EA042997B1 - COMBINATION THERAPY OF CANCER WITH HDAC INHIBITOR AND PD-L1 INHIBITOR - Google Patents

Description

Technical field

The invention relates to a combination of an HDAC inhibitor and a PD-L1 inhibitor and to the use of such a combination for the treatment of cancer.

State of the art

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

Brief description of the essence of the invention

The invention relates to a combination containing a therapeutically effective amount of an inhibitory antibody to PD-L1 and a therapeutically effective amount of a compound represented by the following formula (I):

or a pharmaceutically acceptable salt thereof, wherein said combination is for administration to a subject having colon cancer previously treated with a PD-1 inhibitor, and wherein said compound is present in an amount of at least about 5 mg.

In a preferred embodiment, the combination contains the specified compound in an amount of from about 5 mg to about 50 mg.

In a preferred embodiment, said antibody comprises durvalumab, avelumab, atezolizumab, or BMS-936559.

In a preferred embodiment, said anti-PD-L1 inhibitory antibody is present in an amount of about 0.1 mg/kg to about 30 mg/kg of the patient's body weight.

In a preferred embodiment, said anti-PD-L1 inhibitory antibody is present in an amount of about 0.5 mg/kg to about 15 mg/kg of the patient's body weight.

In a preferred embodiment of the invention, said anti-PD-L1 inhibitory antibody is present in an amount of about: 0.1, 0.3, 1, 2, 3, 5, 10, or 20 mg/kg of the patient's body weight.

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

In yet another aspect, the present invention relates to a kit containing the above combination and individual containers, where the compound of the above formula I and the PD-L1 inhibitory antibody in the specified combination are packaged in individual containers in the kit, and where the compound of formula I is prepared in form for oral administration, and inhibitory antibody to PD-L1 prepared in the form for parenteral administration.

In yet another aspect, the present invention provides a method of treating cancer comprising administering a therapeutically effective amount of the above combination to a patient in need thereof, wherein said combination is for administration to a patient having colon cancer previously treated with a PD-1 inhibitor.

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

In a preferred embodiment of the proposed method, said combination is administered to said cancer patient after treatment with at least one anti-cancer therapy.

- 1 042997

In a preferred embodiment of the proposed method, said anti-cancer therapy comprises chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, or a combination thereof.

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

In a preferred embodiment of the proposed method, said compound and said PD-L1 inhibitor of said combination are administered simultaneously or sequentially.

In a preferred embodiment of the proposed method, the specified connection is administered 2-3 times a week.

In a preferred embodiment of the proposed method, said compound is administered daily.

In a preferred embodiment of the proposed method, the PD-L1 inhibitor and the specified compound are administered simultaneously on day 1 of the administration regimen.

In a preferred embodiment of the proposed method, said PD-L1 inhibitory antibody comprises durvalumab, avelumab, atezolizumab, BMS-936559, STI-A1010, STI-A1011, STIA1012, STI-A1013, STI-A1014, or STI-A1015.

In a preferred embodiment of the proposed method, the specified combination is administered to the specified patient according to the scheme.

In a preferred embodiment of the proposed method, this scheme is repeated until disease progression or unacceptable toxicity occurs.

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

In a preferred embodiment of the proposed method, the specified compound of the specified combination is administered 2-3 times a week according to the specified scheme, and the specified inhibitory antibody to PD-L1 is administered every 2-3 weeks.

In a preferred embodiment of the proposed method, the specified compound of the specified combination is administered once a day for 21 days according to the specified scheme, and the specified inhibitory antibody to PD-L1 is administered every 2-3 weeks.

In a preferred embodiment of the proposed method, said cancer treatment method 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 to progression of said cancer in said patient, prolongs the time life of said patient, prolongs survival of said patient without disease progression.

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 of this document.

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 50 mg/kg in the study described in Example 1 of this document.

Fig. 3 illustrates survival (by the Kaplan-Meier method) 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 50 mg/kg in the study described in Example 1 of this document.

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. 6 illustrates survival (by the Kaplan-Meier method) for all groups studied in the study described in example 2 of this document.

Fig. 7 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 3 of this document.

Fig. 8 illustrates survival (by the Kaplan-Meier method) for all groups studied in the study described in example 3 of this document.

Detailed description of the invention

Definitions.

All patents, applications, published applications, and other publications cited herein are incorporated by reference in their entirety. Unless otherwise indicated, all technical and scientific terms used in this document have the same meanings as commonly understood by those skilled in the art to which the invention pertains. The chemical structures and formulas given in this document are drawn up in accordance with the standard rules of chemical valency known in the field of chemistry. In the event of a discrepancy between a given structure and a name given to that structure, the given structure should be taken as having more 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 some of the terms commonly used in this document and are not intended to limit the scope of the present invention. Where there are multiple definitions for a given term, those given in this section take precedence, unless otherwise noted. The headings used herein are for illustrative purposes only and do not limit the invention described herein in any way.

The term PD-L1 inhibitor refers to a moiety (e.g., compound, nucleic acid, polypeptide, antibody) that reduces, inhibits, blocks, eliminates, or interferes with the activity, binding of PD-L1 to its PD-1 receptor, or expression of PD-L1 (e.g., , programmed cell death ligand 1, PD-L1 (CD274), GI: 30088843), including variants, isoforms, species homologues of human PD-L1 (e.g. murine) and analogs that share at least one epitope with PD-L1 . The PD-L1 inhibitor includes molecules and macromolecules such as, for example, compounds (small molecular weight compounds), nucleic acids, polypeptides, antibodies, peptibodies, diabodies, minibodies, single chain variable fragments (ScFv) and fragments or variants thereof. Thus, as used herein, a PD-L1 inhibitor refers to any moiety that antagonizes PD-L1 activity, its binding to PD-1, or its expression. The potency of a PD-L1 inhibitor can be determined, for example, by the inhibitor concentration at 50% (half-maximal inhibitor concentration or IC ₅₀ ). PD-L1 inhibitors include the exemplary compounds and compositions described herein. An anti-PD-L1 inhibitory antibody refers to a PD-L1 inhibitor, which is the monoclonal or polyclonal antibody described herein.

The terms durvalumab, avelumab, atezolizumab, BMS-936559, STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014 and STI-A1015 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 the amount of a therapeutic agent (for example, a combination provided herein or another active agent, such as an anticancer agent described herein) that is sufficient to achieve the stated goal or otherwise achieve the effect for which it is administered. An effective amount may be sufficient to reduce and/or reduce the progression, development, recurrence, severity and/or duration of a given disease, disorder or condition and/or symptom associated therewith, or may be sufficient to reduce the level of activity or binding of the polypeptide (e.g. , PD-L1). 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 pathological condition, and/or improvement or enhancement of the prophylactic(s) or therapeutic(s) 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 for administering one or more therapy options (e.g., the combinations described herein or another active agent, such as an anticancer agent described herein) for the treatment of a disease, disorder, or condition described herein. 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 may be minimal. The combination of active administration and rest in the regimens described herein may increase the efficacy and/or duration of administration of the combinations and compositions described herein.

The terms therapy options and therapy refer to any protocols, methods and/or agents that can be used in the prevention, treatment, management and/or alleviation of a disease, disorder or condition, or one or more of their symptoms. In some instances, the term refers to active agents, such as the anti-cancer agent described herein. The terms therapy options and therapy may refer to antiviral therapy, antibiotic therapy, antifungal therapy, cancer therapy, biological therapy, supportive therapy and/or other therapy options used to treat, control,

- 3 042997 preventing or alleviating a disease, disorder or pathological condition, or one or more of their symptoms, known to a person skilled in the art, for example, a medical specialist, such as a physician.

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

The terms inhibit, inhibit refer to a reduction in the activity, binding or expression of a polypeptide, or a reduction or reduction in a disease, disorder or condition or symptom thereof. As used herein, inhibition may include partially or completely blocking stimulation, reduction, prevention, or delay in activation or binding, or inactivation, desensitization, or downregulation of a protein or enzymatic activity or binding.

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

Hematologic cancer refers to any cancer of the blood and includes, for example, myelomas, lymphomas, and leukemias. Solid tumor or tumor refers to the lesion and growth and proliferation of neoplastic cells, malignant or benign, and 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 patient tolerance of the injury, pathology, or condition; slowing down the rate of degeneration or deterioration in health; reducing the severity of the course 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 the combination described herein, compared to the protein or cell prior to such administration or contact.

The term administration refers to the act of delivering a combination or composition described herein to a subject by such routes as oral, mucosal, topical, suppository, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration. Parenteral administration includes intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial administration. Administration usually 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 (e.g., administration for patients prone to such a disease, disorder, or condition).

The term co-administration refers to the administration of two or more agents (eg, the combination described herein and another active agent, such as the anticancer agent described herein). The co-administration schedule depends in part on the combination and compositions being administered and may include administration at the same time, shortly before or immediately after administration of one or more additional therapies, for example, anti-cancer therapies such as chemotherapy, hormonal therapy, radiation therapy, or immunotherapy . The compound of the invention may be administered to the patient alone or may be administered together. Co-administration refers to the 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 known to be useful in the treatment of cancer.

The term anticancer agent is used in accordance with its apparent conventional 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 defined herein as an agent useful in methods of treating cancer. In embodiments of the invention, the anticancer agent is an agent approved by the FDA or equivalent regulatory authority in a country other than the United States for the treatment of cancer.

The term chemotherapeutic agent or chemotherapeutic agent is used in accordance with its apparent conventional 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 anti-cancer agent as described herein.

Compositions.

Provided herein is a combination comprising a therapeutically effective amount of an anti-PD-L1 inhibitory antibody and a therapeutically effective amount of a compound represented by the following formula (I):

or a pharmaceutically acceptable salt thereof, wherein said combination is for administration to a subject having colon cancer previously treated with a PD-1 inhibitor, and wherein said compound is present in an amount of at least about 5 mg.

In some cases, the combination contains a compound of formula I (for example, Ia) 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 formula I present in an amount greater than about: 5, 6, 7, 8, 9, or 10 mg. In some cases, the compound of formula I is present in an amount greater than about 5 mg or about 10 mg. The combination may contain a compound of Formula I 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, 50 mg to about 100 mg, or 100 mg to about 200 mg.

The combination may contain a compound 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 formula I present in an amount of at least about 5, 6, 7, 8, 9, or 10 mg. In some cases, the compound of formula I is present in an amount of at least about 5 mg or about 10 mg. The combination may contain a compound of Formula I present in an amount of at least: about 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg.

