeutically effective amount of a combination described herein, wherein the combination contains a compound of Formula I and an anti-PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In some embodiments, the increase is a comparison between the time to disease progression without treatment and when treated with a combination described herein. In some embodiments, the methods described herein prolong the time to disease progression by at least 1, 2, 3, 4 weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 months , 1 year or more,

- 15 045229 including intermediate values.

The methods of treating cancer described herein also provide methods for increasing or otherwise prolonging the life expectancy (including overall life expectancy) of patients diagnosed with cancer as described herein. The life expectancy of a patient can be increased by administering a therapeutically effective amount of a combination described herein, wherein the combination contains a compound of formula I and a PD-1 inhibitor described herein. In one example, the PD-1 inhibitor is AMP224. In another example, a method is provided for prolonging the life expectancy of a patient by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and an anti-PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684 ), PDR 001, SHR-1210 or MEDI0680. In some embodiments, the increase is a comparison between life expectancy without treatment and when treated with a combination described herein. In some embodiments, the methods described herein increase life expectancy by at least 1, 2, 3, 4 weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 months, 1 , 2 years or more, including intermediate values.

The methods of treating cancer described herein also provide methods for increasing progression-free survival of patients diagnosed with cancer as described herein. A patient's progression-free survival can be prolonged by administering a therapeutically effective amount of a combination described herein, wherein the combination contains a compound of formula I and a PD-1 inhibitor described herein. In one example, the PD1 inhibitor is AMP-224. Another example provides a method of increasing progression-free survival of patients diagnosed with cancer by administering a therapeutically effective amount of a combination described herein, wherein the combination contains a compound of formula I and an anti-PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In some embodiments, the increase is a comparison between progression-free survival without treatment and when treated with a combination described herein. In some embodiments, the methods described herein increase progression-free survival by at least 1, 2, 3, 4 weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 months, 1, 2 years or more, including intermediate values.

Also provided herein are methods of reducing the level of myeloid suppressor cells (MSCs) in a patient in need thereof by administering an effective amount of a combination described herein, wherein the combination contains a compound of formula I and a PD1 inhibitor described herein. Another example provides a method of reducing the level of myeloid suppressor cells (MSCs) in a patient in need thereof by administering an effective amount of a combination described herein, wherein the combination comprises a compound of formula I and an anti-PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680, compared to administration of a compound of formula I or a PD-1 inhibitor alone. Reducing the number of MSCs may be useful for the treatment of the cancers described herein. The level of MSCs in a human patient can be measured before, during and after administration of the combination described herein. In some embodiments, it may be useful to compare the number of MSCs in a patient before and after administration. A decrease in the number, level or number of MSCs after administration may indicate the effectiveness of the combination, for example, in the treatment of cancer described herein. MSC levels can be monitored during a course of treatment or a treatment regimen described herein with a combination described herein. In such cases, determination of MSC levels at different time points during the course of administration may indicate the effectiveness of the regimen.

Also provided herein are methods for reducing the percentage or level of Treg cells in a patient in need thereof. Such methods include administering an effective amount of a combination described herein, wherein the combination contains a compound of formula I and a PD1 inhibitor described herein. In one example, the PD-1 inhibitor is AMP-224. Another example provides a method of reducing the percentage or level of Treg cells in a patient in need thereof by administering to the patient an effective amount of a combination described herein, wherein the combination contains a compound of formula I and an anti-PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680, wherein administration reduces the percentage or level of Treg cells in the patient compared to pre-administration levels. Reducing the number of Treg cells may help treat the cancers described herein. The level of Treg cells in a human patient can be measured before, during and after administration of the combination described herein. In some embodiments, it may be useful to compare the number of Treg cells in a patient before and after administration. A decrease in the number, level or number of Treg cells after administration may indicate

- 16 045229 the effectiveness of the combination, for example, in the treatment of cancer described herein. Levels of Treg cells can be monitored during a course of treatment or a treatment regimen described herein with a combination described herein. In such cases, measuring Treg cell levels at different time points during the course of administration may indicate the effectiveness of the regimen.

The combinations described herein may be useful in methods of increasing natural killer (NK) cell activity. The combinations described herein may also be useful in methods of increasing the activity of cytotoxic T cells. Enhancement methods include bringing an NK cell or cytotoxic T cell into contact with a combination described herein, wherein the combination increases the activity of the NK cell or cytotoxic T cell compared to its activity prior to contact. In some embodiments, increased NK cell or cytotoxic T cell activity is observed in a cancer patient who has been administered a combination described herein. Such combinations useful for enhancing NK cell or cytotoxic T cell activity may include AMP-224. In other examples, combinations described herein useful in methods of enhancing NK cell or cytotoxic T cell activity include an anti-PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001 , SHR-1210 or MEDI0680.

The combinations described herein may also enhance antibody-dependent cell-mediated cytotoxicity in a cancer patient following administration of the combination described herein.

The combinations described herein may include administration of each therapy (eg, a compound of Formula I and a PD-1 inhibitor), administered simultaneously or sequentially (in any order). In one embodiment of the invention, the compound of Formula I and the PD-1 inhibitor are administered simultaneously (eg, within at least 1-5 minutes of each other). In another embodiment, the compound of Formula I and the PD-1 inhibitor are administered sequentially (e.g., over at least 10, 15, 30 minutes, 1, 2, 5, 10, 12 hours, 1, 2, 5, 7, 14 or 21 days relative to each other).

In one example, a compound of formula I is administered simultaneously with an anti-PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another example, a compound of formula I can be administered prior to administration of nivolumab. In another example, a compound of formula I can be administered prior to administration of pembrolizumab. In another example, a compound of formula I can be administered prior to administration of pidilizumab. In another example, a compound of Formula I may be administered prior to administration of REGN2810 (also known as SAR-439684). In another example, a compound of Formula I may be administered prior to administration of PDR 001. In another example, a compound of Formula I may be administered prior to administration of MEDI0680. In another example, a compound of formula I can be administered after administration of nivolumab. In another example, a compound of Formula I may be administered following administration of pembrolizumab, atezolizumab, or SHR-1210. In another example, a compound of Formula I may be administered following administration of pidilizumab, atezolizumab, or SHR-1210. In another example, a compound of formula I can be administered after administration of REGN2810 (also known as SAR-439684). In another example, a compound of formula I can be administered after administration of PDR 001. In another example, a compound of formula I can be administered after administration of MEDI0680.

In another example, a compound of formula I is administered simultaneously with AMP-224. In another example, a compound of Formula I is administered prior to administration of AMP-224. In another example, a compound of formula I is administered after administration of AMP-224.

The compound of formula I can be administered, for example, once daily (d/s), twice daily (d/s), once weekly (d/wd), twice weekly (d/wd), three times per week (t/nd) or once a month (r/m). For example, a compound of formula I can be administered twice daily. The compound of formula I can be administered three times a week. In some cases, a compound of formula I is administered 2-3 times per week. In another embodiment of the invention, a compound of formula I is administered once daily. The compound may be administered once daily for about 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. Administration of a compound of formula I may depend, in part, on the patient's tolerance, where greater tolerance may allow higher doses or more frequent administration. Alternatively, in the event that a patient exhibits poor tolerance to a compound of Formula I, a smaller amount of the compound or less frequent dosing may be administered. Administration of the compound may also be stopped when the maximum therapeutic effect is achieved and then resumed when additional administration is required, albeit with an alternative schedule and dose. The compounds of Formula I can be administered according to any regimen described herein.

For example, a compound of formula I can be administered in an amount of about: 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 85, 90 , 100, 125, 150, 175 or 200 mg, once daily. For example, a compound of formula I can be administered in an amount of about: 1, 2, 3, 4, 5, 10, 15, 20, 25,

- 17 045229

30, 35, 40, 45, 50, 60, 70, 80, 85, 90, 100, 125, 150, 175 or 200 mg, twice a week. For example, a compound of formula I can be administered in an amount of about: 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 85, 90 , 100, 125, 150, 175 or 200 mg, three times a week. For example, a compound of formula I can be administered in an amount of about: 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 85, 90 , 100, 125, 150, 175 or 200 mg, once a week. For example, a compound of formula I can be administered in an amount of about: 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 85, 90 , 100, 125, 150, 175 or 200 mg, once every 2 weeks. For example, a compound of Formula I can be administered in an amount of about 5 mg or about 10 mg once daily. For example, a compound of formula I can be administered in an amount of about 5 mg or about 10 mg, twice a week. For example, a compound of Formula I can be administered in an amount of about 5 mg or about 10 mg three times per week. For example, a compound of Formula I can be administered in an amount of about 5 mg or about 10 mg once per week. For example, a compound of Formula I can be administered in an amount of about 5 mg or about 10 mg once every 2 weeks. Administration of the compound of formula I can be continuous. Administration of a compound of formula I may be periodic.

For example, a compound of formula I can be administered in an amount of: 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, once daily. For example, a compound of formula I can be administered in an amount of: 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, twice a week. For example, a compound of formula I can be administered in an amount of: 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, three times a week. For example, a compound of formula I can be administered in an amount of: 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, once weekly. For example, a compound of formula I can be administered in an amount of: 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, once every 2 weeks. Administration of the compound of formula I can be continuous. Administration of a compound of formula I may be periodic.

