COMBINATION THERAPY FOR TREATING CANCER

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62/337, 197, filed May 16, 2016, and U.S. Provisional Application No.

62/343,613, filed May 31 , 2016. The entire teachings of the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] The invention is directed to compositions and combinations

comprising one or more C-C motif chemokine receptor 5 (CCR5) antagonists and one or more checkpoint antagonists; one or more CCR5 antagonists and one or more focal adhesion kinase (FAK) antagonists; or one or more CCR5 antagonists, one or more FAK antagonists, and one or more checkpoint antagonists, for use in inducing an immune response to diseases, such as cancer or for use in the production of a medicament or medicaments for use in inducing an immune response to diseases, such as cancer or to treat cancer. The invention also provides methods of treating cancer with the compositions and combinations of the invention. The compositions or combinations may be administered sequentially or substantially simultaneously to effectively initiate, enable, increase, enhance, or prolong the activity and/or number of immune cells, or beneficial response to a tumor.

[0003] The cancer microenvironment includes the proteins produced by all of the cells present in the tumor that support tumor growth. It also includes the noncancerous cells present in a tumor, such as fibroblasts and immune cells. Increasing evidence suggests that the ability to sidestep the body's immune response is pivotal to tumor development. As such, researchers have begun to look at ways to reinstate the immune response with targeted agents, essentially indirectly treating cancer by treating the immune system. One particularly promising strategy for doing this is to target immune checkpoint proteins, which act as the off-switch on the T cells of the immune system.

[0004] Immune checkpoint antagonist therapies have been developed to enable a patient's own immune system to fight tumors by facilitating an existing immune response or allowing for the initiation of an immune response. These therapies have been shown to be effective at treating some cancers in some subjects. Three immune checkpoint targets are the subject of most on-going clinical work: Programmed cell death protein 1 (PD-1 ), its ligands, PD-L1 , cytotoxic T- lymphocyte-associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), and cluster of differentiation 276 gene (CD276 also known as B7-H3). More recently, a new checkpoint target, GARP, has been investigated. Currently, a number of checkpoint antagonists are being evaluated in clinical trials. These antagonists include fully human and humanized anti-PD-1 monoclonal antibodies (e.g., nivolumab, pembrolizumab), an anti-PD-L1 antibody (e.g., durvalumab, atezolizumab, MEDI4736), a fusion protein comprising PD-L2 extracellular domain and lgG1 , an anti-CTLA-4 antibody (e.g., tremelimumab, ipilimumab), a CD276 inhibitor (e.g., enoblituzumab; pidilizumab, MGD009) and an antibody to GARP (ARGX-1 15).

[0005] Similar cancer therapies are being developed using tyrosine kinase antagonists, one of the first classes of molecules to be suggested as a potential target for anticancer therapy. Lee et al. , Pharmacology & Therapies 146: 132-149 (2015). One target in particular, is a non-receptor tyrosine kinase known as focal adhesion kinase or FAK. FAK activation is the first intracellular step in the signal transduction cascade initiated by the attachment of an integrin to the extracellular matrix at points known as focal adhesions. FAK plays a central role in the development and survival of cancer stem cells and it has been found that FAK expression is greater in some highly invasive and metastatic tumors. Numerous small molecule antagonists of FAK activation are currently in development for the treatment of cancer, including Bl 853529, GSK2256098, NVP-226, PF-573,228, PF- 562,271 (VS-6062), VS-4718, VS-6063, VS-5095, Y15, CFAK-C4, INT2-31 , M13, and R2. Transfection with FAK-silenced RNA (FAK-siRNA) has also been evaluated as an anti-cancer therapy.

[0006] However, patients that benefit from checkpoint antagonist or FAK antagonist therapies are part of a relatively small percentage of the patients with cancer. Not all cancers are impacted by these therapies and not all of the

responding population experiences complete or optimal therapy.

[0007] Recently, combinations of immune checkpoint antagonists have been evaluated. A phase II trial has been conducted combining the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibody nivolumab to treat melanoma that no longer responds to standard-of-care treatments. Combinations of immune checkpoint antagonists with an immunostimulatory CD40-specific antibody have also been evaluated, with an overall response rate of 27%, which included complete responses in two patients and partial responses in four patients out of 24. Combinations of FAK antagonists with other anticancer agents such as gemcitabine have demonstrated synergy in inhibiting certain types of cancer cell growth. Hochwald et al., Cell Cycle 8(15):2435-43 (2009). [0008] Yet, despite the recent clinical success of checkpoint or FAK blocking therapies, there still remains significant unmet medical need in non-responder patients, partial responders, and for unresponsive tumor types.

SUMMARY OF THE INVENTION

[0009] One embodiment of the invention provides methods of treating cancer with a combination of agents comprising one or more CCR5 antagonists and one or more checkpoint antagonist for inducing an immune response to diseases such as cancer. Another embodiment of the invention provides methods of treating cancer with a combination of agents comprising one or more CCR5 antagonists and one or more FAK antagonists for inducing an immune response to diseases such as cancer. Yet another embodiment provides methods of treating cancer with a combination of agents comprising one or more CCR5 antagonists, one or more checkpoint antagonists, and one or more FAK antagonists for inducing an immune response to diseases such as cancer. The agents may be administered sequentially or substantially simultaneously to effectively initiate, enable, increase, enhance, or prolong the activity and/or number of immune cells, or beneficial response to a cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological cancer.

[00010] In some embodiments, the checkpoint antagonist is selected from a CTLA-4 antagonist, PD-1 antagonist, PD-L1 antagonist, and PD-L2 antagonist. In some embodiments, the checkpoint antagonist is a monoclonal antibody, which may be humanized, or fully human. In some embodiments, CTLA-4 antagonists employed in the combinations and methods of the invention are selected from tremelimumab and ipilimumab. In some embodiments, PD-L1 antagonists for use in the combinations and methods of the invention are selected from MDX-1 105, durvalumab, atezolizumab, and MEDI4736. In some embodiments, PD-1

antagonists for use in the combinations and methods of the invention are selected from nivolumab, pembrolizumab, pidilizumab, and AMP-224.

[00011] In some embodiments, the FAK antagonist is a small molecule selected from Bl 853529, GSK2256098, NVP-226, PF-573,228, PF-562,271 (VS- 6062), VS-4718, VS-6063, VS-5095, Y15, C4, INT2-31 , M13, and R2. In some embodiment, that FAK antagonist is a FAK-siRNA. In some embodiments, the FAK antagonist is an anti-FAK antibody or an antibody that binds to another molecule and inhibits FAK activation.

[00012] In some embodiments, the CCR5 antagonist is a small molecule selected from vicriviroc, deuterated vicriviroc, maraviroc, deuterated maraviroc, and pharmaceutically acceptable salts thereof. In some embodiments, the CCR5 antagonist is an antibody to CCR5, CCL3, CCL4, CCL5, or CCL8.

[00013] In some embodiments, this invention relates to a method of treating a solid tumor or a hematological cancer in a subject comprising the steps of administering to the subject:

a. one or more CCR5 antagonists selected from vicriviroc, a deuterated form of vicriviroc, maraviroc, and a deuterated form of maraviroc; or a pharmaceutically acceptable salt thereof; and

b. one or more checkpoint antagonists.