The combination may contain a compound present in an amount of 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 formula I present in an amount of about 5, 6, 7, 8, 9, or 10 mg. In some cases, the compound of formula I is present in an amount of about 5 mg or about 10 mg. The combination may contain a compound of Formula I 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, 50 mg to about 100 mg, or 100 mg to about 200 mg.

The compound of formula I may be present in the combinations described herein in an amount relative to the weight of the patient (eg, mg/kg). In some instances, the compound of Formula I is present in an amount equivalent to: about 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.01 mg/kg to about 200 mg /kg, 0.01 to about 150 mg/kg, 0.01 to 100 mg/kg, 0.01 to 50 mg/kg, 0.01 to 25 mg/kg, 0.01 mg/kg up to about 10 mg/kg or 0.01 mg/kg to about 5 mg/kg, 0.05 to about 200 mg/kg, 0.05 to 150 mg/kg, 0.05 mg/kg to about 100 mg/kg, 0.05 to 50 mg/kg, 0.05 to about 25 mg/kg, 0.05 to 10 mg/kg, or 0.05 to 5 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg 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.

The PD-L1 inhibitory antibody may be a monoclonal or polyclonal antibody. In some embodiments, the anti-PD-L1 inhibitory antibody is a monoclonal antibody.

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

The PD-L1 inhibitory antibody may be durvalumab. Durvalumab is an Fc-optimized monoclonal antibody directed against PD-L1 with potential immune checkpoint inhibitory activity and antineoplastic activity. Without wishing to be bound by any particular theory, it is believed that durvalumab binds to PD-L1, thus blocking its binding to and activation of its PD-1 receptor, which can be expressed on activated T cells. This can reverse T cell inactivation and activate the immune system to produce a cytotoxic T lymphocyte (CTL) response against PD-L1 expressing tumor cells. The Fc region of durvalumab is modified such that it does not induce antibody-dependent cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).

The PD-L1 inhibitory antibody may be avelumab. Avelumab is a human immunoglobulin G1 (IgG1) monoclonal antibody directed against PDL1 with potent immune checkpoint inhibitory activity and antineoplastic activity. Without wishing to be bound by any particular theory, it is believed that avelumab binds to PD-L1 and prevents PD-L1 from interacting with its PD-1 receptor. This inhibits the activation of PD-1 and its downstream signaling pathways. This may restore immune function by activating cytotoxic T lymphocytes (CTLs) targeting tumor cells overexpressing PD-L1. Avelumab appears to induce an antibody-dependent cellular cytotoxic (ADCC) response against PD-L1-expressing tumor cells.

The PD-L1 inhibitory antibody may be atezolizumab. Atezolizumab is a human, Fc-optimized monoclonal antibody directed against the PD-L1 protein ligand with potential immune checkpoint inhibitory activity and antineoplastic activity. Without wishing to be bound by any particular theory, it is believed that atezolizumab binds to PD-L1, blocking its binding to and activation of its PD-1 receptor, which is expressed on activated T cells, which may enhance the T cell-mediated immune response to neoplasms and abolish inactivation of T cells. In addition, by binding to PD-L1, atezolizumab also appears to prevent PD-L1 from binding to B7.1 expressed on activated T cells, which may further enhance the T cell-mediated immune response. The Fc region of atezolizumab is modified such that it does not induce antibody-dependent cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).

The PD-L1 inhibitory antibody may be BMS-936559. BMS-936559 is a fully human IgG4 monoclonal antibody directed against PD-L1 with potential immune checkpoint inhibitory activity. Without wishing to be bound by any particular theory, it is believed that BMS-936559 binds to PD-L1 and inhibits its binding to PD-1 and CD80.

The anti-PD-L1 inhibitory antibody may be

STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014 or STIA1015. STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014 and

STI-A1015 (Sorrento Therapeutics) are fully human monoclonal antibodies, each directed against PD-L1.

The PD-L1 inhibitory antibody may be of any antibody isotype. The term isotype refers to the class of antibody encoded by 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 λ light chains. The term subclass refers to minor differences in heavy chain amino acid sequences 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-L1 antibodies bind to PD-L1 with sufficient strength to inhibit PD-L1 activity. As used herein, the term bind refers to the interaction between molecules to form a complex. Interactions can be, for example, non-covalent interactions, including hydrogen bonds, ionic bonds, hydrophobic interactions and/or van der Waals interactions. The complex may also include the linking of two or more molecules held together by covalent or non-covalent bonds, interactions or forces. Binding of an antibody or functional fragment thereof can be detected using, for example, enzyme-linked immunosorbent assay or any of a variety of methods that are well known to those skilled in the art.

The strength of a complete non-covalent interaction between one antigen-binding site of a PD-L1 inhibitory antibody or functional fragment and one epitope of a target molecule, such

- 6 042997 as PD-L1 represents the affinity of the antibody or functional fragment for this epitope. The ratio of association (k1) to dissociation (k-1) of an antibody or functional fragment thereof with respect to a monovalent antigen (k ₁ /k_ ₁ ) represents the association constant K, which is a measure of affinity. The value of K varies for different complexes of antibodies or functional fragments and antigens and depends on both k1 and k-1. The association constant K for an antibody or functional fragment according to the invention can be determined using any of the methods described herein, or any other method well known to those skilled in the art.

Affinity at a single binding site does not always reflect the true strength of the interaction between an antibody or functional fragment and an antigen. When complex antigens containing a number of repetitive antigenic determinants are contacted with antibodies containing a number of binding sites, the interaction of such an antibody or functional fragment with an antigen in one site increases the likelihood of a reaction in the second site. The strength of such multiple interactions between a multivalent antibody and antigen is 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 sometimes found in IgM pentamer antibodies, which may have lower affinity than IgG, but the high avidity of IgM due to its multivalence allows it to bind antigen efficiently.

The specificity of a PD-L1 inhibitory 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-L1 epitope). An antibody or functional fragment can be considered specific when it can recognize differences in the primary, secondary, or tertiary structure of an antigen or isomeric forms of an antigen.

The PD-L1 inhibitory antibody may be present in an amount based on the weight of the patient in need. For example, the anti-PD-L1 inhibitory antibody may be present in an amount of: 0.1 mg/kg to about 50 mg/kg, 0.1 mg/kg to about 40 mg/kg, 0.1 mg/kg up to about 30 mg/kg, from 0.1 mg/kg to about 25 mg/kg, from 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, 0.1 mg/kg to about 7.5 mg/kg, 0.1 mg/kg to about 5 mg/kg, 0.1 mg/kg up to about 2.5 mg/kg, or from about 0.1 mg/kg to about 1 mg/kg. The anti-PD-L1 inhibitory antibody may be present in an amount of: 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 40 mg/kg, 0.5 mg/kg to about 30 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 20 mg/kg, 0.5 mg/kg to about 15 mg/kg, 0.5 mg/kg to about 10 mg/kg, 0.5 mg/kg to about 7.5 mg/kg, 0.5 mg/kg to about 5 mg/kg, 0.5 mg/kg to about 2 .5 mg/kg or from about 0.5 mg/kg to about 1 mg/kg. The anti-PD-L1 inhibitory antibody may be present in an amount of about 0.5 mg/kg to about 5 mg/kg, or about 0.1 mg/kg to about 10 mg/kg. The anti-PD-L1 inhibitory antibody may be present in an amount of about 0.1 mg/kg to about 20 mg/kg, or about 0.1 mg/kg to about 30 mg/kg.

In other embodiments, the PD-L1 inhibitory antibody may be present in an amount of about: 0.1, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40 or 50 mg/kg. The PD-L1 inhibitory antibody may be present in an amount of about: 1, 2, 3, 5, 10, 15, 20, 25, or 30 mg/kg. The PD-L1 inhibitory antibody may be present in an amount of about: 3, 10, 20, or 30 mg/kg.

The PD-L1 inhibitory 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, or 200 mg . The anti-PDL1 inhibitory antibody may be present in combination in an amount of about: 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 or 2000 mg. The anti-PD-L1 inhibitory antibody may be present in combination in an amount of from about 1000 mg to about 2000 mg. The anti-PD-L1 inhibitory 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 to about 50 mg, 50 mg to about 100 mg, 75 mg to about 150 mg, 100 mg to about 200 mg, 200 mg to about 500 mg, 500 mg to 1000 mg, 1000 mg to 1200 mg, 1000 mg to 1500 mg, 1200 mg to 1500 mg, or 1500 to about 2000 mg.

The PD-L1 inhibitory 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-L1 inhibitory 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, 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, a therapeutically effective amount of an anti-PD-L1 inhibitory antibody is defined as the amount indicated on the package insert supplied with the anti-PD-L1 inhibitory antibody. The term package leaflet refers to the instructions usually included in the commercial packaging of medicines approved by the FDA or other similar regulatory agency.

- 7 042997 countries other than the United States, which contains information, for example, on the use, dosage, administration, contraindications and / or warnings regarding the use of such drugs.

The compounds of formula I described herein may be provided in amounts that are synergistic with the amount of the PD-L1 inhibitor. The term synergistic refers to a combination described herein (e.g., a compound of Formula I and a PD-L1 inhibitor, including co-administration 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 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-L1 inhibitor). The synergistic effect may allow for less frequent use of at least one variant of the applied therapy (eg, a compound of formula I or a PD-L1 inhibitor) to a subject with the 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 therapeutic option (eg, a compound of formula I or a PD-L1 inhibitor) in a subject without compromising the effectiveness of the treatment. The synergistic effect described herein avoids or reduces adverse or unwanted side effects associated with the use of any therapy option.

pharmaceutical compositions.

The combinations described herein may be provided as a pharmaceutical composition suitable for administration to the patient described herein by any route, including, but not limited to: oral, mucosal (e.g., nasal, inhaled, pulmonary, sublingual, vaginal, buccal, or rectal). ), parenteral (eg, subcutaneous, intravenous, bolus injection, intramuscular or intra-arterial), topical (eg, eye drops or other ophthalmic preparations), transdermal, or transdermal administration to a 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) that can be reconstituted into 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 adjuvants 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 instances, contain additional active agents other than those present in the combinations described herein (eg, an anti-cancer agent such as those described herein) in the amount suggested herein.

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

The PD-L1 inhibitors described herein may be provided in forms that are convenient or facilitate administration to a patient. For example, when the PD-L1 inhibitor is an anti-PD-L1 inhibitory antibody as described herein, the PD-L1 inhibitor can be formulated into a ready-to-use solution for parenteral administration. In other examples, a PD-L1 inhibitor, including, for example, an anti-PD-L1 inhibitory antibody, can be formulated into a powder (eg, lyophilized powder) that can be resuspended in a liquid suitable for parenteral administration. In one embodiment, the combination comprises an anti-PD-L1 inhibitory antibody formulated for intravenous administration. In another embodiment, the combination comprises a compound of Formula I formulated in an oral dosage form (eg tablets or capsules) and a PD-L1 inhibitor formulated for intravenous administration.