For example, a compound of formula I can be administered in an amount of: 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 kg, from 0.01 mg/kg to about 150 mg/kg, from 0.01 mg/kg to about 100 mg/kg, from 0.01 mg/kg to about 50 mg/kg, from 0.01 mg/kg kg to about 25 mg/kg, from 0.01 mg/kg to about 10 mg/kg or from 0.01 mg/kg to about 5 mg/kg, from 0.05 mg/kg to about 200 mg/kg, from 0.05 mg/kg to about 150 mg/kg, from 0.05 mg/kg to about 100 mg/kg, from 0.05 mg/kg to about 50 mg/kg, from 0.05 mg/kg to about 25 mg/kg, from 0.05 mg/kg to about 10 mg/kg or from 0.05 mg/kg to about 5 mg/kg, from 0.5 mg/kg to about 200 mg/kg, from 0 .5 mg/kg to about 150 mg/kg, from 0.5 mg/kg to about 100 mg/kg, from 0.5 mg/kg to about 50 mg/kg, from 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, once daily. For example, a compound of formula I can be administered in an amount of: 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 kg, from 0.5 mg/kg to about 150 mg/kg, from 0.5 mg/kg to about 100 mg/kg, from 0.5 mg/kg to about 50 mg/kg, from 0.5 mg/kg 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, twice a week. For example, a compound of formula I can be administered in an amount of: 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 kg, from 0.5 mg/kg to about 150 mg/kg, from 0.5 mg/kg to about 100 mg/kg, from 0.5 mg/kg to about 50 mg/kg, from 0.5 mg/kg 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, three times a week. For example, a compound of formula I can be administered in an amount of: 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 kg, from 0.5 mg/kg to about 150 mg/kg, from 0.5 mg/kg to about 100 mg/kg, from 0.5 mg/kg to about 50 mg/kg, from 0.5 mg/kg 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, once weekly. For example, a compound of formula I can be administered in an amount of: 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 kg, from 0.5 mg/kg to about 150 mg/kg, from 0.5 mg/kg to about 100 mg/kg, from 0.5 mg/kg to about 50 mg/kg, from 0.5 mg/kg kg to about 25 mg/kg, from 0.5 mg/kg to about 10 mg/kg, or from 0.5 mg/kg to about 5 mg/kg, once every 2 weeks. Administration of the compound of formula I can be continuous. Administration of a compound of formula I may be periodic.

For example, a compound of formula I can be administered in an amount of: 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, once daily . For example, a compound of formula I can be administered in an amount of: 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, from 1 mg/kg

- 18 045229 up to about 25 mg/kg, from 1 mg/kg to about 10 mg/kg or from 1 mg/kg to about 5 mg/kg, twice a week. For example, a compound of formula I can be administered in an amount of: 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, three times a week . For example, a compound of formula I can be administered in an amount of: 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, once weekly . For example, a compound of formula I can be administered in an amount of: 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, from 1 mg/kg to about 25 mg/kg, from 1 mg/kg to about 10 mg/kg or from 1 mg/kg to about 5 mg/kg, once every 2 weeks. In one example, a compound of formula I can be administered in an amount ranging from about 15 mg/kg to about 75 mg/kg, once daily. In another example, a compound of formula I can be administered in an amount ranging from about 20 mg/kg to about 50 mg/kg. In another example, the compound of formula I can be administered in an amount of about 0.001, 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30 , 40, 50, 60, 70, 80, 90, 100, 125, 150, 175 or 200 mg/kg. Administration of the compound of formula I can be continuous. Administration of a compound of formula I may be periodic.

As used herein, the term daily means that a therapeutic compound of a combination described herein, such as a compound of Formula I, is administered one or more times per day for a specified period of time. The term continuous means that a therapeutic compound of a combination described herein, such as a compound of Formula I, is administered daily for a continuous period of at least 10 days to 52 weeks. As used herein, the term intermittent or intermittent is intended to mean stopping and starting administration at regular or irregular intervals. For example, periodic administration of a therapeutic compound of a combination described herein, such as a compound of Formula I, includes administration for one to six days per week (e.g., 2-3 times a week or once a day), administration in cycles (e.g., daily administration for two-eight consecutive weeks, then a rest period without administration of at least one day) or, for example, administration every other day.

When the PD-1 inhibitor is an anti-PD-1 antibody, it can be administered according to established regimens such as those suggested in the package insert. The anti-PD-1 antibody can be administered in the amount described herein and can be administered once a week (w/w), once every 2 weeks (w/2w), once every 3 weeks (w/3w) . In one embodiment, the anti-PD-1 antibody is administered once every two or three weeks. In another embodiment, the anti-PD1 antibody is administered once every 2 weeks. In another embodiment, the anti-PD-1 antibody is administered once every 3 weeks. In another embodiment, the anti-PD-1 antibody is administered twice a week for at least 3 weeks.

For example, nivolumab can be administered in an amount ranging from about 0.1 mg/kg to about 10 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8 mg/kg), once a week. For example, nivolumab can be administered in an amount ranging from about 0.1 mg/kg to about 10 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8 mg/kg), once every 2 weeks. For example, nivolumab can be administered in an amount ranging from about 0.1 mg/kg to about 10 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8 mg/kg), once every 4 weeks. For example, nivolumab can be administered in an amount ranging from about 0.1 mg/kg to about 10 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8 mg/kg), twice every 4 weeks (d/4wd). For example, nivolumab can be administered in an amount ranging from about 0.1 mg/kg to about 10 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8 mg/kg), once every 3 weeks. Nivolumab can be administered continuously. Administration of nivolumab may be intermittent.

Nivolumab can be administered as an intravenous infusion over about 10, 20, 30, 40, 50, or 60 minutes or more. Nivolumab can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. Nivolumab can be administered as an intravenous infusion over about 60 minutes once every two weeks. Nivolumab can be administered as an intravenous infusion over about 60 minutes once every three weeks. Nivolumab can be administered as an intravenous infusion over about 60 minutes once every four weeks. Nivolumab can be administered as an intravenous infusion according to the package insert. Nivolumab can be administered continuously. Administration of nivolumab may be intermittent.

For example, pembrolizumab can be administered in an amount ranging from about 0.5 mg/kg to about 20 mg/kg (including, for example, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 mg/kg). For example, pembrolizumab can be administered in an amount ranging from about 0.5 mg/kg to about 20 mg/kg (including, for example, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 mg/kg) once a week.

For example, pembrolizumab can be administered in an amount ranging from about 0.5 mg/kg to about 20 mg/kg (including, for example, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 mg/kg) once every 2 weeks. For example, pembrolizumab can be administered in an amount ranging from about 0.5 mg/kg to about 20 mg/kg (including, for example, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 mg/kg) once every 3 weeks. For example, pembrolizumab can be administered in an amount ranging from about 0.5 mg/kg to about 20 mg/kg (including, for example,

0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 mg/kg) once every 4 weeks. Pembrolizumab can be administered continuously. Pembrolizumab may be administered intermittently.

Pembrolizumab can be administered as an intravenous infusion over about 10, 20, 30, 40, 50, or 60 minutes or more. Pembrolizumab can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. Pembrolizumab can be administered as an intravenous infusion over about 60 minutes once every two weeks. Pembrolizumab can be administered as an intravenous infusion over about 60 minutes once every three weeks. Pembrolizumab can be administered as an intravenous infusion over about 60 minutes once every four weeks. Pembrolizumab can be administered according to the package insert provided. Pembrolizumab can be administered continuously. Pembrolizumab may be administered intermittently.

For example, pidilizumab can be administered in an amount ranging from about 0.1 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once a week. For example, pidilizumab can be administered in an amount ranging from about 0.1 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once every 2 weeks. For example, pidilizumab can be administered in an amount ranging from about 0.1 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once every 3 weeks. For example, pidilizumab can be administered in an amount ranging from about 0.1 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once every 4 weeks. Administration of pidilizumab can be continuous. Administration of pidilizumab may be intermittent.

Pidilizumab can be administered as an intravenous infusion over about 10, 20, 30, 40, 50, or 60 minutes or more. Pidilizumab can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. Pidilizumab can be administered as an intravenous infusion over about 60 minutes once every two weeks. Pidilizumab can be administered as an intravenous infusion over about 60 minutes once every three weeks. Pidilizumab can be administered as an intravenous infusion over about 60 minutes once every four weeks. Administration of pidilizumab can be continuous. Administration of pidilizumab may be intermittent.

For example, AMP-224 can be administered in an amount ranging from about 1 mg/kg to about 50 mg/kg (including, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 mg/kg ), once a week. For example, AMP-224 can be administered in an amount ranging from about 1 mg/kg to about 50 mg/kg (including, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 mg/kg ), once every 2 weeks. For example, AMP-224 can be administered (for example, by subcutaneous administration) in an amount ranging from about 1 mg/kg to about 50 mg/kg (including, for example, 5, 10, 15, 20, 25, 30, 35, 40 , 45, 50 mg/kg), once every 3 weeks. For example, AMP-224 can be administered (for example, by subcutaneous administration) in an amount ranging from about 1 mg/kg to about 50 mg/kg (including, for example, 5, 10, 15, 20, 25, 30, 35, 40 , 45, 50 mg/kg), once every 4 weeks. Administration of AMP-224 can be continuous. Administration of AMP-224 can be periodic.

AMP-224 can be administered as an intravenous infusion over about 10, 20, 30, 40, 50 or 60 minutes or more. AMP-224 can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. AMP-224 can be administered as an intravenous infusion over about 60 minutes once every two weeks. AMP-224 can be administered as an intravenous infusion over about 60 minutes twice every three weeks. AMP-224 can be administered as an intravenous infusion over approximately 60 minutes three times every six weeks. Administration of AMP-224 can be continuous. Administration of AMP-224 can be periodic.