[00014] In some embodiments, this invention relates to a method of treating a solid tumor or a hematological cancer in a subject comprising the steps of administering to the subject: a. one or more CCR5 antagonists selected from vicriviroc, a deuterated form of vicriviroc, maraviroc, and a deuterated form of maraviroc; or a pharmaceutically acceptable salt thereof; and

b. one or more checkpoint antagonists; and

c. one or more FAK antagonists.

[00015] In some embodiments, this invention relates to a method of treating a solid tumor or a hematological cancer in a subject comprising the steps of

administering to the subject:

a. one or more CCR5 antagonists selected from vicriviroc, a deuterated form of vicriviroc, maraviroc, and a deuterated form of maraviroc; or a pharmaceutically acceptable salt thereof; and

b. one or more FAK antagonists.

[00016] In some aspects, wherein the method comprises administering one or more checkpoint antagonist(s), the one or more checkpoint antagonist(s) is a PD-1 antagonist, a PD-L1 antagonist, a CTLA-4 antagonist, and/or a PD-L2 antagonist.

[00017] In some aspects, wherein the method comprises administering more than one checkpoint antagonist, each checkpoint antagonist is independently selected from a PD-1 antagonist, a PD-L1 antagonist, a CTLA-4 antagonist, and/or a PD-L2 antagonist.

[00018] In some aspects, the administration of the checkpoint antagonist comprises administering:

a. a first checkpoint antagonist selected from a PD-1 antagonists, a PD- L1 antagonists, or PD-L2 antagonists; and a second checkpoint antagonist selected from CTLA-4 antagonists; or b. a first checkpoint antagonist selected from a PD-1 antagonists, and a second checkpoint antagonist selected from a PD-L1 and PD-L2 antagonists.

[00019] In some aspects, the PD-1 antagonist is selected from nivolumab, pembrolizumab, and AMP-224.

[00020] In some aspects, the PD-L1 antagonist is selected from MDX-1 105, atezolizumab, and durvalumab.

[00021] In some aspects, the CTLA-4 antagonist is selected from ipulimumab and tremelimumab.

[00022] In some aspects, the checkpoint antagonist is pidilizumab.

[00023] In some aspects, wherein the method comprises administering one or more FAK inhibitor(s), the FAK inhibitor(s) is selected from Bl 853529, GSK2256098, NVP-226, PF-573,228, PF-562,271 (VS-6062), VS-4718, VS-6063, VS-5095, Y15, CFAK-C4, INT2-31 , M13, and R2.

[00024] In some aspects, wherein the method comprises administering one or more FAK inhibitor(s), the one or more FAK inhibitor(s) is an siRNA, a small molecule, or an antibody.

[00025] In some aspects, the CCR5 antagonist is vicriviroc or a deuterated form of vicriviroc, or a pharmaceutically acceptable salt thereof.

[00026] In some aspects, the CCR5 antagonist is a compound of Formula III:

(Formula III)

or a pharmaceutically acceptable salt thereof, wherein: each of R ¹ , R ⁵ and R ⁶ is selected from CH ₃ , CH ₂ D, CHD ₂ and CD ₃ ;

each of R ² , R ³ and R ⁴ is independently selected from H or D; and

at least one R variable comprises a deuterium atom.

[00027] In some aspects, the compound of Formula III is selected from:

(Compound 104),

(Compound 105),

and pharmaceutically acceptable salts thereof.

[00028] In some aspects, the CCR5 antagonist is maraviroc or a deuterated form of maraviroc, or a pharmaceutically acceptable salt thereof.

[00029] In some aspects, the CCR5 antagonist is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

each Y is independently selected from hydrogen or deuterium;

each Z is independently selected from hydrogen or deuterium; and at least one Y or one Z is deuterium.

[00030] In some aspects, the compound of Formula II is Compound 203:

F (Compound 203), or a pharmaceutically acceptable salt thereof.

[00031] In some aspects, the subject has an elevated level of CCR5 expression on their regulatory T-cells as compared to a cancer-free subject.

[00032] In some aspects, the subject has an elevated number of regulatory T- cells in circulation as compared to a cancer-free subject.

[00033] In some aspects, the subject has an elevated level of CCR5 ligand expression as compared to a cancer-free subject.

[00034] In some aspects, the CCR5 ligand is selected from CCL3, CCL4 CCL5, and CCL8.

[00035] In some aspects, the solid tumor is selected from melanoma, renal carcinoma, non-small cell lung cancer, urothelial cancer, pancreatic cancer, breast cancer and colorectal cancer.

[00036] In some aspects, the one or more CCR5 antagonists are

administered simultaneously with the one or more checkpoint antagonists.

[00037] In some aspects, the one or more CCR5 antagonists and the one or more checkpoint antagonists are administered as separate compositions.

[00038] In some aspects, the one or more CCR5 antagonists and the one or more checkpoint antagonists are administered as a single composition. [00039] In some aspects, the one or more CCR5 antagonists are administered before or after the one or more checkpoint antagonists.

[00040] In some aspects, the one or more CCR5 antagonists are

administered simultaneously with the one or more checkpoint antagonists, and the one or more FAK antagonists.

[00041] In some aspects, the one or more CCR5 antagonists, the one or more checkpoint antagonists, and the one or more FAK antagonists are administered as separate compositions.

[00042] In some aspects, the one or more CCR5 antagonists, the one or more checkpoint antagonists, and the one or more FAK antagonists are administered as a single composition.

[00043] In some aspects, the one or more CCR5 antagonists are

administered before or after the one or more checkpoint antagonists and the one or more FAK antagonists.

[00044] In some aspects, the one or more CCR5 antagonists are

administered simultaneously with the one or more FAK antagonists.

[00045] In some aspects, the one or more CCR5 antagonists and the one or more FAK antagonists are administered as separate compositions.

[00046] In some aspects, the one or more CCR5 antagonists and the one or more FAK antagonists are administered as a single composition.

[00047] In some aspects, the one or more CCR5 antagonists are

administered before or after the one or more FAK antagonists.

[00048] In some embodiments, this invention relates to a method of enhancing the efficacy of one or more checkpoint antagonists in the treatment of a cancer, the method comprising the step of administering to a subject a checkpoint antagonist in combination with vicriviroc, a deuterated form of vicriviroc, maraviroc, or a deuterated form of maraviroc; or a pharmaceutically acceptable salt thereof of any of the aforementioned.

[00049] In some embodiments, this invention relates to a method of enhancing the efficacy of one or more FAK antagonists in the treatment of a cancer, the method comprising the step of administering to a subject a checkpoint antagonist in combination with vicriviroc, a deuterated form of vicriviroc, maraviroc, or a deuterated form of maraviroc; or a pharmaceutically acceptable salt thereof of any of the aforementioned.

[00050] In some embodiments, this invention relates to a method of enhancing the efficacy of one or more checkpoint and FAK antagonists in the treatment of a cancer, the method comprising the step of administering to a subject a checkpoint antagonist in combination with vicriviroc, a deuterated form of vicriviroc, maraviroc, or a deuterated form of maraviroc; or a pharmaceutically acceptable salt thereof of any of the aforementioned.

DETAILED DESCRIPTION

Definitions:

[00051] The term "isotopologue" refers to a species in which the chemical structure differs from a specific compound of this invention only in the isotopic composition thereof.

[00052] The term "compound," when referring to a deuterated compound of this invention, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound.

[00053] It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of maraviroc or vicriviroc will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, Wada, E et al. , Seikagaku, 1994, 66: 15; Gannes, LZ et al. , Comp Biochem Physiol Mol Integr Physiol, 1998, 1 19:725.