The combinations described herein can 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 can prolong drug activity, reduce dosing frequency, and increase subject compliance.

In addition, controlled release formulations can be used to influence the time of onset of action or other characteristics, such as blood levels of the drug, 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 or increase the accuracy or ease of preparation for administering the combination. The kit contains a compound of formula I, the compound being provided in the formulation described herein. The kit also contains the PD-L1 inhibitor described herein. In some embodiments, the kit contains a PD-L1 inhibitor such as CA-170 (Curis). In some embodiments, the kit contains an anti-PD-L1 inhibitory antibody described herein, such as, for example, durvalumab, avelumab, atezolizumab, BMS-936559, STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI -A1O14 or STI-A1015. The kit may contain a package insert or other information (eg, prescribing information) useful for administering the combination to a patient in need, such as the cancer patient described herein.

Kits of the invention may contain the combinations described herein (eg, a compound of formula I and an anti-PD-L1 inhibitory antibody) having the same or different compositions. Each component of the combination described herein in a 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 may be a container ready to be administered 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, as a tablet, capsule or sachet). The PD-L1 inhibitor may be provided, for example, as a powder (eg, lyophilized powder) or as a solution for parenteral administration. In some instances, the PD-L1 inhibitor is an anti-PD-L1 inhibitory antibody described herein formulated for parenteral administration, eg intravenous administration.

The contents of the kits described herein may be provided in a sterile form. The kit and its contents may be provided in a form that is ready for administration to a subject in need. In such cases, the components of the kit combination are provided as a formulation and optionally in an administration device, so that administration requires little or no further action from the user. Where kits contain administration devices, such devices include devices known and understood by those skilled in the art for the routes of administration described herein, such as, but not limited to, syringes, pumps, bags, cups, inhalers, droppers, patches, creams or injectors.

Ways.

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

It should be understood that the compound of formula I and the PD-L1 inhibitor, constituting a combination for use in the proposed method, include each therapeutic agent in the amounts described herein, and are administered as described in this document. For example, a compound of formula I may be present in combination administered to a patient in need of it in an amount of about 5 mg to about 50 mg, or about 5 mg to about 100 mg. As another example, a PD-L1 inhibitor may be an anti-PD-L1 inhibitory antibody present in an amount of, for example, from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg up to about 20 mg/kg, or from about 0.1 mg/kg to about 30 mg/kg. In another example, the PD-L1 inhibitor is an anti-PD-L1 inhibitory antibody present in an amount of, for example, about 1000 mg to 2000 mg. 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 kit components, including, for example, containers and administration devices such as those described above.

Cancer is a solid tumor, such as colon cancer.

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The combinations described herein can be administered to a cancer patient at any time after diagnosis.

For example, a cancer patient may not have previously received treatment (eg, not receive anti-cancer therapy for a diagnosed cancer). A cancer patient may not have been previously 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 cancer patient may be naive about the immune checkpoints of one or more cancers. A cancer patient may have cancer that is refractory. In some instances, the combinations described herein are administered as first line therapy (eg, the first treatment option administered to a previously untreated patient) to a patient in need thereof.

The methods of treating cancers herein include treating subjects who were treated with a PD-1 checkpoint inhibitor and did not show any response to treatment, or showed a partial response or stable disease, but then developed resistance to treatment with disease progression, or who showed 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 no response to treatment. Such failed treatment with an anti-PD-1 inhibitory antibody can be compensated for by treating PD-L1 in combination with an HDAC inhibitor such as, but not limited to, HBI-8000 or an HDAC inhibitor that inhibits cancer-associated class I HDAC selected from one or more of the HDAC1 , HDAC2 or HDAC3. In some cases, the HDAC inhibitor also inhibits class IIb HDAC1. HBI-8000 has been reported to inhibit HDAC at 1, 2, 3, and 10 nanomolar concentrations (see Zhi-Qiang Ning et al., Cancer Chemother Pharmacol (2012) 69:901-909). It also has activity against HDAC 8 and 11. Ning et al. also report that HBI-8000 is more potent than Entinostat against HDACs 1, 2, 3, 8, 10 and 11. In addition, HBI-8000 has a favorable pharmacokinetic and safety profile that allows continuous oral dosing pK (t _1/2 about 17 hours).

RECIST response criteria.

RECIST is a set of established criteria or internationally recognized standards for assessing response, stability, and progression in patients in clinical research and clinical practice. Originally published in 2000 and revised in 2009 (Eisenhauer E.A. et al.; New response criteria in solid tumors: revised RECIST guideline (version 1.1); Eur. J. Cancer 2009; 45:228-47) Through the combined efforts of the European Organization for Research and Treatment of Cancer, the United States National Cancer Institute, and the National Cancer Institute Clinical Research Group of Canada, 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, taking as a starting point the original total ND; stable disease (SD): neither a significant decrease to be considered an OR nor a sufficient increase to be considered a PV, taking as a starting point the lowest cumulative NI since the start of treatment; Progressive Disease (PD): At least a 20% increase in the total DI of the target lesions, based on the lowest total 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 the level of tumor markers; incomplete response/stable disease (SC): persistence of one or more off-target lesions or/and persistence of tumor marker levels above normal limits; progressive disease (PD): the appearance of one or more new lesions and/or unequivocal 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 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).

The method of treating cancer of the present invention comprises administering a therapeutically effective amount of the above combination to a patient in need thereof, wherein said combination is for administration to a patient having colon cancer previously treated with a PD-1 inhibitor.

According to the proposed method, the specified combination can be administered to the specified cancer patient as a third, fourth, fifth or sixth line therapy.

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According to the proposed method, the specified combination can be administered to the specified cancer patient after treatment with at least one type of anticancer therapy.

Suggested anti-cancer therapies include chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, or a combination thereof.

According to the proposed method, said cancer is resistant to at least one anticancer agent.

According to the proposed method, said compound and said PD-L1 inhibitor of said combination can be administered simultaneously or sequentially.

According to the proposed method, said compound can be administered 2-3 times per week.

According to the proposed method, said compound can be administered daily.

According to the proposed method, the inhibitory antibody to PD-L1 and the specified compound are administered simultaneously on day 1 of the administration regimen.

According to the proposed method, said PD-L1 inhibitory antibody comprises durvalumab, avelumab, atezolizumab, BMS-936559, STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014 or STI-A1015.

According to the proposed method, the specified combination is administered to the specified patient according to the scheme.

According to the proposed method, the specified scheme is repeated until the progression of the disease or the manifestation of unacceptable toxicity.

According to the proposed method, said scheme includes a rest period of at least 1 day between successive periods of administration.

According to the proposed method, said compound of said combination is administered 2-3 times per week according to said schedule, and said anti-PD-L1 inhibitory antibody is administered every 2-3 weeks.

According to the proposed method, the specified compound of the specified combination is administered once a day for 21 days according to the specified scheme, and the specified inhibitory antibody to PD-L1 is administered every 2-3 weeks.

The proposed cancer treatment method 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 time to progression of said cancer in said patient, prolongs life of said patient, prolongs survival. said patient without disease progression.

The combinations described herein may include administering each therapy (eg, a compound of Formula I and a PD-L1 inhibitor) either simultaneously or sequentially (in any order). In one embodiment, the compound of formula I and the PD-L1 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-L1 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 co-administered with an anti-PD-L1 inhibitory antibody selected from durvalumab, avelumab, atezolizumab, BMS-936559, or STI-A1010, STI-A1011, STIA1012, STI-A1013, STI-A1014, or STI-A1015. In another example, a compound of formula I may be administered prior to administration of durvalumab. In another example, a compound of formula I may be administered prior to administration of avelumab. In another example, a compound of formula I may be administered prior to the administration of atezolizumab. In another example, a compound of formula I may be administered prior to the administration of BMS-936559. In another example, a compound of formula I may be administered prior to the administration of STI-A1010, STI-LAI, STI-A1012, STI-A1013, STI-A1014, or STI-A1015. In another example, a compound of formula I may be administered following administration of durvalumab. In another example, a compound of formula I may be administered following administration of avelumab. In another example, a compound of formula I may be administered following administration of atezolizumab. In another example, a compound of formula I may be administered following administration of BMS-936559. In another example, a compound of formula I may be administered following administration of STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014, or STI-A1015.

The compound of formula I can be administered, for example, once a day (r/s), twice a day (d/s), once a week (r/nd), twice a week (d/nd), three times per week (t/nd) or once a month (r/m) regularly on a continuous basis or periodically, for example, d/n for 3 months, and then resume administration a month later. For example, a compound of formula I may be administered twice daily. The compound of formula I can be administered three times a week. In some cases, the compound of formula I is administered 2-3 times a week. In another embodiment of the invention, the compound of formula I is administered once a day. The compound can 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. The administration of a compound of formula I may, in part, depend on the tolerance of the patient, where greater tolerance may allow higher doses or more frequent administration. Alternatively, in the case where the patient exhibits poor tolerance to the compound of formula I, the administration can be carried out

- 11 042997 less compound or less frequent dosing. The compounds of formula I can be entered according to any scheme described in this document.

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

For example, a compound of formula I may be administered in an amount of about 5 mg or about 10 mg twice a week. For example, a compound of formula I may be administered in an amount of about 5 mg or about 10 mg three times a week. For example, a compound of formula I may be administered in an amount of about 5 mg or about 10 mg once a week. For example, a compound of formula I may be administered in an amount of about 5 mg or about 10 mg once every 2 weeks. The administration of the compound of formula I may be continuous. The administration of a compound of formula I may be intermittent.

For example, a compound of Formula I may be administered 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. mg, 50 mg to about 100 mg, or 100 mg to about 200 mg once a day. For example, a compound of Formula I may be administered 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. mg, 50 mg to about 100 mg, or 100 mg to about 200 mg twice a week. For example, a compound of formula I may be administered 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, 50 mg to about 100 mg, or 100 mg to about 200 mg three times a week. For example, a compound of Formula I may be administered 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. mg, 50 mg to about 100 mg, or 100 mg to about 200 mg once a week. For example, a compound of Formula I may be administered 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. mg, 50 mg to about 100 mg, or 100 mg to about 200 mg once every 2 weeks. The introduction of the compounds of formula I may be continuous. The administration of a compound of formula I may be intermittent.