For example, REGN2810 (also known as SAR-439684) can be administered in an amount ranging from about 0.1 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0. 7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once every 2 weeks. For example, REGN2810 (also known as SAR-439684) can be administered in an amount ranging from about 0.1 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0. 7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once every 4 weeks. For example, REGN2810 (also known as SAR-439684) can be administered in an amount ranging from about 0.1 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0. 7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), twice every 4 weeks. For example, REGN2810 (also known as SAR-439684) can be administered in an amount ranging from about 0.1 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0. 7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once a week. Administration of REGN2810 (also known as SAR-439684) can be continuous. Administration of REGN2810 may be intermittent.

REGN2810 (also known as SAR-439684) can be administered as an intravenous infusion over about 10, 20, 30, 40, 50, or 60 minutes or more. REGN2810 (also known as SAR-439684) can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. REGN2810 (also known as SAR-439684) can be administered as an intravenous infusion over about 60 minutes once every two weeks. REGN2810 (also known as SAR-439684) can be administered as an intravenous infusion over about 60 minutes twice every three weeks. REGN2810 (also known as

- 20 045229

SAR-439684) can be administered as an intravenous infusion over approximately 60 minutes three times every six weeks. Administration of REGN2810 (also known as SAR-439684) can be continuous. Introduction

REGN2810 (also known as SAR-439684) may be periodic.

For example, PDR 001 can be administered in an amount ranging from about 0.5 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3 , 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once a week. For example, PDR 001 can be administered in an amount ranging from about 0.5 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3 , 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once every 2 weeks. For example, PDR 001 can be administered in an amount ranging from about 0.5 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3 , 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once every 3 weeks. For example, PDR 001 can be administered in an amount ranging from about 0.5 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3 , 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once every 4 weeks. Administration of PDR 001 can be continuous. Administration of PDR 001 may be periodic.

PDR 001 can be administered as an intravenous infusion over about 10, 20, 30, 40, 50 or 60 minutes or more. PDR 001 can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. PDR 001 can be administered as an intravenous infusion over approximately 60 minutes once every two weeks. PDR 001 can be administered as an intravenous infusion over approximately 60 minutes twice every three weeks. PDR 001 can be administered as an intravenous infusion over approximately 60 minutes once every three weeks. Administration of PDR 001 can be continuous. Administration of PDR 001 may be periodic.

For example, MEDI0680 can be administered in an amount ranging from about 0.5 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once a week. For example, MEDI0680 can be administered in an amount ranging from about 0.5 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once every 2 weeks. For example, MEDI0680 can be administered in an amount ranging from about 0.5 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once every 3 weeks. For example, MEDI0680 can be administered in an amount ranging from about 0.5 mg/kg to about 30 mg/kg (including, for example, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg), once every 4 weeks. MEDI0680 can be administered continuously. Administration of MEDI0680 may be intermittent.

MEDI0680 can be administered as an intravenous infusion over about 10, 20, 30, 40, 50, or 60 minutes or more. MEDI0680 can be administered as an intravenous infusion over approximately 60 minutes once every 1, 2, 3, 4, 5 or more weeks. MEDI0680 can be administered as an intravenous infusion over approximately 60 minutes once every two weeks. MEDI0680 can be administered as an intravenous infusion over approximately 60 minutes twice every three weeks. MEDI0680 can be administered as an intravenous infusion over approximately 60 minutes once every three weeks. MEDI0680 can be administered continuously. Administration of MEDI0680 may be intermittent.

For example, SHR-1210 can be administered in an amount ranging from about 0.5 mg/kg to about 20 mg/kg (including, for example, 0.1, 0.3, 0.1, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 mg/kg), once a week. For example, SHR-1210 can be administered in an amount ranging from about 0.5 mg/kg to about 20 mg/kg (including, for example, 0.1, 0.3, 1, 3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 mg/kg), once every 2 weeks. For example, SHR-1210 can be administered in an amount ranging from about 0.5 mg/kg to about 20 mg/kg (including, for example, 0.1, 0.3, 1, 3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 mg/kg), once every 3 weeks. For example, SHR-1210 can be administered in an amount ranging from about 0.5 mg/kg to about 20 mg/kg (including, for example, 0.1, 0.3, 1, 3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 mg/kg), once every 4 weeks. Administration of SHR-1210 can be continuous. Administration of SHR-1210 may be intermittent.

SHR-1210 can be administered as an intravenous infusion over about 10, 20, 30, 40, 50 or 60 minutes or more. SHR-1210 can be administered as an intravenous infusion over approximately 60 minutes once every 1, 2, 3, 4, 5 or more weeks. SHR-1210 can be administered as an intravenous infusion over approximately 60 minutes once every two weeks. SHR-1210 can be administered as an intravenous infusion over approximately 60 minutes twice every three weeks. SHR-1210 can be administered as an intravenous infusion over approximately 60 minutes once every three weeks. Administration of SHR-1210 can be continuous. Administration of SHR-1210 may be intermittent.

The combinations described in this document can be entered according to the scheme. The regimen may be designed to provide therapeutically effective amounts of a compound of formula I and a PD-1 inhibitor (eg, anti-PD-1 antibody) for a predetermined period of time (eg, time of administration). The regimen may be designed to limit or prevent side effects or unwanted complications associated with each of the components of the combination described herein. The regimen may be designed in a manner that results in increased effect of both therapies in combination (eg, synergy). Regimens useful for the treatment of cancer can include any number of days of administration, which can be repeated as necessary. The administration periods may be interrupted by a rest period that precludes administration of at least one therapy option. For example, the regimen may include administration periods that include 2, 3, 5, 7, 10, 15, 21, 28 or more days. These periods can be repeated. For example, the circuit may include

- 21 045229 a certain number of days, as described earlier, with the scheme repeated 1, 2, 3, 4, 5, 6, 7, 8, 9,

10, 11, 12, 13 or more times.

The regimens may include a rest period of at least 1, 2, 3, 5, 7, 10 or more days when at least one therapy is not administered to the patient. The rest period can be determined, for example, by monitoring the patient's response to a drug or by determining the effectiveness of the treatment. A rest period may be applied to one therapy option such that during the rest period, administration of only one therapy option from a combination described herein is interrupted while the other therapy option(s) continue to be administered. Rest periods may be applicable to all therapies administered to a subject, such that the subject does not receive therapy for a certain period during the rest period.

The use of the regimens described herein for the treatment of cancer using the combinations described herein can be continued until disease progression or unacceptable toxicity.

Regimens for administering the combinations described herein include, for example, administration of a compound of Formula I twice a week or three times a week and administration of a PD-1 inhibitor. For example, a compound of Formula I can be administered once daily for about 21 days, and an anti-PD-1 antibody described herein can be administered once every 2 weeks or once every 4 weeks. For example, a compound of Formula I can be administered twice a week or three times a week, and an anti-PD-1 antibody described herein can be administered once every 2 weeks. In another exemplary regimen, a compound of Formula I may be administered twice a week or three times a week, and an anti-PD-1 antibody may be administered twice a week for 2 or 3 weeks. In another exemplary regimen, the compound of Formula I may be administered twice a week or three times a week, and the anti-PD-1 antibody may be administered once every 3 weeks. In another exemplary regimen, a compound of Formula I may be administered twice per week, and the anti-PD-1 antibody described herein may be administered once per week, once every 2 weeks, or once every 3 weeks. In some cases, such regimens include administration of an anti-PD-1 antibody once a week, once every 2 weeks, or once every 3 weeks. In another exemplary regimen, a compound of Formula I may be administered three times per week, and a PD-1 inhibitor described herein may be administered once per week, once every 2 weeks, or once every 3 weeks. In some cases, such regimens include administration of an anti-PD-1 antibody once a week, once every 2 weeks, or once every 3 weeks. In some cases, such regimens involve administering a compound of Formula I once daily. In some cases, such regimens include administering a compound of Formula I once daily for at least 21 days. In another exemplary regimen, a compound of Formula I may be administered once daily or once weekly, and a PD-1 inhibitor (eg, anti-PD-1 antibody) may be administered once weekly, once every 2 weeks, or once every 3 weeks. .

The regimen may be a regimen for administering pembrolizumab with a compound of formula I described herein. In one exemplary regimen comprising pembrolizumab, a compound of Formula I may be administered twice a week or three times a week, and pembrolizumab is administered in accordance with the prescribing information provided, for example, on the package insert. In another exemplary regimen, pembrolizumab is administered in an amount of about 1 mg/kg to about 10 mg/kg on day 1 of the regimen and twice weekly thereafter for at least three weeks until disease progression or unacceptable toxicity, and a compound of Formula I is administered twice a week or three times a week for the same period of time. In another exemplary regimen, pembrolizumab is administered in an amount of about 1 mg/kg to about 10 mg/kg on day 1 of the regimen and once every 3 weeks thereafter until disease progression or unacceptable toxicity, and a compound of Formula I is administered twice weekly or three times a week. once a week for the same period of time. Pembrolizumab can be administered twice a week for 3 weeks with a compound of Formula I, with the compound of Formula I being administered, for example, twice a week or three times a week during the course of such a regimen. Pembrolizumab can be administered once a week for 3 weeks with a compound of formula I, with the compound of formula I being administered, for example, twice a week or three times a week during the course of such a regimen. In another exemplary regimen, pembrolizumab may be administered once per week for 3 weeks with a compound of Formula I, wherein the compound of Formula I is administered, for example, once daily or once weekly during the course of such a regimen. Such patterns can be repeated as described above (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more times).