[00054] In the compounds of this invention, when a CCR5 antagonist is referred to as a "deuterated form of maraviroc", "deuterated maraviroc", a

"deuterated form of vicriviroc" or "deuterated vicriviroc", it is understood that deuterium is present on at least one position in the compound and that the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium (which is 0.015% (i.e. , at least 50.1 % incorporation of deuterium).

[00055] In the deuterated compounds of this invention, when a position is designated specifically as "D" or "deuterium", the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium (i.e. , at least 50.1 % incorporation of deuterium). [00056] Unless otherwise stated, in the deuterated compounds of this invention, any atom not designated specifically as "D" or "deuterium" in any of the embodiments set forth herein is present at its natural isotopic abundance.

[00057] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[00058] In some examples, a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium

incorporation), or at least 6633.3 (99.5% deuterium incorporation).

Methods of Treatment:

[00059] The human body has immune checkpoint molecules in place to prevent the immune system from destroying healthy cells. When a cell has become diseased or cancerous, the immune system should engage to kill and remove the cell. However many cancer cells have the ability to evade the immune system and prevent T-cells from attacking. For example, when PD-L1 is expressed on the surface of an antigen presenting cell and binds to a PD-1 receptor expressed on the surface of a T-cell, the interaction sends a signal into the T cell and switches it off, inhibits it, or causes the T cell itself to be destroyed. Cancer cells take advantage of this system by upregulating expression of e.g., PD-L1 , on their surface. This allows them to gain control of the PD-1 pathway and switch off or eliminate any T cells expressing PD-1 that may enter the tumor microenvironment resulting in a suppression of the anticancer immune response. Checkpoint antagonists are designed to block the interaction between e.g., PD-1 and its ligands, and thus keep the immune system from functioning against the cancer cell. Checkpoint proteins include programmed cell death protein 1 (PD-1 ), its ligands, PD-L1 , and cytotoxic T- lymphocyte-associated protein 4 (CTLA-4), GARP, lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin mucin protein-3 (TIM-3), B7-H3, B7-H4, BTLA, HVEM, GAL-9, VISTA, KIR, 2B4, CD160, CGEN-15049, A2aR, B-7 family ligands, and GARP.

[00060] CCL5 (also known as RANTES) is a ligand to CCR5. It is involved in regulating the generation of myeloid-derived suppressor cells (MDSCs), increasing tumor-associated macrophage (TAM) populations, and recruiting regulatory T cells (Tregs) to the tumor microenvironment in some cancers. The tumors of some patient tumor populations (e.g., with pancreatic, colorectal, and breast cancer) have been shown to produce increased levels of CCL5, which in turn increases Treg infiltration and apoptosis of CD8+ T cells (CTLs) in cancer tissue. Tumor infiltrating Tregs express high levels of CCR5. High levels of CCR5 expression in Tregs has been correlated with higher levels of immunosuppression. Administration of CCR5 antagonists reduces the immunosuppressive environment in tumors by inhibiting immunosuppressive cell (e.g., Treg, MDSC and TAM) recruitment to the tumor and reducing cytotoxic T lymphocyte (tumor-killing T cell) apoptosis.

[00061] FAK is a non-receptor tyrosine kinase that is found in the focal adhesions that form among cells attaching to extracellular matrix constituents. FAK plays a significant role in adhesion, motility, invasion, angiogenesis, and cancer stem cell self-renewal. FAK is also involved in cell death signaling, or apoptosis. FAK is overexpressed and activated in many types of solid and non-solid tumors, including prostate, head and neck, esophageal, gastric, laryngeal, lung, ovarian, thyroid, endometrial, cervical, breast, and colorectal cancers resulting in inhibition of apoptosis, promotion of tumor progression and metastasis. Elevated FAK

expression is correlated with an aggressive phenotype in some cancers and has been positively correlated with tumor size and lymphatic invasion in others.

[00062] It has been shown that inhibition of FAK reduces tumor-initiated properties of cancer stem cells, facilitates entry of cytoplasmic T lymphocytes into a tumor by reducing stromal density, and reduces immunosuppressive cell

populations. FAK antagonists have been shown to be potent anti-angiogenic agents, reducing the blood vessels supporting the growth of the cancer cells. Inhibition of FAK signaling can reduce the production of CCL5 and reduce regulatory T-cell recruitment to tumors. As noted above, CCR5 inhibition also reduces regulatory T- cell recruitment to tumors by inhibiting the interaction of CCR5 with its ligands, CCL3, CCL4, CCL5, and CCL8. A combination of CCR5 antagonist with a FAK antagonist, with or without addition of a checkpoint antagonist, can more efficiently inhibit regulatory T-cell recruitment to tumors, allowing the host immune system to more efficiently and effectively clear tumor cells.

[00063] Combination therapy involving a CCR5 antagonist and a checkpoint antagonist and/or a FAK antagonist will reduce immunosuppression and enhance or prolong an anti-tumor response in a patient. The administration of a CCR5

antagonist simultaneously or sequentially with a checkpoint antagonist and or a FAK antagonist may enhance or prolong the effects of the checkpoint and/or FAK antagonists, enable a patient to respond to the checkpoint and/or FAK antagonists, or enable the reduction of the toxicity or the dose of the checkpoint and/or FAK antagonists.

CCR5 Antagonists

[00064] A CCR5 antagonist may include any molecule that inhibits signaling between CCR5 and a CCR5 ligand, such as CCL3, CCL4, CCL5 and CCL8. In some embodiments, the CCR5 antagonist is a monoclonal antibody, including a humanized or fully human antibody to CCL3, CCL4, CCL5, CCL8, or CCR5. Anti- CCR5 antibodies are described in, e.g. , United States Patent 7,851 ,600,

incorporated herein by reference. In some embodiments the CCR5 antagonist may be a bispecific antibody that has at least one binding site that targets CCR5, CCL3, CCL4, CCL5, or CCL8. In other embodiments, the CCR5 antagonist may be a fusion protein comprising the extracellular domain of a CCR5 protein fused to another molecule, such as, e.g. , the Fc domain of IgG, such as, e.g. , lgG1 and lgG4. In some embodiments, the CCR5 antagonist may be a soluble form of the CCR5 ligand that blocks binding of CCL3, CCL4, CCL5, or CCL8 binding to CCR5 but does not activate CCR5 signaling. In some embodiments, the CCR5 antagonist is a small molecule.

[00065] Exemplary CCR5 antagonists are vicriviroc, deuterated vicriviroc, maraviroc, deuterated maraviroc GSK706769, PF-232798, INCB009471 , apiaviroc (also known as GSK-873140 and ONO-4128), TAK-779 (also known as E-921 ), BMS-813160, AZD-5672, DAPTA, RAP-103, RAP-104, Met-RANTES (also known as Met-CCL5), PRO-140, Mab 45531 , CCR5mAb004, HGS1025 and

pharmaceutically acceptable salts thereof.

[00066] Exemplary CCR5 antagonists which are small molecules include vicriviroc, deuterated vicriviroc, maraviroc, deuterated maraviroc, GSK706769, PF- 232798, INCB009471 , aplaviroc, TAK-779, BMS-813160, AZD-5672 and aceutically acceptable salts thereof.