For example, a compound of formula I may 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, 0.01 mg/kg to about 150 mg/kg, 0.01 mg/kg to about 100 mg/kg, 0.01 mg/kg to about 50 mg/kg, 0.01 mg/kg kg to about 25 mg/kg, 0.01 mg/kg to about 10 mg/kg, or 0.01 mg/kg to about 5 mg/kg, 0.05 mg/kg to about 200 mg/kg, 0.05 mg/kg to about 150 mg/kg, 0.05 mg/kg to about 100 mg/kg, 0.05 mg/kg to about 50 mg/kg, 0.05 mg/kg to about 25 mg/kg, 0.05 mg/kg to about 10 mg/kg, or 0.05 mg/kg to about 5 mg/kg, 0.5 mg/kg to about 200 mg/kg, from 0 .5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, once a day. For example, a compound of Formula I may 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, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg 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 may 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, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg 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 may 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, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg 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 a week. For example, a compound of Formula I may 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, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg 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 every 2 weeks. In one example, a compound of Formula I may be administered in an amount of about 15 mg/kg to about 75 mg/kg once daily. In another example, a compound of formula I may be administered in an amount of about 20 mg/kg to about 50 mg/kg. In another example, a compound of formula I may be administered in an amount of about 0.001, 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 10, 15,

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20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175 or 200 mg/kg. The introduction of the compounds of formula I may be continuous. The administration of a compound of formula I may be intermittent.

For example, a compound of Formula I may 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 may 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, twice a week . For example, a compound of Formula I may 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 may 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 a week . For example, a compound of Formula I may 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 every 2 weeks. In one example, a compound of formula I may be administered in an amount of about 15 mg/kg to about 75 mg/kg once daily. In another example, a compound of Formula I may be administered in an amount of about 20 mg/kg to about 50 mg/kg. In another example, a compound of formula I may 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. The administration of the compound of formula I may be continuous. The administration of a compound of formula I may be intermittent.

In the context of this document, the term daily means that the therapeutic compound of the combination described herein, such as a compound of formula I, is administered one or more times a day for a certain 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, intermittent administration of a therapeutic compound of a combination described herein, such as a compound of formula I, includes administration over 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 to eight consecutive weeks, followed by a rest period without administration of at least one day) or, for example, administration every other day.

When the PD-L1 inhibitor is an anti-PD-L1 inhibitory antibody, it can be administered according to established schedules such as those suggested on the package insert. The PD-L1 inhibitory antibody can be administered at the amount described herein and can be administered once a week (p/n.d.), once every 2 weeks (p./2n.d.), once every 3 weeks (p./3n.d.). ) or once every 4 weeks (r / 4 nd). In one embodiment, the PD-L1 inhibitory antibody is administered once every 2 weeks or once every 4 weeks. In another embodiment, the PDL1 inhibitory antibody is administered once every 2 weeks. In another embodiment, the PDL1 inhibitory antibody is administered once every 3 weeks. In another embodiment, the PDL1 inhibitory antibody is administered twice a week for at least 3 weeks. In another embodiment, the PD-L1 inhibitory antibody is administered once every 4 weeks.

For example, durvalumab may be administered in an amount 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, 10, 12, 15, 20, 25, 30 mg/kg), once a week. For example, durvalumab may be administered in an amount 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, 10, 12, 15, 20, 25, 30 mg/kg), once every 2 weeks. For example, durvalumab may be administered in an amount 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, 10, 12, 15, 20, 25, 30 mg/kg), once every 4 weeks. For example, durvalumab may be administered in an amount 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, 10, 12, 15, 20, 25, 30 mg/kg), twice every 4 weeks (2d/4wd). For example, durvalumab may be administered in an amount 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, 10, 12, 15, 20, 25, 30 mg/kg), once every 3 weeks. For example, durvalumab may be administered in an amount of about 1000 mg to about 2000 mg (including, for example, 1000, 1100, 1200, 1300, 1400, 1500, 1600 mg) once every 2 weeks. For example, durvalumab may be administered in an amount of about 1000 mg to about 2000 mg (including, for example, 1000, 1100, 1200, 1300, 1400, 1500, 1600 mg) once every 3 weeks. For example, durvalumab may be administered in an amount of about 1000 mg to about 2000 mg (including, for example, 1000, 1100, 1200, 1300, 1400, 1500, 1600 mg) once every 4 weeks. The administration of durvalumab may be continuous. Administration of durvalumab may be intermittent.

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

For example, avelumab may be administered in an amount of 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). For example, avelumab may be administered in an amount of 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, avelumab may be administered in an amount from about 0.1 mg/kg to about 30 mg/kg (including, for example, 0.1 mg/kg, 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, avelumab may be administered in an amount of 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, avelumab may be administered in an amount of 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. The introduction of avelumab can be continuous. The administration of avelumab may be intermittent.

Avelumab can be administered as an intravenous infusion over about 10, 20, 30, 40, 50, or 60 minutes or more. Avelumab can be given as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. Avelumab can be given as an intravenous infusion over about 60 minutes once every two weeks. Avelumab can be given as an intravenous infusion over about 60 minutes once every three weeks. Avelumab can be given as an intravenous infusion over about 60 minutes once every four weeks. Avelumab may be administered as directed in the package insert provided. The introduction of avelumab can be continuous. The administration of avelumab may be intermittent.

For example, atezolizumab may be administered in an amount 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, atezolizumab may be administered in an amount 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, atezolizumab may be administered in an amount 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, atezolizumab may be administered in an amount 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, atezolizumab may be administered in an amount of about 1000 mg to about 2000 mg (including, for example, 1000, 1100, 1200, 1300, 1400, 1500, 1600 mg) once every 2 weeks. For example, atezolizumab may be administered in an amount of about 1000 mg to about 2000 mg (including, for example, 1000, 1100, 1200, 1300, 1400, 1500, 1600 mg) once every 3 weeks. For example, atezolizumab may be administered in an amount of about 1000 mg to about 2000 mg (including, for example, 1000, 1100, 1200, 1300, 1400, 1500, 1600 mg) once every 4 weeks. In one example, atezolizumab may be administered at about 15 mg/kg once every 2 weeks or once every 4 weeks. In one example, atezolizumab may be administered in an amount of about 1200 mg or 1500 mg once a month. Administration of atezolizumab may be continuous. Administration of atezolizumab may be intermittent. Atezolizumab can be administered as an intravenous infusion over about 10, 20, 30, 40, 50, or 60 minutes or more. Atezolizumab can be given as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. Atezolizumab can be given as an intravenous infusion over about 60 minutes once every two weeks. Atezolizumab can be given as an intravenous infusion over about 60 minutes once every three weeks. Atezolizumab can be given as an intravenous infusion over about 60 minutes once every four weeks. Administration of atezolizumab may be continuous. Administration of atezolizumab may be intermittent.

For example, BMS-936559 can be administered in an amount of 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, BMS-936559 can be administered in an amount of 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, BMS-936559 can be administered in an amount of 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, BMS-936559 can be administered in an amount of 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. The introduction of BMS-936559 can be continuous. The introduction of BMS-936559 may be intermittent.

BMS-936559 can be given as an intravenous infusion for about 10, 20, 30, 40, 50, or 60

- 14 042997 or more minutes. BMS-936559 can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. BMS-936559 can be administered as an intravenous infusion over about 60 minutes once every two weeks. BMS-936559 can be administered as an intravenous infusion over about 60 minutes twice every three weeks. BMS-936559 can be administered as an intravenous infusion over about 60 minutes three times every six weeks. The introduction of BMS-936559 can be continuous. The introduction of BMS-936559 may be intermittent.

For example,

STI-A1010, STI-A1011, STI-A1012, STI-A1013 or STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014 and STIA1015 (Sorrento Therapeutics) can be independently administered in an amount of 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,

STI-A1010, STI-A1011, STI-A1012, STIA1013, or STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014, or STI-A1015 can be independently administered in an amount of 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,

STI-A1010, STI-A1011, STI-A1012, STI-A1013, or STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014, or STI-A1015 can be independently administered in an amount of 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,

STI-A1010,

STI-A1011, STI-A1012, STI-A1013 or STI-A1010, STI-A1011, STIA1012, STI-A1013, STI-A1014 or STI-A1015 can be independently administered in an amount of 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.

Introduction

STI-A1010, STI-A1011, STI-A1012,

STI-A1013 or STI-A1010, STI-A1011, STI-A1012, STI-A1013, STIA1014 or STI-A1015 can be continuous. Introduction

STI-A1010,

STI-A1011, STI-A1012, STI-A1013 or STI-A1010, STI-A1011, STIA1012, STI-A1013, STI-A1014 or STI-A1015 may be periodic.

STI-A1010, STI-A1011, STI-A1012, STI-A1013, or STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014, or STI-A1015 can be independently administered as an intravenous infusion over about 10, 20 , 30, 40, 50 or 60 or more minutes.

STI-A1010, STIA1011, STI-A1012, STI-A1013 or STI-A1010, STI-A1011, STI-A1012,

STI-A1013, STI-A1014 or STI-A1015 can be independently administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks.

STI-A1010, STI-A1011, STI-A1012, STI-A1013, or STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014, or STIA1015 can be independently administered as an intravenous infusion over about 60 min. once in two weeks.

STI-A1010, STIA1011, STI-A1012, STI-A1013 or STI-A1010, STI-A1011, STI-A1012,

STI-A1013, STI-A1014, or STI-A1015 can be independently administered as an intravenous infusion over about 60 minutes twice every three weeks.

- 15 042997

STI-A1010, STI-A1011, STI-A1012, STI-A1013 or STI-A1010,

STI-A1011, STI-A1012, STI-A1013, STI-A1014 or STI-A1015 can be independently administered as an intravenous infusion over about 60 minutes three times every six weeks. Introduction

STI-A1010, STI-A1011, STI-A1012, STI-A1013 or STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014 or STI-A1015 can be continuous. Introduction

STIA1010, STI-A1011, STI-A1012, STI-A1013 or STI-A1010, STI-A1011,

STI-A1012, STI-A1013, STI-A1014 or STI-A1015 may be periodic.

The combinations described herein can be administered according to the scheme. The regimen can be designed to provide therapeutically effective amounts of a compound of Formula I and a PD-L1 inhibitor, such as an anti-PD-L1 inhibitory antibody, over a predetermined period of time (eg, time of administration). The regimen can be designed to limit or prevent side effects or undesirable complications associated with each of the components of the combination described herein. The regimen can be designed in a way that results in an increased effect of both therapy options in combination (eg, synergy). Regimen applicable for the treatment of cancer may include any number of days of administration, which may be repeated as needed. The administration periods may be interrupted by a rest period that precludes the 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 scheme may include a certain number of days, as described earlier, while the scheme is 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 option is not administered to the patient. The rest period can be determined, for example, by monitoring the patient's response to the drug or by determining the effectiveness of the treatment. A rest period may be applicable to one therapy option so that during the rest period, the administration of only one therapy option of the combination described herein is interrupted, while the other therapy option (s) continues to be administered. Rest periods may be applicable to all therapy options 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 with the combinations described herein may be continued until disease progression or unacceptable toxicity.

