COMBINATION THERAPIES

• US 20170209574A1
• Filed: 10/02/2015
• Published: 07/27/2017
• Est. Priority Date: 10/03/2014
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Cao, Zhu Alexander, Rong, Xianhui, Pinzon-Ortiz, Maria Consuelo, Longmire, Tyler, Lee, Benjamin Hyun
• Application Number:
  US15/515,469
• Publication Number:
  US 20170209574A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 39/39541 against normal tissues, cells
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/3015 Breast
• CPC Class Codes: C07K 16/3023 : Lung
• CPC Class Codes: C07K 16/303 : Liver or Pancreas
• CPC Class Codes: C07K 16/3038 : Kidney, bladder
• CPC Class Codes: C07K 16/3046 : Stomach, Intestines
• CPC Class Codes: C07K 16/3053 : Skin, nerves, brain
• CPC Class Codes: C07K 16/3069 : Reproductive system, e.g. ovaria, uterus, testes, prostate
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/52 : Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: G01N 33/574 : for cancer

Abstract

Combination therapies are disclosed. The combination therapies can be used to treat or prevent cancerous conditions and/or disorders. The combination may comprise an immunomodulator and a second therapeutic agent, wherein: (i) the immunomodulator is an inhibitor of an immune checkpoint molecule chosen from the list of inhibitors of one or more of PD-1, PD L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR beta, or the immunomodulator is an activator of a costimulatory molecule chosen from the list of agonists of one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand, and wherein (ii) the second therapeutic agent is chosen from one or more compounds as provided in Table 1, i.e. LCL 161, Rad-001 (Evrolimus), CGM097, LGH-447, LJM716 (Human monoclonal antibody), LB-H589 (Panobinostat), INC424 (Ruxolitinib), BUW078 or BGJ398.

Claims

1. A combination comprising an immunomodulator and a second therapeutic agent for use in treating a cancer in a subject, wherein:

(i) the immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a costimulatory molecule, or a combination thereof,

wherein the inhibitor of an immune checkpoint molecule is chosen from an inhibitor of one or more of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR beta, and

wherein the activator of the costimulatory molecule is chosen from an agonist of one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand; and

(ii) the second therapeutic agent is chosen from one or more of;

     1) an IAP inhibitor;

     2) a TOR kinase inhibitor;

     3) a HDM2 ligase inhibitor;

     4) a PIM kinase inhibitor;

     5) a HER3 kinase inhibitor;

     6) a Histone Deacetylase (HDAC) inhibitor;

     7) a Janus kinase inhibitor;

or

     8) an FGF receptor inhibitor, as provided in Table 1.

6. The use of claim 1 or 2, or the method of any of claims 3-5, wherein the inhibitor of the immune checkpoint molecule is chosen from one or more of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, or any combination thereof.

7. The use of any of claim 1-2 or 6, or the method of any of claims 3-6, wherein the agonist of the costimulatory molecule is chosen from an agonist of one or more of OX40, ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.

8. The use of any of claim 1-2 or 6-7, or the method of any of claims 3-7, wherein the combination of the immunomodulator and the second therapeutic agent is administered together in a single composition or administered separately in two or more different compositions or dosage forms.

9. The use of any of claim 1-2 or 6-8, or the method of any of claims 3-8, wherein the combination of the immunomodulator and the second agent is administered or contacted concurrently with, prior to, or subsequent to, the second agent.

10. The use of any of claim 1-2 or 6-9, or the method of any of claims 8-9, wherein the inhibitor of the immune checkpoint molecule is a soluble ligand or an antibody or antigen-binding fragment thereof, that binds to the immune checkpoint molecule.

11. The use or method of claim 10, wherein the antibody or antigen-binding fragment comprises a constant region from a human IgG1 or IgG4, or an altered form thereof.

12. The use or method of claim 11, wherein the altered constant region is mutated to increase or decrease one or more of:

Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function.

13. The use of method of claim 10, wherein the antibody molecule is a bispecific or multispecific antibody molecule that has a first binding specificity to PD-1 or PD-L1 and a second binding specificity to TIM-3, LAG-3, or PD-L2.

14. The use of any of claim 1-2 or 6-13, or the method of any of claims 3-13, wherein the immunomodulator is an anti-PD-1 antibody chosen from Nivolumab, Pembrolizumab or Pidilizumab.

15. The use of any of claim 1-2 or 6-13, or the method of any of claims 3-13, wherein the immunomodulator is an anti-PD-L1 antibody chosen from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.

16. The use of any of claim 1-2 or 6-13, or the method of any of claims 3-13, wherein the immunomodulator is an anti-LAG-3 antibody molecule.