[00067] Maraviroc, , chemically described as N-{(1 S)-3-[3-(3-lsopropyl-5-methyl-4H-1 ,2,4-triazol-4-yl)-exo-8- azabicyclo[3.2.1 ]oct-8-yl]-1 -phenylpropyl}-4,4-difluorocyclohexanecarboxamide or 4,4-difluoro-N-{(1 S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1 ,2,4-triazol-4-yl)-8- azabicyclo[3.2.1 ]oct-8-yl]-1 -phenylpropyl}cyclohexanecarboxamide and its pharmaceutically acceptable addition salts and hydrates are small molecule modulators of CCR5 and thus useful in the combinations and methods of the invention. Maraviroc is the first CCR5 antagonist approved for use in the US and Europe - for the treatment of human immunodeficiency virus. It is sold under the names Celsentri in Europe and Selzentry in the United States.

[00068] Deuterated small molecule CCR5 antagonists, such as those described in United States Patent 7,932,235, are also useful in the combinations and methods of the inventions. United States Patent 7,932,235 is incorporated herein by reference in its entirety for its teaching of how to make compounds falling within Formula I and Formula II below, and for its description of pharmaceutical

compositions comprising compounds of Formula I and Formula II. In some embodiments, the deuterated CCR5 antagonist is a compound of Formula I: (Formula I)

or a pharmaceutically acceptable salt thereof; wherein:

R ¹ is selected from C ₁ -C6 alkyl optionally substituted by one or more fluorine atoms; C3-C6 cycloalkyl optionally substituted by one or more fluorine atoms; and C3-C6 cycloalkylmethyl optionally ring substituted by one or more fluorine atoms, wherein one or more hydrogen atoms in R ¹ is optionally replaced with deuterium;

R ² is phenyl optionally substituted by one or more fluorine atoms;

each Y is independently selected from hydrogen or deuterium; and at least one Y is deuterium.

[00069] In another embodiment, the deuterated CCR5 antagonist is a compound of Formula II:

(Formula II)

or a pharmaceutically acceptable salt thereof; wherein:

each Y is independently selected from hydrogen or deuterium;

each Z is independently selected from hydrogen or deuterium; and at least one Y or one Z is deuterium.

[00070] In some embodiments of the compound of Formula II, each Y is deuterium and each Z bound to the same carbon atom is the same. In some embodiments of the compound of Formula II, each Y is deuterium and each Z is hydrogen. In some embodiments, each Y is deuterium and each member of at least one pair selected from Zi and Z ₂ ; Z ₃ and Z ₄ ; Z ₅ and Z ₆ ; and Z ₇ and Z ₈ is

simultaneously deuterium. In some embodiments, the deuterated CCR5 antagonist of Formula II is defined as follows:

[00071] In some embodiments, the CCR5 antagonist is Compound 200:

200) or a pharmaceutically acceptable salt thereof. In some embodiments, the deuterated CCR5 antagonist is Compound 203:

(Compound

203)

or a pharmaceutically acceptable salt thereof.

[00072] Vicriviroc, , also known as 5-[4-[4- [2-methoxy-1 (R)-[4-(trifluoromethyl)phenyl]ethyl]-3(S)-methylpiperazin-1 -yl]-4- methylpiperidin-1 -ylcarbonyl]-4,6-dimethylpyrimidine, is another small molecule CCR5 antagonist that may be used in the combinations and methods of the invention. Although clinical development of topical vicriviroc for the treatment of HIV has been halted, clinical studies with vaginal rings containing vicriviroc are ongoing.

[00073] Deuterated compounds of Formula III and pharmaceutically acceptable salts thereof may also be used in the combinations and methods of the invention: (Formula III) wherein:

each of R ¹ , R ⁵ and R ⁶ is selected from CH ₃ , CH ₂ D, CHD ₂ and CD ₃ ;

each of R ² , R ³ and R ⁴ is independently selected from H or D; and

at least one R variable comprises a deuterium atom.

[00074] In some embodiments, the deuterated CCR5 antagonist of Formula IIImpound of Formula IMA:

(Formula IMA)

armaceutically acceptable salt thereof, wherein:

R ¹ is selected from -CH ₃ , -CH ₂ D, -CHD ₂ and -CD ₃ ;

each of R ² , R ³ and R ⁴ is independently selected from H or D; and

at least one R variable comprises a deuterium atom.

[00075] In other embodiments of Formula I, IA or both:

a) R ¹ is selected from CH ₃ and CD ₃ ;

b) R ⁵ is selected from CH ₃ and CD ₃ ;

c) R ⁶ is selected from CH ₃ and CD ₃ ;

d) R ⁵ and R ⁶ are the same; and

e) R ² and R ³ are the same. [00076] In a more specific embodiment, a compound of Formula IIIA has the features set forth in at least two of a) through e), above. Exemplary combinations include, but are not limited to: b+a; c+a; e+a; e+b; e+c; d+a; d+b; d+c; d+e; c+b+a; e+b+a; e+c+a; d+b+a; d+c+a; d+e+a; d+e+b; d+e+c; e+c+b+a; d+c+b+a; d+e+b+a; and d+e+c+a.

[00077] In still another embodiment of Formula III, R ² and R ³ are deuterium, the compound having the structure depicted in Formula 1MB:

(Formula NIB)

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from CH ₃ and CD ₃ ;

R ⁴ is selected from hydrogen and deuterium; and

each of R ⁵ and R ⁶ is independently selected from CH ₃ and CD ₃ .

[00078] In one embodiment of Formula 1MB, R ¹ is CD ₃ . In one aspect of this embodiment, R ⁴ is hydrogen and R ⁵ and R ⁶ are CD ₃ . In an alternate aspect, R ⁴ is hydrogen, and R ⁵ and R ⁶ are CH ₃ . In another embodiment of Formula 1MB, R4 is hydrogen and each of R ¹ , R ⁵ , and R ⁶ are CH ₃ .

[00079] In another embodiment of Formula III, each of R ¹ , R ⁵ and R ⁶ are CD ₃ , the compound having the structure depicted in Formula IMC:

(Formula IMC)

or a pharmaceutically acceptable salt thereof, wherein each of R ² , R ³ , and R ⁴ is independently selected from hydrogen and deuterium. In one aspect of this embodiment, each of R ² and R ³ is hydrogen. In an alternate aspect of this embodiment, each of R ² and R ³ is deuterium.

[00080] In yet another embodiment, the compound is selected from Compounds 100-108:

(Compound 100)

(Compound 101 )

(Compound 102) ompound 103)

(Compound 104) (Compound 105) (Compound 106) (Compound 107) and pound 108)

and pharmaceutically acceptable salts of any one of compounds 100-108. In some embodiments, the CCR5 antagonist is Compound 104 or Compound 105.

[00081] In some embodiments, in a deuterated compound of this invention, each designated deuterium atom has deuterium incorporation of least 52.5%.

[00082] In some embodiments, in a deuterated compound of this invention, each designated deuterium atom has deuterium incorporation of least 60%.

[00083] In some embodiments, in a deuterated compound of this invention, each designated deuterium atom has deuterium incorporation of least 67.5%.

[00084] In some embodiments, in a deuterated compound of this invention, each designated deuterium atom has deuterium incorporation of least 75%.

[00085] In some embodiments, in a deuterated compound of this invention, each designated deuterium atom has deuterium incorporation of least 82.5%.

[00086] In some embodiments, in a deuterated compound of this invention, each designated deuterium atom has deuterium incorporation of least 90%.