The regimens for administering the combinations described herein include, for example, administering a compound of formula I twice weekly or thrice weekly and administering a PD-L1 inhibitor. For example, a compound of Formula I may be administered once a day for about 21 days, and an anti-PD-L1 inhibitory antibody described herein may be administered once every 2 weeks or once every 4 weeks. For example, a compound of Formula I may be administered twice a week or three times a week, and an anti-PD-L1 inhibitory antibody described herein may 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-L1 inhibitory antibody may be administered twice a week for 2 or 3 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-L1 inhibitory antibody may be administered once every 4 weeks. In another exemplary regimen, a compound of formula I may be administered twice a week, and an anti-PDL1 inhibitory antibody described herein may be administered once every 2 weeks, once every 3 weeks, or once every 4 weeks. In some cases, such regimens include the administration of an inhibitory antibody to PD-L1 once every 2 weeks, once every 3 weeks, or once every 4 weeks. In another exemplary regimen, a compound of formula I may be administered three times a week, and an anti-PD-L1 inhibitory antibody described herein may be administered once every 2 weeks, once every 3 weeks, or once every 4 weeks. In some cases, such regimens include the administration of an inhibitory antibody to PD-L1 once every 2 weeks, once every 3 weeks, or once every 4 weeks. In some cases, such regimens include the introduction of the compounds of formula I once a day. In some cases, such regimens include the introduction of the compounds of formula I once a day for at least 21 days. In another exemplary regimen, a compound of formula I may be administered once a day or once a week, and a PD-L1 inhibitor (e.g., an anti-PD-L1 inhibitory antibody) is administered once every 2 weeks, once every 3 weeks, or once every 4 weeks.

The regimen may be a regimen for administering avelumab with a compound of formula I as described herein. In one exemplary regimen including avelumab, a compound of formula I can be

- 16 042997 administered twice a week or three times a week, and avelumab is administered according to the information for use given, for example, on the package insert. In another exemplary regimen, avelumab is administered at about 1 mg/kg to about 20 mg/kg on day 1 of the regimen and once every 2 weeks thereafter until disease progression or unacceptable toxicity, and the compound of formula I is administered twice a week or three once a week for the same period of time. In another exemplary regimen, avelumab is administered at about 1 mg/kg to about 20 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 a week or three once a week for the same period of time. Avelumab can be administered once every 4 weeks with a compound of formula I, with the compound of formula I administered, for example, twice a week or three times a week during the course of such a regimen. Avelumab can be administered once every 2 weeks with a compound of formula I, 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, avelumab may be administered once every 2 weeks or once every 4 weeks with a compound of formula I, with the compound of formula I administered, for example, once daily or once weekly during the course of such a regimen. Such regimens 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 involving avelumab, the compound of formula I may be administered once a day and avelumab administered according to the information for use given, for example, on the package insert. In another exemplary regimen, avelumab is administered at about 1 mg/kg to about 20 mg/kg on day 1 of the regimen and every 2 weeks thereafter until disease progression or unacceptable toxicity, and a compound of Formula I is administered once daily for the same period of time. In another exemplary regimen, avelumab is administered at about 1 mg/kg to about 20 mg/kg on day 1 of the regimen and once every 3 weeks thereafter until disease progression or unacceptable toxicity, and the compound of Formula I is administered once daily for the same period of time. Avelumab can be administered once every 4 weeks with a compound of formula I, with the compound of formula I being administered once a day during the course of such a regimen. Avelumab can be administered once every 2 weeks with a compound of formula I, with the compound of formula I being administered once a day during the course of such a regimen. Such regimens can be repeated as described above (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more times).

The regimen may be a regimen for administering durvalumab with a compound of formula I described herein. In one exemplary regimen involving durvalumab, the compound of formula I may be administered twice a week or three times a week, and durvalumab is administered according to the information for use given, for example, on the package insert. In another exemplary regimen, durvalumab is administered at about 1 mg/kg to about 20 mg/kg on Day 1 and thereafter once every 2 weeks until disease progression or unacceptable toxicity, and the compound of formula I is administered twice a week or three times per week for the same period of time. In another exemplary regimen, durvalumab is administered at about 1 mg/kg to about 20 mg/kg on Day 1 and thereafter once every 4 weeks until disease progression or unacceptable toxicity, and the compound of Formula I is administered twice weekly or three times per week for the same period of time. In another exemplary regimen, durvalumab may be administered once every 2 weeks, with a 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, durvalumab may be administered once every 4 weeks, with a 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, durvalumab may be administered once every 2 weeks or once every 4 weeks, with the compound of formula I being administered, for example, once daily or once per week during the course of such regimen. Such regimens 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 involving durvalumab, the compound of formula I may be administered once daily and durvalumab administered according to the prescribing information provided, for example, on the package insert. In another exemplary regimen, durvalumab is administered at about 1 mg/kg to about 20 mg/kg on Day 1 and every 2 weeks thereafter until disease progression or unacceptable toxicity, and the Formula I compound is administered once daily for that the same period of time. In another exemplary regimen, durvalumab is administered at about 1 mg/kg to about 20 mg/kg on Day 1 and thereafter once every 4 weeks until disease progression or unacceptable toxicity, and the Formula I compound is administered once daily for that the same period of time. In another exemplary regimen, durvalumab may be administered once every 2 weeks, with the compound of formula I being administered once daily for the course of such regimen. In another exemplary regimen, durvalumab may be administered once every 4 weeks, with the compound of formula I being administered once daily for the course of such regimen. In another exemplary regimen, durvalumab may be administered once every 3 weeks, with the compound of formula I being administered once daily for the course of such regimen. Such regimens can be repeated as described above (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more times).

The regimen may be a regimen for administering atezolizumab with a compound of formula I as described herein. In one exemplary atezolizumab regimen, a compound of formula I may be administered twice a week or three times a week and atezolizumab administered according to the information for use given, for example, on the package insert. In another pattern

atezolizumab is administered at about 10 mg/kg to about 20 mg/kg on day 1 and thereafter once every 3 weeks until disease progression or unacceptable toxicity, and the compound of formula I is administered twice a week or three times a day. week during the same time period. In another exemplary regimen, atezolizumab is administered at about 10 mg/kg to about 20 mg/kg on Day 1 and thereafter once every 4 weeks until disease progression or unacceptable toxicity, and the compound of Formula I is administered twice a week or three times per week for the same period of time. In another exemplary regimen, atezolizumab is administered at about 15 mg/kg on day 1 and every 3 weeks thereafter until disease progression or unacceptable toxicity, and a compound of Formula I is administered twice weekly or three times weekly for the same period. time. In another exemplary regimen, atezolizumab is administered at about 15 mg/kg on day 1 and every 4 weeks thereafter until disease progression or unacceptable toxicity, and the compound of Formula I is administered twice weekly or three times per week for the same period. time. In another exemplary regimen, atezolizumab is administered in an amount of about 1000 mg to about 2000 mg on Day 1 and thereafter once every 3 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, atezolizumab is administered in an amount of from about 1000 mg to about 2000 mg on Day 1 and thereafter once every 4 weeks until disease progression or unacceptable toxicity, and the compound of formula I is administered twice a week or three times a week for the same period of time. In another exemplary regimen, atezolizumab is administered in an amount of about 1200 mg or about 1500 mg on Day 1 and thereafter once every 3 weeks until disease progression or unacceptable toxicity, and the compound of formula I is administered twice a week or three times a week for that the same period of time. In another exemplary regimen, atezolizumab is administered in an amount of about 1200 mg or about 1500 mg on Day 1 and thereafter once every 4 weeks until disease progression or unacceptable toxicity, and the compound of formula I is administered twice a week or three times a week for that the same period of time. In another exemplary regimen, atezolizumab may be administered once every 3 weeks, with a 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, atezolizumab may be administered once every 4 weeks, with a 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, atezolizumab may be administered once every 2 weeks or once every 4 weeks, with the compound of formula I being administered, for example, once daily or once weekly during the course of such regimen. Such regimens can be repeated as described above (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more times). The regimen may be a regimen for administering atezolizumab with a compound of formula I as described herein. In one exemplary regimen involving atezolizumab, the compound of formula I may be administered once daily and atezolizumab administered according to the information for use given, for example, on the package insert. In another exemplary regimen, atezolizumab is administered at about 10 mg/kg to about 20 mg/kg on Day 1 and thereafter once every 3 weeks until disease progression or unacceptable toxicity, and the compound of Formula I is administered once daily for that the same period of time. In another exemplary regimen, atezolizumab is administered at about 10 mg/kg to about 20 mg/kg on Day 1 and thereafter once every 4 weeks until disease progression or unacceptable toxicity, and the compound of Formula I is administered once daily for that the same period of time. In another exemplary regimen, atezolizumab is administered at about 15 mg/kg on day 1 and every 3 weeks thereafter until disease progression or unacceptable toxicity, and the compound of Formula I is administered once daily for the same period of time. In another exemplary regimen, atezolizumab is administered at about 15 mg/kg on day 1 and every 4 weeks thereafter until disease progression or unacceptable toxicity, and the compound of Formula I is administered once daily for the same period of time. In another exemplary regimen, atezolizumab is administered in an amount of from about 1000 mg to about 2000 mg on Day 1 and thereafter once every 3 weeks until disease progression or unacceptable toxicity, and the compound of Formula I is administered once daily for the same period of time. In another exemplary regimen, atezolizumab is administered in an amount of about 1000 mg to about 2000 mg on Day 1 and thereafter once every 4 weeks until disease progression or unacceptable toxicity, and the compound of Formula I is administered once daily for the same period of time. In another exemplary regimen, atezolizumab is administered in an amount of about 1200 mg or about 1500 mg on Day 1 and thereafter once every 3 weeks until disease progression or unacceptable toxicity, and the compound of Formula I is administered once daily for the same period of time. In another exemplary regimen, atezolizumab is administered in an amount of about 1200 mg or about 1500 mg on Day 1 and thereafter once every 4 weeks until disease progression or unacceptable toxicity, and the compound of Formula I is administered once daily for the same period of time. In another exemplary regimen, atezolizumab may be administered once every 3 weeks, with the compound of formula I being administered once daily for the course of such regimen. In another exemplary regimen, atezolizumab may be administered once every 4 weeks, with the compound of formula I being administered once daily for the course of such regimen. In another exemplary regimen, atezolizumab may be administered once every 2 weeks, once every 3 weeks, or once every 4 weeks, with the compound of formula I being administered once daily for the course of such a regimen. Such schemes can be repeated as described above (for example, 1, 2, 3, 4,

- 18 042997

5, 6, 7, 8, 9, 10, 11, 12 or more times).