In another exemplary regimen comprising pembrolizumab, a compound of Formula I may be administered once daily and pembrolizumab is administered in accordance with the prescribing information provided, for example, on the package insert. In another exemplary regimen, pembrolizumab is administered in an amount of about 1 mg/kg to about 10 mg/kg on day 1 of the regimen and twice weekly thereafter for at least three weeks until disease progression or unacceptable toxicity, and a compound of Formula I is administered once a day for the same period of time. In another exemplary regimen, pembrolizumab is administered in an amount of about 1 mg/kg to about 10 mg/kg on day 1 of the regimen and once every 3 weeks thereafter until disease progression or unacceptable toxicity, and a compound of Formula I is administered once daily for the same period of time. Pembrolizumab can be administered twice weekly for 3 weeks with a compound of Formula I, with the compound of Formula I being administered, for example, once daily during the course of such a regimen. Pembrolizumab can be administered once a week for 3 weeks with a compound of formula I, wherein the compound of formula I is administered, for example, once a day during the course of such a regimen. Such patterns can be repeated as described above (for example, 1, 2, 3, 4, 5, 6,

7, 8, 9, 10, 11, 12 or more times).

The regimen may be a regimen for administering nivolumab with a compound of formula I described herein. In one exemplary regimen comprising nivolumab, the compound of Formula I may be administered twice weekly or thrice weekly, and nivolumab is administered according to the dosage information provided, for example, on the package insert. In another exemplary regimen, nivolumab is administered in an amount of about 1 mg/kg to about 5 mg/kg on day 1 and twice weekly thereafter for 3 weeks until disease progression or unacceptable toxicity, and a compound of Formula I is administered twice weekly or three times a week for the same period of time. In another exemplary regimen, nivolumab is administered in an amount of about 1 mg/kg to about 5 mg/kg on day 1 and every 2 weeks thereafter until disease progression or unacceptable toxicity, and a compound of Formula I is administered twice weekly or three times. per week for the same period of time. In another exemplary regimen, nivolumab may be administered once every 2 weeks, with the compound of formula I administered, for example, twice a week or three times a week during the course of such a regimen. In another exemplary regimen, nivolumab may be administered once every 2 weeks, with the compound of formula I administered, for example, once daily or once weekly during the course of such a regimen. Such patterns can be repeated as described above (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more times).

In another exemplary regimen comprising nivolumab, a compound of Formula I may be administered once daily and nivolumab is administered in accordance with the prescribing information provided, for example, on the package insert. In another exemplary regimen, nivolumab is administered in an amount of about 1 mg/kg to about 5 mg/kg on day 1 and twice weekly thereafter for 3 weeks until disease progression or unacceptable toxicity, and the compound of Formula I is administered once daily over the same period of time. In another exemplary regimen, nivolumab is administered in an amount of about 1 mg/kg to about 5 mg/kg on day 1 and every 2 weeks thereafter until disease progression or unacceptable toxicity, and a compound of Formula I is administered once daily thereafter. same period of time. In another exemplary regimen, nivolumab may be administered once every 2 weeks, with the compound of Formula I administered, for example, once daily during the course of such a regimen. Such patterns can be repeated as described above (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more times).

It should also be understood that the combinations described herein for the treatment of cancer may be co-administered with other active agents other than those present in the combinations described herein (eg, anticancer agents). The regimens for administering the combination described herein, including the exemplary regimens set forth above, can be modified as necessary to include the administration of such active agents. Administration of such active agents, for example anticancer agents, can be done once daily, once weekly, once monthly, twice daily, twice weekly, thrice weekly, once every 2 weeks, once every 3 weeks or once every 4 weeks or in accordance with the information on the use of such anticancer agents given, for example, on the package insert. Typical anticancer agents include, but are not limited to: abraxane; abiraterone; ACE-11; aclarubicin; acivicin; acodazole hydrochloride; acronin; actinomycin; acylfulvene; acepenol; adozelesin; adriamycin; aldesleukin; all-trans retinoic acid (ATRA); altretamine; ambamustine; ambomycin; amethanthron acetate; amidox; amifostine; aminoglutethimide; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; antarelix; anthramycin; aphidicolin glycinate; apuric acid; apa-CDP-DL-PTBA; arginine deaminase; ARRY-162; ARRY-300; ARRY-142266; AS703026; asparaginase; asperlin; asulacrine; atamestan; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; azacitidine; AZD8330; azetepu; azotomycin; balanol; batimastat; BAY 11-7082; BAY 43-9006; BAY 869766; bendamustine; benzochlorines; gas station; benzoylstaurosporine; beta-alethine; betaclamycin B; betulinic acid; b-FGF inhibitor; bicalutamide; bisanthrene; bisaziridinylspermine; bisnafid; bisnafide dimesylate; bistratene A; bisantrene hydrochloride; bleomycin; bleomycin sulfate; busulfan; bizelesin; breflat; bortezomib; brequinar sodium; bropyrimine; budotitanium; buthionine sulfoximine; bryostatin; cactinomycin; calusterone; calcipotriol; calphostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; caracemid; carbetimer; carboplatin; carmustine; pyridine hydrochloride; karzelezin; castanospermine; cecropin B; sedefingol; celecoxib; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; chlorambucil; chlorfusin; cirolemicin; cisplatin; CI-1040; cisporphyrin; cladribine; clomiphene analogues; clotrimazole; collimycin A; collimycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; chrysnatol; Crisnatol mesylate; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentantraquinones; cycloplatam; cypemycin; cyclophosphamide; cytarabine; cytarabine oxphosphate; cytolytic factor; cytostatin; dacarbazine; dactinomycin; daunorubicin; daunorubicin hydrochloride; decarbazine; dacliximab; dasatinib; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; dexormaplatin; desaguanine; desaguanine mesylate; diaziquon; didemnin B; didox; diethylnorspermine; Dihyd-23 045229 rho-5-azacytidine; dihydrotaxol; 9-dioxamycin; diphenylpyromustine; docosanol; dolasetron; docetaxel; doxorubicin; doxorubicin hydrochloride; doxyfluridine; droloxifene; droloxyphene citrate; dromostanolone propionate; dronobinol; duazomycin; duocarmycin SA; ebselen; ecomustin; edelfosine; edrecolomab; edatrexate; eflornithine hydrochloride; eflornithine; element; emitefur; elsamitrucin; enloplatin; enpromat; epipropidine; epirubicin; epirubicin hydrochloride; epristeride; erbulozole; eribulin; ezorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprine; exemestane; fadrozole; fadrozole hydrochloride; phasarabine; fenretinide; filgrastitis; finasteride; flavopiridol; fleselastin; fluasterone; floxuridine; fludarabine phosphate; fludarabine; fluorounorubicin hydrochloride; forfenimex; formstan; fluorouracil; floxuridine; flurocitabine; phosquidone; fostriecin sodium; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; halocitabine; ganirelix; gelatinase inhibitors; gemcitabine; geldanamycin; gossifol; GDC-0973; 63K1120212/trametinib; herceptin; hydroxyurea; hepsulfame; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; ibrutinib; idarucibin; idarubicin hydrochloride; ifosfamide; canfosfamide; ilmofosine; iproplatin; idoxifene; ydramanton; ilmofosine; ilomastat; imidazoacridones; imatinib (eg, GLIVEK); imiquimod; yobenguan; iodoxorubicin; ipomeanol; irinotecan; irinotecan hydrochloride; irsogladine; isobengazole; isohomoalicondrin B; itasetron; imofosine; interleukin IL-2 (including recombinant interleukin II or rIL2); interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-1a; interferon gamma-1b; jasplakinolide; kahalalide F; lamellarin N triacetate; lanreotide; leinamycin; lenograstim; lantinan sulfate; leptolstatin; letrozole; leuprorelin; levamisole; lenalidomide; lenvatinib; liarozole; lissoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; Lurtotecan; lutetium-texaphyrin; lysophylline; lanreotide acetate; lapatinib; letrozole; leucovorin; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; pomalidomide; LY294002; maytansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; menogaryl; merbaron; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; reconcilable; mitoguazone; mitolactol; mitonafide; mitoxantrone; mofarotene; we are literate; mopidamole; mycaperoxide B; myriaporon; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; mercaptopurine; methotrexate; methotrexate sodium; methoprine; meturedepu; mitindomide; mitocarcin; mitocromine; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nafarelin; nagrestip; napavine; nafterpine; nartograstim; nedaplatin; nerubicin; neridic acid; nilutamide; nizamycin; nitric oxide modulators; nitroxyl antioxidant; nitrulline; nocodazole; nogalamycin; oblimersen (GENASENS); octreotide; okicenon; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; oxysuran; oxaloplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptin; pegaspargase; peldesin; sodium pentosan polysulfate; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; pyritrexim; placetin A; placetin B; porfiromycin; prednisolone; prostaglandin J2; pyrazoloacridine; paclitaxel; PD035901; PD184352; PD318026; PD98059; peliomycin; pentamustine; peplomycin sulfate; RKS412; pipobromance; Piposulfan; pyroxantrone hydrochloride; plicamycin; plomestan; podophyllotoxin; polyphenol E; sodium porfimer; porfiromycin; prednimustine; procarbazine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; raltitrexed; ramosetron; retelliptin demethylated; rhizoxin; rituximab; RII retinamide; rogletimide; rohitukin; romurtide; rohinimex; rubiginone B1; ruboxil; riboprine; romidepsin; safingol; safingol hydrochloride; saintopine; sarcophytol A; sargramostim; semustine; sisofiran; sobuzoxan; sodium borocaptate; sodium phenylacetate; solverol; sonermin; sorafenib; sunitinib; sparphosic acid; spikamycin D; spiromustine; splenopentin; spongistatin 1; spongistatin 2; spongistatin 3; spongistatin 4; spongistatin 5; spongistatin 6; spongistatin 7; spongistatin 8; and spongistatin 9; squalamine; stipiamide; stromelysin inhibitors; sulfinosine; suradist; suramin; swainsonine; SB239063; selumetinib/AZD6244; simtrazen; SP600125; sodium sarphosate; sparsomycin; spirogermanium hydrochloride; spiroplatin; streptonigrine; streptozocin; sulofenur; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; sodium tecohalane; tegafur; tellurium pyrylium; temoporfin; temozolamide; teniposide; tetrachlorodecaoxide; tetrazamine; taliblastine; thiocoraline; thrombopoietin; thymalfasin; thymopoietin receptor agonist; timotrinan; tirapazamine; titanocene bichloride; topsentin; toremifene; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrphostin; talisomycin; TAK-733; taxotere; tegafur; teloxantrone hydrochloride; teroxiron; testolactone; thiamiprin; thioguanine; thiotep; tiazofurin; tirapazamine; toremifene citrate; trastuzumab; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); UBC inhibitors; ubenimex; U0126; uracil mustard; uredepu; Vapreotide; variolin B; velaresol; veramine; verteporfin; vinorelbine; Vinxaltin; Vitaxin; vinblastine; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinicinate sulfate; vineleurine sulfate; vinorelbine - 24 045229 tartrate; vinirosidine sulfate; vinzolidine sulfate; vorozol; wortmannin; XL518; zanoterone; zeniplatin;

zylascorb; cytostatin; cynostatin; and zorubicin hydrochloride.