[00087] In some embodiments, in a deuterated compound of this invention, each designated deuterium atom has deuterium incorporation of least 95%.

[00088] In some embodiments, in a deuterated compound of this invention, each designated deuterium atom has deuterium incorporation of least 97.5%.

[00089] In some embodiments, in a deuterated compound of this invention, each designated deuterium atom has deuterium incorporation of least 99%. [00090] In some embodiments, in a deuterated compound of this invention, each designated deuterium atom has deuterium incorporation of least 99.5%.

[00091] The synthesis of compounds of Formula III, MIA, 1MB, and IMC can be readily achieved by synthetic chemists of ordinary skill. Relevant procedures and intermediates are disclosed, for instance in United States Patents 6,689,765 and 6,391 ,865, and in PCT publications WO2000066551 , WO2003084950, and WO 2006074264, and in the following literature articles: Tagat, JR et al. , J Med Chem, 2004, 47(10): 2405-2408; and Revill, P et al., Drugs Fut, 2007, 32(5): 417; and Tagat, JR et al. , J Med Chem, 2001 , 44(21 ): 3343-3346; and McCombie, SW et al. , Bioorg. Med. Chem. Lett. , 2003, 13: 567-571 . The specific CCR5 antagonist compounds of any Formula III are described in detail in United States Patent 8,367,674, incorporated by reference for its teaching of how to make these compounds and pharmaceutical compositions comprising them.

Checkpoint Antagonists

[00092] A checkpoint antagonist suitable for use in the combinations and methods of the invention inhibits the immunomodulatory activity of a checkpoint protein such as, e.g. , CTLA-4, PD-L1 , PD-L2, PD-1 , B7-H3, B7-H4, BTLA, HVEM, TIM-3, GAL-9, LAG-3, VISTA, KIR, 2B4, CD160, CGEN-15049, A2aR, B-7 family ligands, GARP, or a combination thereof. In some embodiments, the checkpoint antagonist is a monoclonal antibody, including a humanized or fully human antibody to a checkpoint protein. In some embodiments, the checkpoint antagonist is a bispecific antibody that contains at least one binding site for a check point protein. In other embodiments, the checkpoint antagonist may be a fusion protein comprising the extracellular domain of a checkpoint protein fused to another molecule, such as, e.g., the Fc domain of IgG, such as, e.g., lgG1 and lgG4. In some embodiments, the checkpoint antagonist may be a soluble form of the checkpoint protein that blocks binding of the protein to its binding partner to prevent inhibition of the immune system. These antagonists may be made by any method known in the art for preparing antibodies, fusion proteins, and soluble proteins. Alternatively, many checkpoint antagonists are currently being developed and may soon be

commercially available.

[00093] The first checkpoint antagonist approved by the FDA (ipilimumab) targets CTLA-4. Blockade of CTLA-4 may induce an antitumor or immune regression by sustaining the activation and proliferation of tumor-specific T cells. CTLA-4 is a co-antagonisty receptor expressed on activated T cells. Upon binding to B7 ligands, CTLA-4 delivers an antagonisty signal to reduce the amplitude of T-cell activation. Ipilimumab is anti-CTLA-4 monoclonal antibody that may be used in the

combinations and methods of the invention. It has been evaluated in clinical trials for the treatment of cancer, alone and in combination with anti-PD-1 antibody

nivolumab. A. Eggermont et al., The Lancet Oncology 16(5): 522-530 (2015); J. Larkin et al., N. Eng. J. Med. 373:23-34 (2015). Tremehmumab is a fully human lgG2 monoclonal antibody antagonist of CTLA-4. A. Ribas et al., The Oncologist, 12(7):873-883 (2007). It promotes T-cell activity through CTLA-4 inhibition but does not deplete regulatory T cells. Tremehmumab is being clinically investigated as a monotherapy and combination therapy for the potential treatment of cancer. When used in combination with an anti-PD-L1 agent, tremehmumab is believed to boost the biological and clinical effect of PD-L1 inhibition. Tremehmumab may also be used in in combination with durvalumab (MEDI4736). S. Antonia et al., The Lancet

Oncology 17(3):299-308 (2016). [00094] Anti-PD-1 antibodies nivolumab, lambrolizumab (MK3475), and pembrolizumab block the binding of PD-1 receptor to its 2 ligands, PD-L1 and PD- L2. Another PD-1 antagonist is AMP-224, a fusion protein that combines the extracellular domain of PD-L2 and human lgG1 Fc to inhibit PD-1. Anti-PD-L1 antibodies durvalumab (MEDI4736), atezolizumab (MPDL3280A), MDX-1 105 (anti- PD-L1 ), and BMS-936559 are also being evaluated in the clinic and was recently granted Breakthrough Therapy designation by the FDA for treatment of inoperable or metastatic urothelial bladder cancer.

[00095] Other checkpoint antagonists include pidilizumab (maybe anti-PD-1 ), lirlumab (anti-KIR), ARGX-1 15 (anti-GARP), and IPH2101 (blocks HLA-C binding to KIR2D receptors).

Focal Adhesion Kinase Antagonists

Any antagonist of FAK activation/signaling may be used in the combinations and compositions of the invention. Several small molecule antagonists of FAK that are currently in development are provided in Table 1 .

TABLE 1

PF-562,271 was the first FAK antagonist to enter clinical testing. Antibodies specific to FAK and FAK-siRNA may also be used in the combinations and compositions of the invention. Other antagonists of FAK activation/signaling for use in the

combinations and compositions of the invention may include agents that inhibit PEA- 3, which has been determined to induce FAK expression necessary for cancer cell migration and metastasis. Shufeng eta al., PLoS ONE 8(1 1 ):e79336 (2013). Compositions

[00096] The invention also provides combinations comprising one or more CCR5 antagonists, one or more immune checkpoint antagonists, and/or one or more FAK antagonists formulated together or as separate dosage forms for administration to a patient suffering from cancer. In some embodiments, the cancer is a solid tumor. In some embodiments the cancer is a hematological cancer. In some embodiments, the one or more checkpoint antagonists are formulated together in a single dosage form for administration to a patient sequentially or substantially simultaneously with one or more CCR5 antagonists that are formulated together in a single dosage form. In some embodiments the checkpoint antagonists is

administered in a single composition with the CCR5 antagonist. In some

embodiments, the checkpoint and CCR5 antagonists are administered in separate dosage forms.

[00097] An protein antagonist, e.g., an antibody, a fusion protein, or a soluble receptor, will typically be formulated for parenteral administration. If the antagonist that is administered is a small molecule, it may be administered orally. The combination or compositions of the invention may be packaged together in a kit with instructions for sequential or substantially simultaneous administration.

[00098] In some exemplary embodiments, the CCR5 antagonist(s) and checkpoint antagonist(s) used in the combinations and compositions of the invention are selected from the following combinations in Table 2.