It should also be understood that the cancer treatment combinations described herein may be 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 above, may be modified as necessary to include the administration of such active agents. The administration of such active agents, for example anti-cancer agents, can be once a day, once a week, once a month, twice a day, twice a week, three times a week, once every 2 weeks, once a 3 weeks or once every 4 weeks or according to the information on the use of such anti-cancer agents given, for example, on the package insert. Exemplary anticancer agents include, but are not limited to: abraxane; abiraterone; ace-11; aclarubicin; acivicin; acodazole hydrochloride; acronin; actinomycin; acylfulvene; adcipenol; adoselezin; adriamycin; aldesleukin; all-trans retinoic acid (ATRA); altretamine; ambamustine; ambomycin; amethantron acetate; amidox; amifostine; aminoglutethimide; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; antarelix; anthramycin; aficoline glycinate; apuric acid; apa-CDP-DL-PTBA; arginine deaminase; ARRY-162; ARRY-300; ARRY-142266; AS703026; asparaginase; asperlin; asulacrin; atamestan; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; Azasetron; azatoxin; azatyrosine; azacitidine; AZD8330; azetepa; azotomycin; balanol; batimastat; BAY 11-7082; BAY 43-9006; BAY 869766; bendamustine; benzochlorines; benzodepa; benzoyl-staurosporine; beta-alethine; betaclamycin B; betulinic acid; b-FGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafid; bisnafide dimesylate; bistratene A; bisantrene hydrochloride; bleomycin; bleomycin sulfate; busulfan; bizelesin; breflat; bortezomib; brekvinar sodium; bropyrimine; budotitan; butionine sulfoximine; bryostatin; cactinomycin; calusterone; calcipotriol; calphostin C; derivatives of camptothecin; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; caracemide; carbetimer; carboplatin; carmustine; pyridine hydrochloride; carzelesin; castanospermine; cecropin B; sedefingol; celecoxib; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; chlorambucil; chlorfusin; cirolemycin; cisplatin; CI-1040; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; collimycin A; collimycin B; combretastatin A4; analogue of combretastatin; conagenin; crambescidin 816; crisnatol; crisnatol mesylate; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cyclophosphamide; cytarabine; cytarabine phosphate; cytolytic factor; cytostatin; dacarbazine; dactinomycin; daunorubicin; daunorubicin hydrochloride; decarbazine; dacliximab; dasatinib; decitabine; dehydrodydemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; dexormaplatin; desaguanine; deaguanine mesylate; diaziquon; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol; 9dioxamycin; diphenylpyromustine; docosanol; dolasetron; docetaxel; doxorubicin; doxorubicin hydrochloride; doxyfluridine; droloxifene; droloxyphencitrate; dromostanolone propionate; dronobinol; duazomycin; duocarmycin SA; ebselen; ecomustine; edelfosin; edrecolomab; edatrexate; eflornithine hydrochloride; eflornithine; element; emitfur; elsamitrucin; enloplatin; enpromat; epipropidin; epirubicin; epirubicin hydrochloride; episteride; erbulozol; eribulin, esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprine; exemestane; fadrozole; fadrozole hydrochloride; fazarabine; fenretinide; filgrastitis; finasteride; flavopiridol; flezelastin; fluasterone; floxuridine; fludarabine phosphate; fludarabine; fluorounorubicin hydrochloride; forfenimeks; formestane; fluorouracil; floxuridine; flurocitabine; fosquidon; fostriecin sodium; fostriecine; fotemustine; gadolinium-texafirin; gallium nitrate; halocytabine; ganirelix; gelatinase inhibitors; gemcitabine; geldanamycin; gossifol; GDC-0973; 63K1120212/trametinib; herceptin; hydroxyurea; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; ibrutinib; idarucybin; idarubicin hydrochloride; ifosfamide; canfosfamide; ylmofosine; iproplatin; idoxifen; idramantone; ylmofosine; ilomastat; imidazoacridones; imatinib (eg, GLIVEC); imiquimod; jobenguan; iododoxorubicin; ipomeanol; irinotecan; irinotecan hydrochloride; irsogladin; isobengazole; isohomoalicondrin B; itasetron; iimophosine; interleukin IL (including recombinant interleukin IL-2 or rIL2); interferon alpha-2a; interferon alfa-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-1a; interferon gamma-1b; jasplakinolide; kahalalide F; lamellarin N triacetate; lanreotide; leunamycin; lenograstim; lantinan sulfate; leptostatin; letrozole; leuprorelin; levamisole; liarozol; lissoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribin; lurtothecan; lutetium-texafirin; lysophyllin; lanreotide acetate; lapatinib; letrozole; leucovorin; leuprolide acetate; liarozol hydrochloride; lometrexol sodium; lomustine; lenalidomide; lenvatinib; losoxantrone hydrochloride; LY294002; pomalidomide; maytansine; mannostatin A; marimastat; mazoprocol; maspin; matrilysin inhibitors; menogaryl; merbaron; metererin; methioninase; metoclopramide; an MIF inhibitor; mifepristone; miltefosine; peaceful; mitoguazone; mitolactol; mitonafid; mitoxantrone; mofarotene; molgramming; mopidamol; micaperoxide B; myriaporone; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; mercaptopurine; methotrexate; sodium methotrexate; methoprine; meturedepu; mitindomide; mitocar

- 19 042997 qin; mitocromine; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nafarelin; pile; napavin; nafterpine; nartograstim; nedaplatin; nemorubicin; neridic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxy antioxidant; nitrulline; nocodazole; nogalamycin; oblimersen (GENASENS); octreotide; okicenon; oligonucleotides; onapriston; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; oxysuran; oxaloplatin; osateron; oxaliplatin; oxaunomycin; palauamine; palmitoyl rhizoxine; pamidronic acid; panoxytriol; panomifen; parabactin; paselliptin; pegaspargas; peldesin; sodium pentosan polysulfate; pentostatin; pentrosol; perflubron; perphosphamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pyrarubicin; pyrithrexim; placetin A; placetin B; porphyromycin; prednisolone; prostaglandin J2; pyrazoloacridine; paclitaxel; PD035901; PD184352; PD318026; PD98059; peliomycin; pentamustine; peplomycin sulfate; RKS412; pipobroman; piposulfan; pyroxantrone hydrochloride; plicamycin; plomestan; podophyllotoxin; polyphenol E; sodium porfimer; porphyromycin; prednimustine; procarbazine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; raltitrexed; ramosetron; retelliptin demethylated; rhizoxin; rituximab; RII retinamide; rogletimide; rohitukin; romurtide; roquinimex; rubiginone B1; ruboxyl; riboprin; romidepsin; safingol; safingol hydrochloride; saintopin; sarcophytol A; sargramostim; semustine; sisofiran; sobuzoxan; sodium borocaptate; sodium phenylacetate; solverol; sonermin; sorafenib; sunitinib; sparphosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; spongistatin 2; spongistatin 3; spongistatin 4; spongistatin 5; spongistatin 6; spongistatin 7; spongistatin 8; and spongistatin 9; squalamine; stypiamide; stromelysin inhibitors; sulfinosine; suradist; suramin; swinsonine; SB239063; selumetinib; AZD6244; symtrazen; SP600125; sodium sarphosate; sparsomycin; spirogermanium hydrochloride; spiroplatin; streptonigrin; streptozocin; sulofenur; thallimustin; tamoxifen metiodide; tauromustine; tazarotene; sodium tecogalan; tegafur; tellurapyrylium; temporfin; temozolamide; teniposide; tetrachlorodecoxide; tetrazomin; taliblastin; thiocoralin; thrombopoietin; thymalfasin; thymopoietin receptor agonist; thymotrinan; tirapazamine; titanocene bichloride; topsentin; toremifene; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrphostin; talisomycin; TAK733; taxotere; tegafur; teloxantrone hydrochloride; teroxirone; testolactone; thiamiprin; thioguanine; thiotep; thiazofurin; tirapazamine; toremifencitrate; trastuzumab; Trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulosole hydrochloride; tumor necrosis factor related apoptosis inducing ligand (TRAIL); UBC inhibitors; ubenimex; U0126; uracil mustard; uredepu; vapreotide; variolin B; velaresol; veramin; verteporfin; vinorelbine; vinxaltin; vitaxin; vinblastine; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; winepidin sulfate; vinicinate sulfate; wineleurine sulfate; vinorelbintartrate; vinirozidine sulfate; vinzolidine sulfate; vorozol; wortmannin; XL518; zanoterone; zeniplatin; zilascor; cytostatin; cynostatin; and zorubicin hydrochloride.

Other exemplary anticancer agents include erbulosole (eg R-55104); dolastatin 10 (eg DLS-10 and NSC-376128); mivobulin isethionate (eg CI-980); NSC-639829; discodermolide (eg NVP-XX-A-296); ABT-751 (Abbott; e.g. E-7010); altorirtin A; altorirtin 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 (eg TZT-1027); LS-4559-P (Pharmacia; eg LS-4577); LS-4578 (Pharmacia; eg 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; canadenzole; CA-170 (Curis, Inc.); centauridine (eg NSC106969); T-138067 (Tularik; for example, T-67; TL-138067 and TI-138067); COBRA-1 (Parker Hughes Institute; eg DDE-261 and WHI-261); H10 (Kansas State University); H16 (Kansas State University); oncocidin A1 (eg WTO-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; eg MF-569); narcosine (eg NSC-5366); nascapine; D-24851 (Asta Medica); A-105972 (Abbott); hemiasterlin; 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine; eg 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 (Tuiarik; e.g. T-900607); RPR-115781 (Aventis); eleutherobins (eg, desmethyleleutherobin; desaethyleleutherobin; 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); tacalonolide A; TUB-245 (Aventis); A-259754 (Abbott); diosostatin; (-)-phenylaistine (for example

- 20 042997 measures, 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; BPR-OY-007 (National Health Research Institutes); and SSR-250411 (Sanofi); goserelin; leuprolide; triptolide; homogarringtonin; topotecan; itraconazole; deoxyadenosine; sertraline; pitavastatin; clofazimine; 5-nonyloxytryptamine; vemurafenib; dabrafenib; gefitinib (IRESSA); erlotinib (TARCEVA); cetuximab (ERBITUKS); lapatinib (TYKERB); panitumumab (VECTIBIX); vandetanib (CAPRESLA); afatinib/BIBW992; 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/EKV-569; CUDC-101; WZ8040; WZ4002; WZ3146; AG-490; XL647; PD153035; 5-azathioprine; 5-aza-2'-deoxycytidine; 17-N-allylamino-17-demethoxygeldanamycin (17AAG); 20-epi-1,25 dihydroxyvitamin D3; 5 ethinyluracil; and BMS-599626.