Other exemplary anticancer agents include erbulozole (eg, R-55104); dolastatin 10 (eg DLS-10 and NSC-376128); mivobulin isethionate (eg, CI-980); NSC-639829; discodermolide (eg NVP-XX-A-296); AVT-751 (Abbott; e.g. E-7010); altoryrtin A; altoryrtin C; cemadotin hydrochloride (eg, LU-103793 and NSC-D-669356); epothilone A; epothilone B; epothilone C; epothilone D; epothilone E; epothilone F; epothilone B N-oxide; epothilone A N-oxide; 16-aza-epothilone B; 21aminoepothilone B; 21-hydroxyepothilone D; 26-fluoroepothilone; auristatin PE (eg NSC-654663); soblidotin (for example, 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); SDZ268970 (Lilly/Novartis); AM-97 (Armad/Kyowa Hakko); AM-132 (Armad); AM-138 (Armad/Kyowa Hakko); IDN-5005 (Indena); cryptophycin 52 (eg LY-355703); AC-7739 (Ajinomoto; e.g. AVE-8063A and CS-39.HCl); AC-7700 (Ajinomoto; e.g. AVE-8062; AVE-8062A; CS-39-L-Ser.HCl; and RPR258062A); vitilevuamide; tubulisin A; canadanzole; CA-170 (Curis, Inc.); centaureidine (eg NSC106969); 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 A1 (eg, BTO-956 and DIME); DDE-313 (Parker Hughes Institute); fijianolide B; laulimalide; SPA-2 (Parker Hughes Institute); SPA-1 (Parker Hughes Institute; e.g. SpIKET-P); 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine; e.g. MF-569); narcotic (eg NSC-5366); naskapin; 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; inanocin (eg NSC-698666); 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine); A-204197 (Abbott); T-607 (Tuarik; for example, T-900607); RPR-115781 (Aventis); eleutherobins (eg, desmethyl eleutherobin; desaethyl eleutherobin; isoeleutherobin A; and Z-eleutherobin); caribaeoside; caribaeolin; halichondrin B; D-64131 (Asta Medica); D-68144 (Asta Medica); Diazonamide A; A-293620 (Abbott); NPI-2350 (Nereus); taccalonolide A; TUB-245 (Aventis); A-259754 (Abbott); diozostatin; (-)-phenylagistine (eg NSCL-96F037); D-62638 (Asta Medica); D-62636 (Asta Medica); myoseverin B; D-43411 (Zentaris; e.g. D-81862); A-289099 (Abbott); A-318315 (Abbott); HTI-286 (eg, SPA-110; trifluoroacetate) (Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI); resverastatin phosphate sodium salt; BPR-OY-007 (National Health Research Institutes); and SSR-250411 (Sanofi); goserelin; leuprolide; triptolide; homogarringtonine; topotecan; itraconazole; deoxyadenosine; sertraline; pitavastatin; clofazimine; 5-nonyloxytryptamine; vemurafenib; dabrafenib; gefitinib (IRESSA); erlotinib (TARTCEVA); cetuximab (ERBITUX); lapatinib (TYKERB); panitumumab (VEKTIBIX); vandetanib (CAPRESLA); afatinib/BIBW2992; CI-1033/canertinib; neratinib/HKI-272; SR-724714; TAK-285; AST-1306; ARRY334543; ARRY-380; AG-1478; dacomitinib/PF299804; OSI-420/desmethyl-erlotinib; AZD8931; AEE726; pelitinib/EKB-569; CUDC-101; WZ8040; WZ4002; WZ3146; AG-490; XL647; PD153035; 5azathioprine; 5-aza-2'-deoxycytidine; 17-I-allylamino-17-demethoxygeldanamycin (17-AAG); 20-epi1,25 dihydroxyvitamin D3; 5 ethynyluracil; and BMS-599626.

In some embodiments, the combinations described herein are administered in conjunction with an anticancer agent described above, wherein the anticancer agent has known activity against a particular cancer (eg, gemcitabine administered with a combination described herein for the treatment of pancreatic cancer). The above anticancer agents may be approved for use in the treatment of certain indications (eg, certain types of cancer) in concentrations, amounts and using treatment regimens known in the art.

It is understood that modifications that do not significantly affect the activity of the various embodiments of this invention are also included within the definition of the invention presented herein. Accordingly, the following examples are intended to illustrate, but not limit, the present invention.

Examples

Example 1.

In this example, HBI-8000 was studied as monotherapy and in combination with anti-PD-1 at 5 mg/kg. The experiment included a basal solution group and an anti-PD-1 monotherapy group, which served as control groups for efficacy analysis. Tumors were measured twice a week until the end of the study on day 47. Each animal was sacrificed when the tumor reached a final volume of 1000 mm ³ or on the last day of the study, whichever occurred first, and the time to end point (TET) was calculated for each mouse. Response to treatment was determined by analysis of percent tumor growth inhibition (%TGR), defined as the percent increase in median time to endpoint (MTE) for treated and control mice; and by log-rank significance of differences in survival among groups and regression responses.

Mice: Female C57BL/6 mice (Charles River Laboratories) were eight weeks old and weighed

- 25 045229 body (BW) - from 15.4 to 22.0 g on day 1 of the study. The animals were given water ad libitum (reverse osmosis,

1 ppm Cl) and were fed a modified and irradiated Lab Diet® NIH 31 diet consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fiber. Mice were housed on Enrich-o'cobs™ irradiated laboratory animal bedding in stationary microisolators on a 12-hour light cycle at 20-22°C (68-72°F) and 40-60% humidity.

Tumor cells: MC38 murine colon carcinoma cells were maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and 2 mM glutamine, 100 units/ml sodium penicillin G, 100 μg/ml streptomycin sulfate and 25 μg/ml ml gentamicin. Cell cultures were maintained in tissue culture flasks in a humidified incubator at 37°C in an atmosphere of 5% CO2 and 95% air.

Tumor implantation: Cells were harvested during exponential growth and resuspended in cold DMEM. Each mouse was inoculated subcutaneously into the right flank with 1 x 10 ⁶ cells (0.1 ml of cell suspension). Tumors were measured in two dimensions to monitor growth as their average volume approached the required range of 100-150 mm ³ . Tumor load was calculated using the formula

Tumor volume (mm ³ ) where w is the width and l is the length of the tumor in mm. Tumor weight can be estimated based on the assumption that 1 mg is equivalent to 1 mm ³ tumor volume. Fourteen days after the day of tumor implantation, which was designated as day 1 of the study, animals with individual tumor volumes from 75 to 221 mm ³ were sorted into eleven groups (n = 10/group) with an average tumor volume per group of 130-133 mm ³ .

Study drugs: HUYA Bioscience International provided HBI-8000 (Lot No. 1384:0033). Anti-PD-1 antibody RMP1-14 (Lot No. 5611-10/0615) was purchased from BioXcell.

Dosing solutions: Fresh antibody dosing solutions were prepared daily and stored at 4°C. HBI-8000 was dissolved in 0.2% CMC (carboxymethylcellulose) in 0.1% Tween 80. Anti-PD-1 antibody dosing solution was prepared by diluting an aliquot of the stock solution (6.48 mg/ml) to 0.5 mg /ml in sterile PBS, giving a dosage of 5 mg/kg with a dosing volume of 10 ml/kg.

Six groups of C57BL/6 mice were dosed according to the protocol shown in Table. 2. All doses were prepared as described above. HBI-8000 was administered orally (po) once daily for twenty-one days (r/dx21). The dosage was adjusted taking into account the body weight of the animal. The antibody regimen was administered at a concentration of 5 mg/kg intraperitoneally (i.p.), twice weekly for three weeks (d/ndx3), and the dosage was adjusted based on the animal's body weight.

table 2

Group Treatment Frequency Group 1 Stock solution (2% CMC: 0.1% Tween 80) p/o, p/s x 21 Group 2 HBI-8000 at 20 mg/kg p/o, p/s x 21 Group 3 HBI-8000 at 50 mg/kg p/o, p/s x 21 Group 4 Anti-PD-1 inhibitory antibody at 5 mg/kg w/b, d/nd x 3 Group 5 HBI-8000 at 20 mg/kg plus PD-1 inhibitory antibody at 5 mg/kg p/o, p/s x 21 w/b, d/nd x 3 Group 6 HBI-8000 at 50 mg/kg plus PD-1 inhibitory antibody at 5 mg/kg p/o, p/s x 21 w/b, d/nd x 3

Tumor growth inhibition: Tumors were measured using a caliper twice a week and each animal was sacrificed when the tumor reached a volume of 1000 mm ³ or at the end of the study (C47), whichever occurred first. Animals that withdrew from the study due to reaching the endpoint of tumor growth were recorded as sacrificed due to tumor progression (TP) with the date of sacrifice indicated. The time to endpoint (ETP) for analysis was calculated for each mouse using the following equation:

vkdt = log ₁₀ (final volume) - bm

where VDCT is expressed in days, the final volume is expressed in mm ³ , b is the intercept, am is the slope of the line obtained using linear regression of the logarithmically transformed tumor growth data set. The data set consisted of the first observation that exceeded the final volume used in the analysis and the results of three consecutive observations that immediately preceded reaching that final volume.