Table 2

CCR5 Antagonist Checkpoint Antagonist FAK Antagonist maraviroc anti-PD-L1 human or humanized

monoclonal antibody optionally

selected from durvalumab and

atezolizumab

maraviroc anti-CTLA-4 human or humanized

monoclonal antibody optionally

selected from tremelimumab and

ipilimumab

maraviroc anti-CTLA and anti PD-L1 human or

humanized antibodies- optionally

tremelimumab and durvalumab

maraviroc anti-CTLA and anti PD-1 human or

humanized antibodies- optionally

ipilimumab and nivolumab

maraviroc anti-PD-1 and anti- PD-L1 or PD-L2

human or humanized antibodies

optionally nivolumab and

durvalumab

maraviroc VS-6062 maraviroc VS-6063 maraviroc VS-4718 maraviroc GSK2256098 maraviroc Bl 853529 maraviroc CFAK-C4 maraviroc anti-PD-1 antibody, anti-PD-L1 VS-6062 and/or antibody, and/or anti-CTLA VS-6063 antibody

maraviroc anti-PD-1 antibody, anti-PD-L1 VS-4718 and/or antibody, and/or anti-CTLA GSK2256098 antibody

maraviroc anti-PD-1 antibody, anti-PD-L1 Bl 853529 and/or antibody, and/or anti-CTLA CFAK-C4 antibody

maraviroc anti-PD-1 and anti- PD-L1 or PD-L2 VS-6062 and/or antibodies VS-6063 and/or

VS-4718 and/or GSK2256098 and/or Bl 853529 and/or CFAK-C4 compound of anti-PD-1 human or humanized

Formula II or a monoclonal antibody optionally CCR5 Antagonist Checkpoint Antagonist FAK Antagonist pharmaceutically selected from nivolumab and

acceptable salt pembrolizumab

thereof

compound of anti-PD-L1 human or humanized

Formula II or a monoclonal antibody optionally

pharmaceutically selected from durvalumab and

acceptable salt atezolizumab

thereof

compound of anti-CTLA-4 human or humanized

Formula II or a monoclonal antibody optionally

pharmaceutically selected from tremelimumab and

acceptable salt ipilimumab

thereof compound of anti-CTLA and anti PD-L1 human or

Formula II or a humanized antibodies- optionally

pharmaceutically tremelimumab and durvalumab

acceptable salt

thereof

compound of anti-CTLA and anti PD-1 human or

Formula II or a humanized antibodies- optionally

pharmaceutically ipilimumab and nivolumab

acceptable salt

thereof compound of anti-PD-1 and anti- PD-L1 or PD-L2

Formula II or a human or humanized antibodies

pharmaceutically optionally nivolumab and

acceptable salt durvalumab

thereof

compound of VS-6062

Formula II or a

pharmaceutically

acceptable salt

thereof compound of VS-6063

Formula II or a

pharmaceutically

acceptable salt

thereof

compound of VS-4718

Formula II or a

pharmaceutically

acceptable salt

thereof

compound of GSK2256098 Formula II or a CCR5 Antagonist Checkpoint Antagonist FAK Antagonist pharmaceutically

acceptable salt

thereof

compound of Bl 853529 Formula II or a

pharmaceutically

acceptable salt

thereof

compound of CFAK-C4

Formula II or a

pharmaceutically

acceptable salt

thereof

compound of anti-PD-1 antibody, anti-PD-L1 VS-6062 and/or Formula II or a antibody, and/or anti-CTLA VS-6063 pharmaceutically antibody

acceptable salt

thereof

compound of anti-PD-1 antibody, anti-PD-L1 VS-4718 and/or Formula II or a antibody, and/or anti-CTLA GSK2256098 pharmaceutically antibody

acceptable salt

thereof

compound of anti-PD-1 antibody, anti-PD-L1 Bl 853529 and/or Formula II or a antibody, and/or anti-CTLA CFAK-C4 pharmaceutically antibody

acceptable salt

thereof

compound of anti-PD-1 and anti- PD-L1 or PD-L2 VS-6062 and/or Formula II or a antibodies VS-6063 and/or pharmaceutically VS-4718 and/or acceptable salt GSK2256098 thereof and/or Bl 853529 and/or CFAK-C4 compound 203 or anti-PD-1 human or humanized

a pharmaceutically monoclonal antibody optionally

acceptable salt selected from nivolumab and

thereof pembrolizumab compound 203 or anti-PD-L1 human or humanized

a pharmaceutically monoclonal antibody optionally

acceptable salt selected from durvalumab and

thereof atezolizumab

compound 203 or anti-CTLA-4 human or humanized

a pharmaceutically monoclonal antibody optionally

acceptable salt selected from tremelimumab and

ipilimumab CCR5 Antagonist Checkpoint Antagonist FAK Antagonist compound 203 or anti-CTLA and anti PD-L1 human or

a pharmaceutically humanized antibodies- optionally

acceptable salt tremelimumab and durvalumab

thereof

compound 203 or anti-CTLA and anti PD-1 human or

a pharmaceutically humanized antibodies- optionally

acceptable salt ipilimumab and nivolumab

thereof

compound 203 or anti-PD-1 and anti- PD-L1 or PD-L2

a pharmaceutically human or humanized antibodies

acceptable salt optionally nivolumab and

thereof durvalumab

compound 203 or VS-6062 a pharmaceutically

acceptable salt

thereof

compound 203 or VS-6063 a pharmaceutically

acceptable salt

compound 203 or VS-4718 a pharmaceutically

acceptable salt

thereof

compound 203 or GSK2256098 a pharmaceutically

acceptable salt

thereof

compound 203 or Bl 853529 a pharmaceutically

acceptable salt

thereof

compound 203 or CFAK-C4 a pharmaceutically

acceptable salt

thereof

compound 203 or anti-PD-1 antibody, anti-PD-L1 VS-6062 and/or a pharmaceutically antibody, and/or anti-CTLA VS-6063 acceptable salt antibody

compound 203 or anti-PD-1 antibody, anti-PD-L1 VS-4718 and/or a pharmaceutically antibody, and/or anti-CTLA GSK2256098 acceptable salt antibody

thereof compound 203 or anti-PD-1 antibody, anti-PD-L1 Bl 853529 and/or a pharmaceutically antibody, and/or anti-CTLA CFAK-C4 acceptable salt antibody

thereof CCR5 Antagonist Checkpoint Antagonist FAK Antagonist compound 203 or anti-PD-1 and anti- PD-L1 or PD-L2 VS-6062 and/or a pharmaceutically antibodies VS-6063 and/or acceptable salt VS-4718 and/or thereof GSK2256098 and/or Bl 853529 and/or CFAK-C4 vicriviroc anti-PD-1 human or humanized

monoclonal antibody optionally

selected from nivolumab and

pembrolizumab

vicriviroc anti-PD-L1 human or humanized

monoclonal antibody optionally

selected from durvalumab and

atezolizumab

vicriviroc anti-CTLA-4 human or humanized

monoclonal antibody optionally

selected from tremelimumab and

ipilimumab

vicriviroc anti-CTLA and anti PD-L1 human or

humanized antibodies- optionally

tremelimumab and durvalumab

vicriviroc anti-CTLA and anti PD-1 human or

humanized antibodies- optionally

ipilimumab and nivolumab vicriviroc anti-PD-1 and anti- PD-L1 or PD-L2

human or humanized antibodies

optionally nivolumab and

durvalumab

compound of anti-PD-1 human or humanized

Formula III monoclonal antibody optionally

optionally selected selected from nivolumab and

from compounds pembrolizumab

104 and 105 or a

pharmaceutically

acceptable salt

thereof

vicriviroc VS-6062 vicriviroc VS-6063 vicriviroc VS-4718 vicriviroc GSK2256098 vicriviroc Bl 853529 CCR5 Antagonist Checkpoint Antagonist FAK Antagonist vicriviroc CFAK-C4 vicriviroc anti-PD-1 antibody, anti-PD-L1 VS-6062 and/or antibody, and/or anti-CTLA VS-6063 antibody

vicriviroc anti-PD-1 antibody, anti-PD-L1 VS-4718 and/or antibody, and/or anti-CTLA GSK2256098 antibody

vicriviroc anti-PD-1 antibody, anti-PD-L1 Bl 853529 and/or antibody, and/or anti-CTLA CFAK-C4 antibody

vicriviroc anti-PD-1 and anti- PD-L1 or PD-L2 VS-6062 and/or antibodies VS-6063 and/or