In some embodiments, the combinations described herein are administered together with an anticancer agent described above, wherein the anticancer agent has known activity against a particular cancer (e.g., gemcitabine administered with the 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) at 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 in the definition of the invention presented herein. Accordingly, the following examples are intended to illustrate but not limit the invention.

Examples

Example 1

Example 1 tested HBI-8000 at two doses as monotherapy and at two doses in combination with an anti-PD-L1 inhibitory antibody at 5 mg/kg. The experiment included a stock solution treated group and an anti-PD-L1 inhibitory antibody monotherapy group, which served as control groups for efficacy analysis. Tumors were measured twice a week until completion of the study on day 47. Each animal was sacrificed when the tumor had reached a final volume of 1000 mm ³ , or on the last day of the study, whichever came first, and the time to endpoint (TDCT) for each mouse was calculated. Treatment response was determined by analysis of percentage tumor growth retardation (%TRD), defined as the percentage increase in median time to endpoint (MTD) for treated and control mice; and log-rank difference in survival between groups and regression responses.

Mice: Female C57BL/6 mice (Charles River Laboratories) were eight weeks old and weighed 15.4 to 22.0 g on day 1 of the study. Animals were given water ad libitum (reverse osmosis, 1 ppm Cl) and maintained on a modified and irradiated Lab Diet® NIH 31 diet consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fibers. Mice were housed on irradiated Enrich-o'cobs™ laboratory animal mats in stationary microisolators with a 12-hour light cycle at 20-22°C (68-72°F) and 40-60% humidity.

Tumor Cell Culture: Mouse MC38 colon carcinoma cells were maintained in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum and 2 mM glutamine, 100 U/mL penicillin G sodium, 100 μg/mL streptomycin sulfate, and 25 μg /ml gentamicin. Cell cultures were maintained in tissue culture flasks in a humidified incubator at 37° C. in 5% CO2 and 95% air. Tumor Implantation: Cells were harvested during exponential growth and resuspended in cold DMEM. Each mouse was inoculated subcutaneously in the right flank with 1 x 10 ⁶ cells (0.1 ml of cell suspension). Tumors were measured in two dimensions to track growth when their average volume approached the desired range of 100-150 mm ³ . The tumor load was calculated using the formula . ₃ . w ² χ I

Tumor volume (mm) = —-— where w is the width; and l is the length of the tumor in mm.

Tumor mass 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 study day 1, 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 .

Investigational Products: HUYA Bioscience International provided HBI-8000 (Lot # 1384:0033). Ahtu-PDL-1 10F.9G2 (antu-PDL-1 lot #5786-7-8/0815) was purchased from Bio X cell (West Lebanon, NH). All agents were prepared according to protocol instructions.

- 21 042997

Dosing solutions: HBI-8000 were prepared by diluting 0.2% CMC: 0.1% Tween 80 to give a 5 mg/mL dosing solution. Fresh dosing solutions were prepared weekly 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. Dosing solution with antiPDL-1 antibodies was prepared twice a week and stored at 4°C.

C57BL/6 mice were dosed according to protocol MC38-e063 shown in Table 1. 2. All doses were prepared as described above. HBI-8000 was administered orally (po) once a day for twenty-one days (p/dx21). The dosage was adjusted according to the body weight of the animal. All antibody regimens were administered at a concentration of 5 mg/kg intraperitoneally (ip), twice a week for three weeks (d/ndx3), and the dosage was adjusted according to the body weight of the animal.

table 2

Group Treatment Frequency Group 1 Stock solution (2% CMC: 0.1% Tween 80) p / o, r / s x 21 Group 2 HBI-8000 at 20 mg/kg p / o, r / s x 21 Group 3 HBI-8000 at 50 mg/kg p / o, r / s x 21 Group 4 Anti-PD-L1 inhibitory antibody at 5 mg/kg i/b, d/nd x 3 Group 5 HBI-8000 at 20 mg/kg plus Anti-PD-L1 inhibitory antibody at 5 mg/kg p / o, r / s x 21 i/b, d/nd x 3 Group 6 HBI-8000 at 50 mg/kg plus Anti-PD-L1 inhibitory antibody at 5 mg/kg p / o, r / s x 21 i/b, d/nd x 3

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

VCDT = log ₁₀ (final volume) - bm

where VDKT is expressed in days, the final volume is expressed in mm ³ ;

b - cut off segment; a m is the slope of a line obtained from a linear regression of a log-transformed tumor growth data set.

The dataset consisted of the first observation that exceeded the end volume used in the analysis and three consecutive observations that immediately preceded that end volume. The calculated TDCT is usually less than the date of PO, the day the animal was sacrificed due to tumor burden. Animals with tumors that did not reach the final volume were assigned a TBCT value corresponding to the last day of the study. In cases where the log-transformed calculated TDCT preceded the day before reaching the end point or exceeded the day of reaching the final tumor volume, linear interpolation was performed to approximate the TDCT. Any animal classified as having died of HCO (non-treatment related) causes due to an accident (HCAs) or due to unknown etiology (HCOne) was excluded from the TDCT calculations (and further analysis). Animals classified as dying of PO (treatment-related) or HCO (non-treatment-related death due to metastases) were assigned a TD value corresponding to the day of death.

Treatment Outcome: Treatment outcome was assessed by tumor growth retardation (TGR), which is defined as the increase in median time to endpoint (MTD) in the treated group compared to the control group.

ZRO \u003d T - C, expressed in days or as a percentage of the median CDT for the control group

T-C % ZRO = _Q x 100 where T is the median VDKT for the treated group; A

C is the median TDCT for the assigned control group.

Treatment Efficacy: Treatment efficacy can be determined by the volume of animal tumors remaining in the study on the last day. MOO (n) was defined 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. Treatment efficiency can also be determined by the frequency and magnitude of regression responses observed during the study. The treatment may cause partial regression (PR) or complete regression (CR) of the tumor in the animal. With PR response, tumor volume was 50% or less of

- 22 042997 volume on the 1st day in 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. With a PR response, the 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 additionally classified as a tumor-free survivor (TMS). Animals were observed for regressive responses.

Statistics: Prism (GraphPad) for Windows 6.07 was used for graphical presentation and statistical analysis. The log-rank test, which evaluates overall survival, was used to analyze the significance of the difference between the values of TBCT for the two groups. Log-rank analysis includes data for all animals in the group, except for HCO deaths. Two-sided statistical analysis was performed at a significance level of P=0.05. Graphs of the median volume of tumors by groups 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. The Kaplan-Meier plots illustrate the percentage of animals remaining in the study in each group over time.

Animals in example 1 were treated in accordance with the protocol described in table. 1. In FIG. 1 shows the median tumor growth curves for all study groups, and FIG. 2 shows median tumor volume curves for the combination of HBI-8000 at 50 mg/kg with an anti-PD-L1 inhibitory antibody compared to single agent and stock solution controls. In FIG. 3 shows Kaplan-Meier plots for all groups, and FIG. 4 shows Kaplan-Meier plots for the combination of HBI-8000 at 50 mg/kg with an anti-PD-L1 inhibitory antibody compared to a single agent control. In table. Table 2.1 shows the values calculated for TDCT and %ZRO for each treated group.

Table 2.1. Median values of TBCT and %ZRO

Group η Processing scheme Median TDCT %ZR0 Agent 1 Agent 2 1 10 stock solution - 20.5 - 2 10 HBI-8000 (20 mg/kg) - 18.9 -8 3 10 HBI-8000 (50mg/kg) - 22.8 eleven 4 10 anti-PDL-l - 21.7 6 5 10 HBI-8000 (20 mg/kg) anti-PDL-l 25.5 24 6 10 HBI-8000 (50mg/kg) anti-PDL-l 33.2 62

Example 2

In this example, HBI-8000 was tested as monotherapy and in combination with an anti-PD-L1 inhibitory antibody at 5 mg/kg. The experiment included a stock solution treated group and an anti-PD-L1 inhibitory antibody monotherapy group, which served as control groups for efficacy analysis. Tumors were measured twice a week until completion of the study on the 50th day. Each animal was sacrificed when the tumor had reached a final volume of 1000 mm ³ , or on the last day of the study, whichever came first, and the time to endpoint (TDCT) for each mouse was calculated. Treatment response was determined by analysis of percentage tumor growth retardation (%TRD), defined as the percentage increase in median time to endpoint (MTD) for treated and control mice; and log-rank significance of differences in survival between groups and regression responses.

Mice: Details of the animals used in this example can be found in the description above.

Tumor cell culture: Data on the tumor cells used in this example can be found in the description above.

Tumor Implantation and Measurement: Tumor implantation and tumor growth measurement data used in this example can be found in the description above.

In this example, each mouse was inoculated subcutaneously in the right flank with 5x105 cells (0.1 ml cell suspension).

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

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

Treatment: Four groups of C57BL/6 mice (n=10) were dosed according to the protocol in Table. 3. Dosing started on day 1 unless otherwise indicated. HBI-8000 was administered po at 50 mg/kg. Inhibitory antibody to PD-1 and anti-PDL-1 was administered ip at 5 mg/kg. The stock solution (0.2% carboxymethylcellulose: 0.1% Tween 80 in deionized water) was injected p/o. All agents were administered at a dosing volume of 10 ml/kg adjusted for body weight of individual animals.

- 23 042997

Table 3

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

Tumor growth retardation: Tumor growth retardation measurements and calculations can be found in the description above.

Processing result: data on measurement and calculation of processing results can be found in the description above.

Processing Efficiency: Efficiency measurements and processing efficiency calculations can be found in the description above.

Statistics: Data on statistics and software used in this study can be found in the description above. In FIG. 5 shows measurements of median tumor volume for all groups, and FIG. 6 is a Kaplan-Meier plot illustrating the percentage of animals in each group remaining in the study over time. In table. Table 3.2 shows the values calculated for TBCT and %ZRO for each treated group.