The calculated VDCT is usually less than the CR date, the day on which the animal was sacrificed due to tumor load. Animals with tumors that did not reach the final volume were assigned the VDCT value corresponding to the last day of the study. In cases where logarithmically

- 26 045229 the converted calculated VDCT preceded the day before reaching the end point or exceeded the day before reaching the final tumor volume, linear interpolation was performed to approximate the VDCT. Any animal classified as dying from non-handling (non-handling) causes due to accident (NSOns) or due to unknown etiology (NSOne) was excluded from the VDCT calculations (and further analyses). Animals classified as dying from PO (treatment-related) or NSOm (non-treatment-related death due to metastasis) were assigned a TBCT value corresponding to the day of death.

Treatment outcome: Treatment outcome was assessed by tumor growth slowdown (TGGR), which is defined as an increase in median time to end point (MTE) in the treated group compared to the control group

expressed in days or as a percentage of the median TBDC for the control group m-c %TGD = c _x yus where T is the median TBDC for the treated group, and C is the median TBDC for the assigned control group.

Treatment Efficiency: Treatment effectiveness can be determined by the volume of tumors in animals remaining in the study during the last 24 hours. MOO (n) was determined as the median tumor volume on the last day of the study in the remaining animals (n) whose tumors did not reach the final volume. The effectiveness of the treatment can also be determined by the frequency and magnitude of regression responses observed during the study. The treatment can cause partial regression (PR) or complete regression (CR) of the tumor in the animal. For a PR response, the tumor volume was 50% or less of the volume on day 1 on three consecutive measurements during the study and was equal to or greater than 13.5 mm ³ in one or more of these three measurements. For PR response, tumor volume was less than 13.5 mm ³ on three consecutive measurements during the study. An animal with a PR response at the end of the study is further classified as a tumor-free survivor (TFS). Animals were observed for regression responses.

Statistics: Prism (GraphPad) for Windows 6.07 was used for graphical presentation and statistical analysis. The log-rank test, which assesses overall survival, was used to analyze the significance of the difference between the VDCT values for the two groups. Log-rank analysis includes data for all animals in the group, excluding NSO deaths. Two-way statistical analysis was performed at a significance level of P=0.05. Graphs of the median tumor volume by group were plotted as a function of time. When an animal withdrew from the study due to tumor burden, the final tumor volume recorded for the animal was included in the data used to calculate the median volume at subsequent time points. Kaplan-Meier plots illustrate the percentage of study animals in each group remaining in the study as a function of time.

Animals in example 1 were treated in accordance with the protocol described in table. 1. In FIG. Figure 1 shows median tumor growth curves for all study groups, and FIG. Figure 2 shows median tumor volume curves for the combination of HBI-8000 at 50 mg/kg with a PD-1 inhibitory antibody compared to single agent and vehicle controls. The combination of HBI-8000 at a concentration of 50 mg/kg plus a PD-1 inhibitory antibody resulted in statistically significant inhibition of tumor growth. In fig. 3 shows Kaplan-Meier plots for all groups, and Fig. Figure 4 shows Kaplan-Meier plots for the combination of HBI-8000 at 50 mg/kg with a PD-1 inhibitory antibody compared to a single agent control. The combination of HBI-8000 at a concentration of 50 mg/kg plus a PD-1 inhibitory antibody resulted in a statistically significant increase in survival. In table Table 3 shows the values calculated for VDKT and %ZRO.

Table 3. Median values of VDCT and %ZRO (example 1)

Group η Processing scheme Median VDCT Value %ZRO Agent 1 Agent 2 1 10 base solution - 20.5 - 2 10 HBI-8000 (20 mg/kg) - 18.9 -8 3 10 HBI-8000 (50 mg/kg) - 22.8 eleven 4 10 anti-PD-l - 22.0 7 5 10 HBI-8000 (20 mg/kg) anti-PD-l 26.1 27 6 10 HBI-8000 (50 mg/kg) anti-PD-l 28.7 40

Example 2.

In this example, HBI-8000 was studied as monotherapy and in combination with an inhibitor

- 27 045229 with anti-PD-1 antibody at 5 mg/kg. The experiment included a basal solution group and a PD-1 inhibitory antibody monotherapy group, which served as control groups for efficacy analysis. Tumors were measured twice a week until the end of the study on day 50. Each animal was sacrificed when the tumor reached a final volume of 1000 mm ³ or on the last day of the study, whichever occurred first, and the time to end point (TET) was calculated for each mouse. Response to treatment was determined by analysis of percent tumor growth inhibition (%TGR), defined as the percent increase in median time to endpoint (MTE) for treated and control mice; and by log-rank significance of differences in survival among groups and regression responses.

Mice: Data on the animals used in this example can be found in one of the paragraphs above.

Tumor Cell Culture: Data for the tumor cells used in this example can be found in one of the paragraphs above.

Implantation and Tumor Measurement: The tumor implantation and tumor growth measurement data used in this example can be found in one of the paragraphs above. In this example, each mouse was inoculated subcutaneously into the right flank with 5 x 105 cells (0.1 ml cell suspension).

Study Drugs: Data for the study drugs used in this example can be found in the description earlier.

Dosing Solutions: Data for the dosing solutions used in this example can be found in the description previously.

Treatment: Four groups of C57BL/6 mice (n=10) were dosed according to the protocol in Table. 4. Dosing began on day 1 unless otherwise indicated. HBI-8000 was administered po at 50 mg/kg. Anti-PD-1 inhibitory antibody was administered i.p. at 5 mg/kg. A stock solution (0.2% carboxymethylcellulose: 0.1% Tween 80 in deionized water) was administered po. All agents were administered at a dosage volume of 10 ml/kg, adjusted for the body weight of individual animals.

Table 4

Group Treatment Frequency Group 1 Stock solution (2% CMC: 0.1% Tween 80) p/o, p/s x 21 Group 2 HBI-8000 at 50 mg/kg p/o, p/s x 21 Group 3 Anti-PD-1 inhibitory antibody at 5 mg/kg w/b, d/nd x 3 Group 4 HBI-8000 at 50 mg/kg plus PD-1 inhibitory antibody at 5 mg/kg p/o, r/s x 21 v/b, d/nd x 3

Tumor growth inhibition: Tumor growth inhibition measurements and calculations can be found in the description earlier.

Processing result: data on measurements and calculations of processing results can be found in the description earlier.

Processing Efficiency: Data on efficiency measurements and calculations of processing efficiency can be found in the description earlier.

Statistics: Statistics and software used in this study can be found in the description earlier. In fig. Figure 5 shows median tumor volume measurements for all groups, and FIG. Figure 6 is a Kaplan-Meier plot illustrating the percentage of animals in each group remaining in the study as a function of time. In table Table 6 shows the values calculated for HFCT and %ZRO for each treated group.

Animals in example 2 were treated in accordance with the protocol described in table. 4. In FIG. Figure 5 shows median tumor growth curves for all study groups; the combination of HBI-8000 at 50 mg/kg with a PD-1 inhibitory antibody approached statistical significance in the context of tumor growth inhibition. In fig. Figure 6 shows Kaplan-Meier plots for all groups; the combination of HBI-8000 at a concentration of 50 mg/kg plus a PD-1 inhibitory antibody resulted in a statistically significant increase in survival compared with the basal solution as well as the individual agents. In fig. Table 7 shows individual values of time to the end point for all groups in example 7. Table. Table 5 shows the values calculated for VDKT and %ZRO.

Table 5. Median values of VDKT and %ZRO (example 2)

Group η Processing scheme Median VDCT Value %ZRO Agent 1 Agent 2 1 10 base solution - 16.3 - 2 10 HBI-8000 (50 mg/kg) - 19.4 19 3 10 anti-PD-l - 18.0 eleven 4 10 HBI-8000 (50 mg/kg) anti-PD-l 28.5 75

- 28 045229

Example 3.

In this model, a subset of animals treated with first-line PD-L1 checkpoint inhibitory antibody therapy demonstrate complete tumor regression. However, the same proportion of animals treated with first-line anti-PD-L1 inhibitory antibody therapy demonstrate rapid tumor progression. The remaining animals treated in this manner show slow tumor progression or stable disease, a result that approximates the situation in large numbers of human cancer patients receiving anti-PD-L1 inhibitory antibody therapy, i.e. they demonstrate a transient partial response, including stable disease, but then develop resistance and begin rapid progression, consistent with failure of anti-PD-1 inhibitory antibody therapy. This example assessed the effectiveness of HBI-8000 as a second-line therapy, alone and in combination with the anti-PD-1 inhibitory antibody RMPI-14, in inducing tumor growth inhibition (TGGR) in animals whose tumors progressed after first-line therapy. inhibitory antibody to PD-L1, in the syngeneic MC38 murine colon carcinoma model in immunocompetent C57BL/6 mice. Thus, this relates to the need for clinical therapy for patients after failure of PD-L1 inhibitory antibody therapy.