VS-4718 and/or GSK2256098 and/or Bl 853529 and/or CFAK-C4 compound of anti-PD-L1 human or humanized

Formula III monoclonal antibody optionally

optionally selected selected from durvalumab and

from compounds atezolizumab

104 and 105 and

pharmaceutically

acceptable salts

thereof compound of anti-CTLA-4 human or humanized

Formula III monoclonal antibody optionally

optionally selected selected from tremelimumab and

from compounds ipilimumab

104 and 105 and

pharmaceutically

acceptable salts

thereof compound of anti-CTLA and anti PD-L1 human or

Formula III humanized antibodies- optionally

optionally selected tremelimumab and durvalumab

from compounds

104 and 105 and

pharmaceutically

acceptable salts

thereof

compound of anti-CTLA and anti PD-1 human or

Formula III humanized antibodies- optionally

optionally selected ipilimumab and nivolumab

from compounds

104 and 105 and CCR5 Antagonist Checkpoint Antagonist FAK Antagonist pharmaceutically

acceptable salts

thereof

compound of anti-PD-1 and anti- PD-L1 or PD-L2

Formula III human or humanized antibodies

optionally selected optionally nivolumab and

from compounds durvalumab

104 and 105 and

pharmaceutically

acceptable salts

thereof compound of VS-6062

Formula III

optionally selected

from compounds

104 and 105 and

pharmaceutically

acceptable salts

thereof compound of VS-6063

Formula III

optionally selected

from compounds

104 and 105 and

pharmaceutically

acceptable salts

thereof compound of VS-4718

Formula III

optionally selected

from compounds

104 and 105 and

pharmaceutically

acceptable salts

thereof

compound of GSK2256098 Formula III

optionally selected

from compounds

104 and 105 and

pharmaceutically

acceptable salts

thereof CCR5 Antagonist Checkpoint Antagonist FAK Antagonist

75 compound of Bl 853529

Formula III

optionally selected

from compounds

104 and 105 and

pharmaceutically

acceptable salts

thereof

76 compound of CFAK-C4

Formula III

optionally selected

from compounds

104 and 105 and

pharmaceutically

acceptable salts

thereof

77 compound of anti-PD-1 antibody, anti-PD-L1 VS-6062 and/or Formula III antibody, and/or anti-CTLA VS-6063 optionally selected antibody

from compounds

104 and 105 and

pharmaceutically

acceptable salts

thereof

78 compound of anti-PD-1 antibody, anti-PD-L1 VS-4718 and/or Formula III antibody, and/or anti-CTLA GSK2256098 optionally selected antibody

from compounds

104 and 105 and

pharmaceutically

acceptable salts

thereof

79 compound of anti-PD-1 antibody, anti-PD-L1 Bl 853529 and/or Formula III antibody, and/or anti-CTLA CFAK-C4 optionally selected antibody

from compounds

104 and 105 and

pharmaceutically

acceptable salts

thereof

80 compound of anti-PD-1 and anti- PD-L1 or PD-L2 VS-6062 and/or Formula III antibodies VS-6063 and/or optionally selected VS-4718 and/or CCR5 Antagonist Checkpoint Antagonist FAK Antagonist from compounds GSK2256098 104 and 105 and and/or Bl 853529 pharmaceutically and/or CFAK-C4 acceptable salts

thereof

81 anti-CCR5 human anti-PD-1 human or humanized

or humanized monoclonal antibody optionally

monoclonal selected from nivolumab and

antibody pembrolizumab

82 anti-CCR5 human anti-PD-L1 human or humanized

or humanized monoclonal antibody optionally

monoclonal selected from durvalumab and

antibody atezolizumab

83 anti-CCR5 human anti-CTLA-4 human or humanized

or humanized monoclonal antibody optionally

monoclonal selected from tremelimumab and

antibody ipilimumab

84 anti-CCR5 human anti-CTLA and anti PD-L1 human or

or humanized humanized antibodies- optionally

monoclonal tremelimumab and durvalumab

antibody

85 anti-CCR5 human anti-CTLA and anti PD-1 human or

or humanized humanized antibodies- optionally

monoclonal ipilimumab and nivolumab

antibody

86 anti-CCR5 human anti-PD-1 and anti- PD-L1 or PD-L2

or humanized human or humanized antibodies

monoclonal optionally nivolumab and

antibody durvalumab

87 anti-CCR5 human VS-6062

or humanized

monoclonal

antibody

88 anti-CCR5 human VS-6063

or humanized

monoclonal

antibody

89 anti-CCR5 human VS-4718

or humanized CCR5 Antagonist Checkpoint Antagonist FAK Antagonist monoclonal

antibody

90 anti-CCR5 human GSK2256098

or humanized

monoclonal

antibody

91 anti-CCR5 human Bl 853529

or humanized

monoclonal

antibody

92 anti-CCR5 human CFAK-C4

or humanized

monoclonal

antibody

93 anti-CCR5 human anti-PD-1 antibody, anti-PD-L1 VS-6062 and/or or humanized antibody, and/or anti-CTLA VS-6063

monoclonal antibody

antibody

94 anti-CCR5 human anti-PD-1 antibody, anti-PD-L1 VS-4718 and/or or humanized antibody, and/or anti-CTLA GSK2256098 monoclonal antibody

antibody

95 anti-CCR5 human anti-PD-1 antibody, anti-PD-L1 Bl 853529 and/or or humanized antibody, and/or anti-CTLA CFAK-C4

monoclonal antibody

antibody

96 anti-CCR5 human anti-PD-1 and anti- PD-L1 or PD-L2 VS-6062 and/or or humanized antibodies VS-6063 and/or monoclonal VS-4718 and/or antibody GSK2256098

and/or Bl 853529 and/or CFAK-C4

[00099] A composition of this invention is formulated for pharmaceutical use with a pharmaceutically acceptable carrier. The carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament. [000100] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose,

polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[000101] If required, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art. One method includes the use of lipid excipients in the formulation. See "Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences)," David J. Hauss, ed. Informa Healthcare, 2007; and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples," Kishor M. Wasan, ed. Wiley-lnterscience, 2006.

[000102] Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROLTM and PLURONICTM (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent 7,014,866; and United States patent publications 20060094744 and 20060079502. [000103] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermal^ (e.g. , using a transdermal patch or iontophoretic techniques). Other formulations may conveniently be presented in unit dosage form, e.g. , tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).

[000104] Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[000105] In certain embodiments, the CCR5 antagonist is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. [000106] In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and

suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

[000107] Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[000108] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile

suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[000109] Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[000110] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These

compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and

polyethylene glycols.

[000111] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g.: Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031 , assigned to Alexza Molecular Delivery Corporation.

[000112] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.

Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.

[000113] Application of the subject therapeutics may be local, so as to be administered at the site of interest. Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.