Table 3.1. VDKT and% ZRO

Group η Agent Schedule Agent Schedule Median TDCT %ZR0 1 10 stock solution r/s X 21 - - 17.5 - 2 10 HBI8000 r/s X 21 - - 28.4 62 4 10 antiPDL-l n/a X 3 - - 25.7 47 6 10 HBI8000 r/s X 21 anti-PDL-l d/n x 3 48.8 179

Example 3

In this model, a subset of animals treated with 1st line therapy with an inhibitory anti-PD-1 checkpoint antibody demonstrate complete tumor regression. However, the same proportion of animals treated with 1st line anti-PD-1 inhibitory antibody therapy show rapid tumor progression. The remaining animals treated in this way show slow tumor progression or stable disease, a result that approximates that of a large number of human cancer patients receiving anti-PD-1 inhibitory antibody therapy, i.e. they show a transient partial response. , including stable disease, but then develop resistance and progress rapidly, consistent with failure of anti-PD-1 inhibitory antibody therapy. This example evaluated the efficacy of HBI8000 (DZ1) as a second-line therapy, alone and in combination with the PDL-1 inhibitory antibody 10F.9G2 (anti-PDL-l), on the ability to induce tumor growth retardation (TGR) in animals in which tumors progressed after first-line anti-PD-1 inhibitory antibody therapy in a syngeneic MC3 8 mouse colon carcinoma model in immunocompetent C57BL/6 mice. Thus, this is due to the need for clinical therapy for patients who have failed anti-PD-1 inhibitory antibody therapy.

C57BL/6 females bearing subcutaneous MC38 tumors (mean tumor volume: 114 mm ³ at the start of treatment) were treated with first-line therapy with an inhibitory antibody to PD-1 administered intraperitoneally (ip) at a dose of 5 mg/kg, twice a day. a week for two weeks (d/nd x2). When tumors met the failure criteria and showed two consecutive increases in tumor volume and tumor volume was <500 mm ³ , they were then re-enrolled in a second-line efficacy study that consisted of six groups (n=10 per group) of mice (study MC38 -eO94 - e099). Dosing started with C1, which represented day of inclusion and varied among mice (these data were normalized for each group). The second line treatment options were as follows. The stock solution was administered orally (po). HBI-8000 was administered po at 50 mg/kg. Inhibitory antibody to PDP-1 and anti-PDL-l was administered intraperitoneally (ip) at 5 mg/kg. Group 1 mice served as controls and received 0.2% carboxymethylcellulose: 0.1% Tween 80 in deionized water (stock solution) once daily for twenty-one days (p/c x 21). Group 2 received HBI-8000 r/s x21. Group 3 received a second course of PD-1 inhibitory antibody d/nd x2. Group 4 received HBI-8000 r/s x21 and inhibitory antibody to PD-1 d/nd x2. Group 5 received anti-PDL-l d/nd x2. Group 6 received HBI-8000 r/s x21 and anti-PDL-l d/nd x2. The end point of the study was

-24042997 tumor volume 1500 mm ³ or day 45, whichever happened first. Tumor measurements were taken twice a week up to C44, with individual animals dropping out of the study when final tumor volume was reached.

Mice: At the start of primary treatment with PD-1 inhibitory antibody, female C57BL/6 mice (Charles River) were 8 weeks old and had a BW range of 18.1-24.1 g. Animals were given water ad libitum (reverse osmosis, 1 m d. Cl) and maintained on 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 fixed microisolators with a 12-hour light cycle at 20-22°C (68-72°F) and 40-60% humidity.

Tumor Implantation and Measurement: Tumor implantation and tumor growth measurement data used in this example can be found in the description above. In this example, each mouse was subcutaneously inoculated into the right flank with 5x10 ⁵ cells (0.1 ml of cell suspension).

Investigational Products: HUYA Bioscience International provided HBI-8000 (Lot # 1384:0033). Anti-PD-1 inhibitory antibody RMPI-14 (lot no. 5611-10/0615) and anti-PDL-1 antibody 10F.9G2 (anti-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.

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

Treatment: In the initial phase of this study with failed anti-PD-1 inhibitory antibody therapy, 120 C57BL/6 mice were dosed ip with first line anti-PD-1 inhibitory antibody at 5 mg/kg, d/n.d. x2. Animals meeting the re-inclusion 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 placed consecutively into the six efficacy study groups until the groups were filled; this occurred sixteen or twenty-two days after the initiation of the first dosing line. For efficacy studies, six groups of C57BL/6 mice (n=10) were dosed according to the protocol in Table 1. 4. Second line therapy was started on day 1, which was the day of inclusion of each individual animal.

Table 4

Group Treatment Frequency Group 1 Stock solution (2% CMC: 0.1% Tween 80) By r/s X 21 Group 2 HBI-8000 at 50 mg/kg By r/s X 21 Group 3 inhibitory antibody to PD-1 at 5 mg/kg i/b n/a X 3 Group 4 HBI-8000 with Inhibitor 50 mg/kg antibody PLUS to PD-1 at 5 mg/kg p/o v/b r/s X d/nd X 21 3 Group 5 inhibitory antibody to PD-L1 at 5 mg/kg i/b y/n X 3 Group 6 HBI-8000 with Inhibitor 50 mg/kg antibody PLUS to PD-L1 at 5 mg/kg p/o v/b r/s X d/nd X 21 3

Tumor growth retardation: Tumor growth retardation measurements and calculations can be found in the description above.

Processing result: data on measurement and calculation of processing results can be found in the description above.

Processing Efficiency: Efficiency measurements and processing efficiency calculations can be found in the description above.

Statistics: Data on statistics and software used in this study can be found in the description above. In table. 7 shows the responses of each group, classified as no response (OO), partial response (PR) and complete response (CR) to the applied therapy. In FIG. 7 shows mean tumor volume measurements for all groups, and FIG. 8 is a Kaplan-Meier plot illustrating the percentage of animals in each group remaining in the study over time.

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Table 5. Response rates to different treatments in mice bearing progressive tumors

MC38 after failed initial therapy with anti-PD-1 inhibitory antibody in Example 3

Base solution HBI-8000 PD-1 PD-1+HBI-8000 PD-L1 PD-L1+HBI-8000 00 100% 40% 60% 13% 33% thirty% 40 0% 40% thirty% 88% 44% 20% By 0% 20% 10% 0% 22% 50%

Example 4 HDAC Enzyme Inhibition Assay An HDAC isotype selectivity and inhibition potency assay was performed using human recombinant HDAC proteins and as described in Ning et al. All enzymatic reactions were incubated for 17 h at room temperature in 50 µl of the reaction mixture containing HDAC assay buffer (BPS catalog number 50031), 5 µg of BSA, HDAC substrate, purified recombinant HDAC enzyme, and test compound at a given concentration. After enzymatic reactions, 50 µl of 29 HDAC Developer (BPS catalog number 50030) was added to each well and the plate was incubated at room temperature for an additional 20 minutes. Fluorescence intensity was measured at 360 nm excitation and 460 nm emission using a Synergy™ 2 microplate reader from BioTek (Winooski, VT, USA). Each compound concentration was tested in duplicate. IC ₅₀ values were determined by analyzing concentration-response inhibition curves.

Although the invention has been described with reference to the embodiments shown, those skilled in the art will readily appreciate that the specific examples and studies detailed above are merely illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is only limited by the following claims.

Claims (24)

1. A combination containing a therapeutically effective amount of an anti-PDL1 inhibitory antibody and a therapeutically effective amount of a compound represented by the following formula (I): or a pharmaceutically acceptable salt thereof, wherein said combination is for administration to a subject having colon cancer previously treated with a PD-1 inhibitor, and wherein said compound is present in an amount of at least about 5 mg. 2. A combination according to claim 1, wherein said compound is present in an amount of from about 5 mg to about 50 mg. 3. Combination according to claim 1, characterized in that said antibody comprises durvalumab, avelumab, atezolizumab, or BMS-936559. 4. The combination of claim 3, wherein said anti-PD-L1 inhibitory antibody is present in an amount of about 0.1 mg/kg to about 30 mg/kg of the patient's body weight. 5. The combination of claim 3, wherein said anti-PD-L1 inhibitory antibody is present in an amount of about 0.5 mg/kg to about 15 mg/kg of the patient's body weight. 6. Combination according to claim 3, characterized in that said inhibitory antibody to PD-L1 is present in an amount of about: 0.1, 0.3, 1, 2, 3, 5, 10 or 20 mg/kg of body weight patient. 7. Pharmaceutical composition containing a combination according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient. 8. A kit containing a combination according to any one of claims 1 to 6 and individual containers, wherein the compound of formula I and the PD-L1 inhibitory antibody in said combination are packaged in individual containers in a kit, and wherein the compound of formula I is formulated for oral administration, and the PD-L1 inhibitory antibody is formulated for parenteral administration. 9. A method of treating cancer, comprising administering a therapeutically effective amount of the combination of claim 1 to a patient in need thereof, wherein said combination is for administration to a patient having colon cancer previously treated with a PD-1 inhibitor. 10. The method of claim 9, wherein said combination is administered to said cancer patient as third, fourth, fifth, or sixth line therapy. 11. The method of claim 9, wherein said combination is administered to said cancer patient after treatment with at least one anti-cancer therapy. 12. The method according to claim 11, characterized in that said anticancer therapy includes chemotherapy - 26 042997 rape, radiation therapy, surgery, targeted therapy, immunotherapy, or a combination thereof. 13. The method of claim 9, wherein said cancer is resistant to at least one anticancer agent. 14. The method of claim 9, wherein said compound and said PD-L1 inhibitor of said combination are administered simultaneously or sequentially. 15. The method according to claim 9, characterized in that said compound is administered 2-3 times per week. 16. The method according to claim 9, characterized in that said compound is administered daily. 17. The method according to claim 9, characterized in that the PD-L1 inhibitor and said compound are administered simultaneously on day 1 of the administration regimen. 18. The method of claim 9 wherein said PD-L1 inhibitory antibody comprises durvalumab, avelumab, atezolizumab, BMS-936559, STI-A1010, STI-A1011, STI-A1012, STI-A1013, STIA1014 or STI- A1015. 19. The method of claim 9, wherein said combination is administered to said patient according to a schedule. 20. The method of claim 19, wherein said regimen is repeated until disease progression or unacceptable toxicity occurs. 21. The method of claim 19, wherein said regimen includes a rest period of at least 1 day between successive administration periods. 22. The method of claim 19, wherein said compound of said combination is administered 23 times per week according to said schedule, and said anti-PD-L1 inhibitory antibody is administered every 23 weeks. 23. The method of claim 19, wherein said compound of said combination is administered once daily for 21 days according to said schedule, and said anti-PDL1 inhibitory antibody is administered every 2-3 weeks. 24. The method according to any one of claims 20-23, characterized in that said cancer treatment method 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 to the progression of said cancer in said patient, prolongs the survival time of said patient, prolongs survival of said patient without disease progression.