C57BL/6 females bearing subcutaneous MC38 tumors (mean tumor volume: 114 ^mm3 at treatment initiation) were treated with first-line anti-PD-L1 inhibitory antibody therapy administered intraperitoneally (i.p.) at a dose of 5 mg/kg, twice daily. a week for two weeks (d/ndx2). When tumors met failure criteria and demonstrated two consecutive increases in tumor volume and tumor volume was <500 mm ³ , they were then re-enrolled in the second-line efficacy study, which consisted of six groups (n=10 per group) of mice. Dosing started at C1, which represents the on-day and varied among mice (these data were normalized for each group). Second-line treatment options were as follows. The stock solution was administered orally (po). HBI-8000 was administered po at 50 mg/kg. Anti-PD-1 and anti-PDL-1 inhibitory antibody were administered intraperitoneally (i.p.) at 5 mg/kg. Mice from group 1 served as a control and received 0.2% carboxymethylcellulose: 0.1% Tween 80 in deionized water (stock solution) once daily for twenty-one days (p/cx21). Group 2 received HBI-8000 r/cx21. Group 3 received a second course of PD-L1 inhibitory antibody d/ndx2. Group 4 received HBI-8000 r/cx21 and the PD-L1 inhibitory antibody d/ndx2. Group 5 received anti-PD-1 d/ndx2. Group 6 received HBI8000 r/cx21 and anti-PD-1 d/ndx2. The end point of the study was a tumor volume of 1500 mm ³ or 45 days, whichever occurred first. Tumor measurements were performed twice weekly until C44, with individual animals withdrawing from the study when the final tumor volume was reached.

Mice: At the start of primary treatment with PD-1 inhibitory antibody, female C57BL/6 (Charles River) mice were 8 weeks old and had a BW range of 18.1-24.1 g. Animals were provided with water ad libitum (reverse osmosis, 1 m. d. Cl) and were fed a modified and irradiated Lab Diet® NIH 31 diet consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fiber. Mice were housed on irradiated Enrich-o'cobs™ bedding in stationary microisolators with a 12-hour light cycle at 20-22°C (68-72°F) and 40-60% humidity.

Implantation and Tumor Measurement: The tumor implantation and tumor growth measurement data used in this example can be found in the description previously. In this example, each mouse was inoculated subcutaneously into the right flank with 5 x 105 cells (0.1 ml of cell suspension).

Study drugs: HUYA Bioscience International provided HBI-8000 (Lot No. 1384:0033). Anti-PD-1 inhibitory antibody RMPI-14 (lot no. 5611-10/0615) and anti-PDL-1 antibody 10F.9G2 (αntu-PDL-1, lot no. 5786-7-8/0815) were purchased from Bio X cell (West Lebanon, NH). All agents were prepared according to protocol instructions.

Dosing Solutions: HBI-8000 was prepared by diluting 0.2% CMC:0.1% Tween 80 to produce a 5 mg/mL dosing solution. Fresh dosing solutions were prepared weekly and stored at 4°C. Anti-PD-1 inhibitory antibody dosing solution was prepared by diluting an aliquot of the stock solution (8.62 mg/mL) to 0.5 mg/mL in sterile PBS. The dosing solution was prepared twice a week and stored at 4°C. Anti-PDL-1 antibody dosing solution was prepared by diluting an aliquot of the stock solution (5.37 mg/mL) to 0.5 mg/mL in sterile PBS. Anti-PDL-1 antibody dosing solution was prepared twice weekly and stored at 4°C.

Treatment: In the initial phase of this study with failure of anti-PD-L1 inhibitory antibody therapy, 150 C57BL/6 mice were dosed IP with first-line anti-PD-L1 inhibitory antibody at 5 mg/kg, d/ndx2. Animals meeting readmission criteria were included in the efficacy study; it included animals with two consecutive increases in tumor volume and tumor volumes less than 500 mm ³ . The first sixty animals that became available were sequentially allocated to the six efficacy study arms until all arms were filled; this occurred sixteen or twenty-two days after initiation of the first dosing line. For

- 29 045229 efficacy study six groups of C57BL/6 mice (n=10) were dosed according to the protocol in table. 6. Second-line therapy began on day 1, which was the day each individual animal was included.

Table 6

Group Treatment Frequency Group 1 Stock solution (2% CMC: 0.1% Tween 80) p/o, p/s x 21 Group 2 HBI-8000 at 50 mg/kg p/o, p/s x 21 Group 3 Anti-PD-L1 inhibitory antibody at 5 mg/kg w/b, d/nd x 3 Group 4 HBI-8000 at 50 mg/kg plus Anti-PD-L1 inhibitory antibody at 5 mg/kg p/o, p/s x 21 w/b, d/nd x 3 Group 5 Anti-PD-1 inhibitory antibody at 5 mg/kg w/b, d/nd x 3 Group 6 HBI-8000 at 50 mg/kg plus Anti-PD-1 inhibitory antibody at 5 mg/kg p/o, p/s x 21 w/b, d/nd x 3

Tumor growth inhibition: Tumor growth inhibition measurements and calculations used in the study can be found in the description previously described.

Processing Result: Data on measurements and calculations of processing results used in the study can be found in the description earlier.

Processing Efficiency: Measurements and calculations of processing efficiency used in the study can be found in the earlier description.

Statistics: Statistics and software used in this study can be found in the description earlier. The responses of each group were tabulated and classified as no response (OO), partial response (PR), and complete response (CR) to the therapy used. Measurements of mean tumor volume for all groups and data for a Kaplan-Meier plot illustrating the percentage of animals in each group remaining in the study as a function of time were obtained.

Animals in example 3 were treated in accordance with the protocol described in table. 6. In FIG. Figure 8 shows median tumor growth curves for all study groups. In fig. 8 shows Kaplan-Meier plots for all groups; the combination of HBI-8000 at a concentration of 50 mg/kg plus a PD-1 inhibitory antibody resulted in a statistically significant increase in survival compared with the basal solution as well as the individual agents. In fig. Table 9 shows individual values of time to the end point for all groups in example 3. Table. Table 7 shows the values calculated for VDKT and %ZRO.

Table 7

Processing group Median VDCT value Average T-S % ZRO BUT CHO BY Base solution 9.8 0.0 0.0 8 2 0 HBI-8000 11, 4 3.0 31, 8 8 1 1 PD-1 Ab 13, 8 10, 4 106, 3 6 2 2 PD-1 Ab+HBI-8000 24.2 10, 1 103.3 3 1 6 PD-L1 Ab 17.7 8.5 86, 7 5 3 2 PD-L1 Ab+HBI- 8000 14.7 3.8 39, 2 6 4 0

Example 4.

This Example 4 examined the characteristics of antitumor responses induced by HBI-8000 administered alone and in combination with anti-PD-1 RMP1-14 (anti-PD-1) in a 4T1 murine carcinoma xenograft model in BALB/c mice. The effect of these treatment options on lung metastases was assessed.

Treatment began on day 1 (C) in BALB/c mice bearing established 4T1 tumors. HBI-8000 was administered orally (PO) and anti-PD-1 was administered intraperitoneally (IP) as a single dose. Study agents were administered alone and in combination with HBI-8000. Control animals received the basic solution. The study ended at C14 when the metastatic endpoint was reached. Response to treatment was determined based on the number of metastases obtained from animals remaining at C14.

Mice: Female BALB/c mice (BALB/c AnNcr1, Charles River) were seven weeks old at C1 of the study and body weight (BW) ranged from 14.7 to 20.7 g. Animals were given water ad libitum (reverse osmosis, 1 ppm Cl) and were fed a modified and irradiated Lab Diet® NIH 31 diet consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fiber. Mice were housed on irradiated Enrich-o'cobs™ bedding in stationary microisolators with a 12-hour light cycle at 20-22°C (68-72°F) and 40-60% humidity.

- 30 045229

Tumor cell culture: The 4T1 breast carcinoma cell line was grown to mid-log phase in RPMI medium containing 10% fetal bovine serum, 2 mM glutamine, 100 units/ml sodium penicillin G, 25 μg/ml gentamicin, and 100 μg/ml streptomycin sulfate. . Cells were cultured in tissue culture flasks in a humidified incubator at 37°C in an atmosphere of 5% CO ₂ and 95% air.

In Vivo Implantation and Tumor Growth: 4T1 tumor cells were harvested during exponential growth and resuspended in PBS. Each study mouse was orthotopically injected into the mammary fat layer with 1x10 ⁶ cells (0.1 ml of cell suspension). Tumor growth was monitored as the average tumor size approached the target range of 80-120 mm ³ .

Study Agents: HUYA Bioscience International, LLC provided HBI-8000 (Lot #1384:0033). Anti-PD-I RMP-14 (anti-PD-1, lot no. 5792-599016J1) was purchased from Bio X cell (West Lebanon, NH). All agents were prepared according to protocol instructions. The stock solution used in this study consisted of 0.2% carboxymethylcellulose:0.1% Tween 80 in DI water. HBI-8000 was prepared by diluting 0.2% CMC:0.1% TB80 to produce a 5 mg/mL dosing solution. Fresh dosing solutions were prepared weekly and stored at 4°C. Anti-PD-1 antibody dosing solution was prepared by diluting an aliquot of the stock solution (6.37 mg/mL) to 0.5 mg/mL in sterile PBS. Dosing solution was prepared for each dosing day and stored at 4°C.