[000114] Thus, according to yet another embodiment, the compounds of this invention may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in US Patents 6,099,562;

5,886,026; and 5,304, 121 . The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of

fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.

[000115] According to another embodiment, the invention provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.

[000116] According to another embodiment, the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention. Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.

[000117] According to another embodiment, the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active. [000118] According to another embodiment, the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.

[000119] Where an organ or tissue is accessible because of removal from the patient, such organ or tissue may be bathed in a medium containing a

composition of this invention, a composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.

[000120] In another embodiment, a composition or compositions of the invention further comprises a therapeutic agent in addition to the CCR5 and checkpoint antagonists. The therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a checkpoint or CCR5 antagonists. Preferably, the therapeutic agent is an agent useful in the treatment of cancer or that boosts the immune system.

[000121] In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term "effective amount" refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat (therapeutically or prophylactically) the target disorder. For example, an effective amount can be an amount which is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy. [000122] The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich et al. , (1966) Cancer Chemother. Rep 50: 219. Body surface area may be approximately determined from height and weight of the patient. See, e.g. , Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y. , 1970, 537. Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the patient, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. In some embodiments, the appropriate dosage of an antibody for us in the combinations and methods of the invention will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician.

[000123] In some embodiments, an antibody composition for use in the combinations or methods of the invention is administered in one or more separate administrations. In other embodiments, the antibody is administered by continuous infusion. One typical daily dosage of an antibody might range from about 0.1 -100 mg/kg or more, depending on the factors mentioned above. For repeated

administrations over several days or longer, depending on the condition, the treatment would generally be sustained until a desired suppression of disease symptoms occurs. One exemplary dosage of the antibody would be in the range from about 0.05 mg/kg to about 20 mg/kg. Thus, one or more doses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, 10 mg/kg, 12 mg/kg, 15 mg/kg, or 20 mg/kg (or any combination thereof) may be administered to the patient. Such doses may be administered intermittently, e.g. every week, every two weeks, or every three weeks (e.g. such that the patient receives from about two to about twenty, or e.g. about six doses of the antibody). An initial higher loading dose, followed by one or more lower doses may be administered. An exemplary dosing regimen comprises administering an initial loading dose of about 4 mg/kg, followed by a weekly maintenance dose of about 2 mg/kg of the antibody. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.

[000124] In some embodiments, an effective amount of a FAK antagonist can range from 20 - 600 mg/day orally and may be administered daily, twice daily, weekly, bi-weekly, or triweekly. In some embodiments, the effective amount is 100- 300 mg daily. In some embodiments, the oral dosage amount administered is 125 mg twice twice a day.

[000125] In some embodiments, an effective amount of an antibody antagonist to CCR5 can range from 0.4-40 mg/kg and may be administered weeky, biweekly, or triweekly. In some embodiments, an effective amount of an antibody antagonist to an immune checkpoint protein can range from 0.1 -30.0 mg/kg and may be administered weekly, biweekly, or triweekly. An effective amount of a CCR5 small molecule antagonist can range from about 0.001 mg/kg to about 300 mg/kg, more preferably 0.01 mg/kg to about 30 mg/kg, more preferably 0.01 mg/kg to about 15 mg/kg. Alternatively, a CCR5 small molecule antagonist, such as maraviroc, vicriviroc, or a compound of Formula 1 , Formula II, or Formula III may be

admininstered in 20-600 mg doses once or twice daily. In some embodiments, the CCR5 antagonist used in the compositions and/or combinations of the invention is 30 mg of vicriviroc, compound 104, or compound 105. [000126] For pharmaceutical compositions that comprise a therapeutic agent in addition to the CCR5 antagonist(s) and checkpoint antagonist(s), an effective amount of the therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent. Preferably, an effective amount is between about 70% and 100% of the normal monotherapeutic dose. The normal monotherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g. , Wells et al. , eds. , Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety.

Methods of Treatment

[000127] In another embodiment, the invention provides a method of inducing an immune response to diseases, such as cancer and treating cancer with a combination of agents comprising at least one CCR5 antagonist and at least one checkpoint antagonist. The agents may be administered sequentially or substantially simultaneously to effectively initiate, enable, increase, enhance, or prolong the activity and/or number of immune cells, or beneficial response to a tumor.

[000128] In some embodiments, the subject to be treated has an elevated level of CCR5 expression on Tregs as compared to a cancer free subject. In some embodiments, the subject has an elevated number of regulatory T-cells in circulation as compared to a cancer free subject. In some embodiments, the subject to be treated has an elevated level of CCL5 expression as compared to a cancer free subject. In some embodiments, the subject to be treated is suffering from pancreatic cancer, colorectal cancer or breast cancer. In some embodiments, the subject to be treated is suffering from melanoma, renal carcinoma, non-small cell lung cancer, or urothelial cancer.

[000129] Accordingly, other embodiments of the invention provide methods of treating a cancer selected from pancreatic cancer, colorectal cancer, breast cancer, melanoma, renal carcinoma, non-small cell lung cancer, or urothelial cancer with a combination or composition(s) of the invention. Some embodiments of the invention provide a method for treating a cancer selected from prostate, head and neck, esophageal, gastric, laryngeal, lung, ovarian, thyroid, endometrial, cervical, breast, or colorectal cancer. Other aspects of the invention provide methods of manufacturing a medicament comprising the combination or

compositions of the invention for treatment of a cancer selected from pancreatic cancer, colorectal cancer, breast cancer, melanoma, renal carcinoma, non-small cell lung cancer, or urothelial cancer, prostate cancer, head and neck cancer,

esophageal cancer, gastric cancer, laryngeal cancer, lung cancer, ovarian cancer, thyroid cancer, endometrial cancer, and cervical cancer. In still other embodiments, the cancer to be treated with the methods or compositions/combinations of the invention is selected from glial blastoma breast cancer, lung cancer, colon cancer, ovarian cancer, malignant pleural mesothelioma, squamous cell carcinoma, and glioma.

[000130] Methods delineated herein also include those wherein the patient is identified as in need of a particular stated treatment. Identifying a patient in need of such treatment can be in the judgment of a patient or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method). [000131] In another embodiment, any of the above methods of treatment comprises the further step of co-administering to the patient one or more additional therapeutic agents. The choice of additional therapeutic agents may be made from any therapeutic agent known to be useful for stimulating the immune system and/or treating cancer. The choice of additional therapeutic agent(s) is also dependent upon the particular disease or condition to be treated.

[000132] The term "co-administered" as used herein means that the second additional agent(s) may be administered together with a combination or composition(s) of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms.

Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a combination or composition(s) of this invention. The combination or composition(s) of this invention with or without any additional therapeutic agent(s) are administered by conventional methods. The administration of a combination or composition(s) of this invention and an additional therapeutic agent to a patient does not preclude the separate administration of that same therapeutic agent, any other additional therapeutic agent or any composition of this invention to said patient at another time during a course of treatment.

[000133] Effective amounts of the additional second therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is well within the skilled artisan's purview to determine the additional therapeutic agent's optimal effective-amount range.

[000134] In one embodiment of the invention, where an additional therapeutic agent is administered to a subject, the effective amount of the

combination or composition(s) of this invention is less than its effective amount would be where the additional therapeutic agent is not administered. In another embodiment, the effective amount of the additional therapeutic agent is less than its effective amount would be where the combination or composition(s) of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.