Treatment: At C1 of the study, dosing of mice bearing established 4T1 tumors began according to the treatment plan below. All agents were administered at a dosage volume of 10 ml/kg; volumes were adjusted based on the BW of the individual animal.

Group 1 served as an effectiveness control and received the basic solution, po, daily, for thirteen days (p/d x13).

Group 2 received HBI-8000 at 50 mg/kg, po, r/cx13.

Group 3 received anti-PD-1 at 5 mg/kg, i.p., twice a week for two weeks (d/ndx2).

Group 4 received HBI-8000 at 50 mg/kg, po, r/cx13, and anti-PD-1 at 5 mg/kg, i.p., d/ndx2. Endpoint: number of metastases.

The results were analyzed by counting metastatic lesions in the lungs at C14, the last day of the study. Animals were sacrificed at end point using isoflurane anesthesia and necropsy was performed to identify metastases. The total number was obtained by summing the number of lesions in the upper, middle, lower and postcaval lobes of the right lung and the number of lesions in the left lung. Percent inhibition was determined as the difference between the number of metastatic lesions in the assigned control group and the number of metastatic lesions in the drug-treated group, expressed as a percentage of the number of metastatic lesions in the assigned control group:

(#Focuses when treated with the drug % Inhibition^-------------------------#Focuses for control)] x 100

Results: on the 14th day, the number of metastatic foci in the lungs for control animals of group 1 was 35.0±2.17 (Fig. 10). HBI-8000 monotherapy resulted in negligible inhibition of -26%. Anti-PD-1 monotherapy resulted in an inhibition rate of 30%. Combination therapy with HBI-8000 and anti-PD-1 resulted in lesion inhibition of 72%, which was statistically significant. The results are shown in Fig. 10.

Example 5.

In this example, HBI-8000 was studied as monotherapy and in combination with anti-PD-I antibody at 10 mg/kg or anti-PD-L1 antibody at 10 mg/kg. The model used was the syngeneic RENCA model of renal cell carcinoma (RCC). The experiment included a basal solution group and both anti-PD-1 inhibitory antibody and anti-PD-L1 inhibitory antibody monotherapy groups, which served as control groups for efficacy analysis. Tumors were measured twice a week until the end of the study on day 25. Response to treatment was determined by analyzing the percentage of tumor growth inhibition (%TGR).

Mice: The data for the animals used in this example are similar to those found in the description earlier.

Tumor cell culture: The data for the tumor cells used in this example are similar to those found in the description earlier.

Implantation and Tumor Measurement: The tumor implantation and tumor growth measurement data used in this example are similar to those found in the description previously. In this example, each mouse was subcutaneously inoculated into the right flank with 1 x 10 ⁶ RENCA cells (0.1 ml cell suspension).

Study Drugs: Data for the study drugs used in this example can be found in the description earlier.

Dosing Solutions: Data for dosing solutions used in this application.

Claims (26)

re, can be found in the description earlier. Treatment: Six groups of female BALB/c mice bearing subcutaneous RENCA tumors (mean tumor volume: 62 mm ³ at the beginning of treatment) were treated according to the protocol in table. 7. Dosing began on day 1 unless otherwise indicated. HBI-8000 was administered po at 50 mg/kg. Inhibitory antibodies to PD-1 and PD-L1 were administered intravenously at 10 mg/kg. A stock solution (0.2% carboxymethylcellulose: 0.1% Tween 80 in deionized water) was administered po. All agents were administered at a dosage volume of 10 ml/kg, adjusted for the body weight of individual animals. Table 8 Group Treatment Frequency Group 1 Stock solution (2% CMC: 0.1% Tween 80) p/o, p/s x 21 Group 2 HBI-8000 at 50 mg/kg p/o, p/s x 21 Group 3 Anti-PD-L1 inhibitory antibody at 10 mg/kg w/b, d/nd x 3 Group 4 HBI-8000 at 50 mg/kg plus Anti-PD-L1 inhibitory antibody at 10 mg/kg p/o, p/s x 21 w/b, d/nd x 3 Group 5 Anti-PD-1 inhibitory antibody at 10 mg/kg w/b, d/nd x 3 Group 6 HBI-8000 at 50 mg/kg plus Anti-PD-1 inhibitory antibody at 10 mg/kg p/o, p/s x 21 w/b, d/nd x 3 Tumor growth inhibition: Tumor growth inhibition measurements and calculations used in the study can be found in the description previously described. Processing Result: Data on measurements and calculations of processing results used in the study can be found in the description earlier. Processing Efficiency: Measurements and calculations of processing efficiency used in the study can be found in the earlier description. Statistics: Statistics and software used in this study can be found in the previous description. The responses of each group were tabulated and classified as no response (OO), partial response (PR), and complete response (CR) to the therapy used. Measurements of mean tumor volume for all groups and data for a Kaplan-Meier plot illustrating the percentage of animals in each group remaining in the study as a function of time were obtained. Animals in example 5 were treated in accordance with the protocol described in table. 8. In FIG. Figure 11 shows median tumor growth curves for all study groups; the combination of HBI-8000 at 50 mg/kg with a PD-1 inhibitory antibody was statistically significant and different from both basal solution (P=0.026) and anti-PD-1 monotherapy (P=0.036) in terms of tumor growth inhibition . Example 6 HDAC Enzyme Inhibition Assay. Analysis of the selectivity and chidamide inhibition efficiency of HDAC isotypes was performed using human recombinant HDAC proteins as described in Ning et al. All enzymatic reactions are incubated for 17 hours at room temperature in a 50-μl reaction mixture containing HDAC assay buffer (catalog number BPS 50031), 5 μg of BSA, HDAC substrate, purified recombinant HDAC enzyme, and the test compound at the specified concentration. After the enzymatic reactions, add 50 µl of 29 HDAC Developer (cat. no. BPS 50030) to each well and incubate the plate at room temperature for an additional 20 min. Fluorescence intensity was measured at excitation at 360 nm and emission at 460 nm using a Synergy™ 2 microplate reader from BioTek (Winooski, VT, USA). Each compound concentration was tested in duplicate. IC ₅₀ values are determined by analyzing concentration-response inhibition curves. Although the invention has been described with reference to the provided embodiments, those skilled in the art will readily understand that the specific examples and studies detailed above are purely illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims. CLAIM 1. A combination containing a therapeutically effective amount of an anti-PD-1 antibody and a compound represented by the following structure: - 32 045229 or a pharmaceutically acceptable salt thereof, wherein said compound is present in an amount of at least 5 mg, and wherein said combination is intended for administration to a patient suffering from colon cancer. 2. The combination according to claim 1, characterized in that said compound is present in an amount of 5 to 50 mg. 3. The combination according to claim 1, wherein said anti-PD-1 antibody is a monoclonal antibody, a human antibody, a mouse antibody, a chimeric antibody, a humanized antibody or a chimeric humanized antibody, a peptibody, a diabody, a minibody, a single chain variable fragment (ScFv ) or a fragment or variant thereof. 4. The combination of claim 3, wherein said humanized antibody comprises nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR1210 or MEDI0680. 5. The combination according to claim 3 or 4, characterized in that said antibody to PD-1 is present in an amount of 0.1 to 10 mg/kg relative to body weight. 6. The combination according to claim 3 or 4, characterized in that said antibody to PD-1 is present in an amount of 0.5 to 5 mg/kg relative to body weight. 7. The combination according to claim 3 or 4, characterized in that said antibody to PD-1 is present in an amount of: 1, 2, 3 or 5 mg/kg relative to body weight. 8. A pharmaceutical composition containing a combination according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient. 9. A kit containing a combination according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 and additionally containing one or more containers, instructions for use and/or medical devices for administration. 10. A method of treating colon cancer, comprising administering a therapeutically effective amount of the combination according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 to a patient in need thereof. 11. The method according to claim 10, characterized in that said cancer patient has not previously undergone treatment. 12. The method according to claim 10 or 11, characterized in that said combination is administered to said cancer patient as first-line therapy. 13. The method according to any one of claims 10 to 12, characterized in that said combination is administered to said cancer patient as second, third, fourth, fifth or sixth line therapy. 14. The method according to any one of claims 10 to 13, characterized in that said combination is administered to said cancer patient after treatment with at least one anticancer therapy. 15. The method of claim 14, wherein said anticancer therapy includes chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, or a combination thereof. 16. Method according to any one of claims 10-15, characterized in that said cancer is resistant to at least one anticancer agent. 17. Method according to any one of claims 10 to 16, characterized in that said compound of formula I and said PD-1 inhibitor of said combination are administered simultaneously or sequentially. 18. Method according to any one of claims 10-17, characterized in that said compound of formula I is administered 2-3 times a week. 19. Method according to any one of claims 10 to 18, characterized in that said compound of formula I is administered daily. 20. The method according to any one of claims 10-19, characterized in that the PD-1 inhibitor and the specified compound of formula I are administered simultaneously on day 1 of the administration regimen. 21. The method according to claims 10-20, wherein said anti-PD-1 antibody is a peptibody, diabody, minibody, single chain variable fragment (ScFv) or a variant thereof. 22. The method of claim 21, wherein said anti-PD-1 antibody includes nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. 23. The method according to claim 11, characterized in that the specified combination is administered to the specified patient according to the scheme. 24. The method according to claim 11, characterized in that the specified scheme is repeated until the disease progresses or unacceptable toxicity occurs. 25. The method according to claim 22, characterized in that said regimen includes a rest period of at least 1 day between successive periods of administration. 26. The method according to claim 22, characterized in that the specified compound of the specified combination is administered 23 times a week according to the specified schedule, and the specified antibody to PD-1 is administered every 2-3 weeks. -