17. The use or method of claim 16, wherein the anti-LAG-3 antibody molecule is BMS-986016.

18. The use of any of claim 1-2 or 6-13, or the method of any of claims 3-13, wherein the immunomodulator is an anti-PD-1 antibody comprising the heavy chain amino acid sequence of SEQ ID NO:

2 and the light chain amino acid sequence of SEQ ID NO;

3;

or the heavy chain amino acid sequence of SEQ ID NO;

4 and the light chain amino acid sequence of SEQ ID NO;

5.

19. The use of any of claim 1-2 or 6-13, or the method of any of claims 3-13, wherein the immunomodulator is the anti-PD-L1 antibody comprising the heavy chain variable amino acid sequence of SEQ ID NO:

6 and the light chain variable amino acid sequence of SEQ ID NO;

7.

20. The use of any of claim 1-2 or 6-13, or the method of any of claims 3-13, wherein the immunomodulator is a TIM-3 inhibitor.

21. The use or method of claim 20, wherein the TIM-3 inhibitor is an antibody molecule to TIM-3.

22. The use of any of claim 1-2 or 6-21, or the method of any of claims 3-21, wherein the cancer is a solid tumor, or a soft tissue tumor chosen from a hematological cancer, leukemia, lymphoma, or myeloma, or a metastatic lesion of any of the aforesaid cancers.

23. The use of any of claim 1-2 or 6-21, or the method of any of claims 3-21, wherein the cancer is a solid tumor from the lung, breast, ovarian, lymphoid, gastrointestinal (e.g., colon), anal, genitals and genitourinary tract (e.g., renal, urothelial, bladder cells, prostate), pharynx, CNS (e.g., brain, neural or glial cells), head and neck, skin (e.g., melanoma), pancreas, colon, rectum, renal-cell carcinoma, liver, lung, non-small cell lung cancer, small intestine or the esophagus.

24. The use of any of claim 1-2 or 6-21, or the method of any of claims 3-21, wherein the cancer is a hematological cancer chosen from a Hogdkin lymphoma, a non-Hodgkin lymphoma, a lymphocytic leukemia, or a myeloid leukemia.

25. The use of any of claim 1-2 or 6-21, or the method of any of claims 3-21, wherein the cancer is chosen from a cancer disclosed in Table 1.

26. The use of any of claim 1-2 or 6-25, or the method of any of claims 3-25, wherein the subject is a human (e.g., a patient having, or at risk of having, a cancer).

27. The use of any of claim 1-2 or 6-26, or the method of any of claims 3-26, wherein the immunomodulator is an anti-PD-1 antibody molecule administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about 3 mg/kg, e.g., once a week to once every 2, 3, or 4 weeks.

28. The use or method of claim 27, wherein the anti-PD-1 antibody molecule is administered at a dose from about 1 to 20 mg/kg every other week.

29. The use or method of claim 26, wherein the anti-PD-1 antibody molecule, e.g., Nivolumab, is administered intravenously at a dose from about 1 mg/kg to 3 mg/kg, e.g., about 1 mg/kg, 2 mg/kg or 3 mg/kg, every two weeks.

30. The use or method of claim 26, wherein the anti-PD-1 antibody molecule, e.g., Nivolumab, is administered intravenously at a dose of about 2 mg/kg at 3-week intervals.

31. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with an IAP inhibitor.

32. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with LCL161 to treat a cancer or disorder described in Table 1, e.g., a solid tumor, e.g., a breast cancer, a colon cancer, or a pancreatic cancer;

or a hematological malignancy, e.g., multiple myeloma or a hematopoeisis disorder, wherein LCL161 is (S)—

N—

((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide.

33. The use or method of claim 32, wherein LCL161 is administered at an oral dose of about 10-3000 mg, e.g., about 20-2400 mg, about 50-1800 mg, about 100-1500 mg, about 200-1200 mg, about 300-900 mg, e.g., about 600 mg, about 900 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, or about 2400 mg. In an embodiment, LCL161 is administered once a week or once every two weeks.

34. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with a TOR kinase inhibitor.

35. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with Rad-001 to treat a cancer or disorder described in Table 1, e.g., a solid tumor, e.g., a sarcoma, a lung cancer (e.g., a non-small cell lung cancer (NSCLC) (e.g., a NSCLC with squamous and/or non-squamous histology)), a melanoma (e.g., an advanced melanoma), a digestive/gastrointestinal cancer, a gastric cancer, a neurologic cancer, a prostate cancer, a bladder cancer, a breast cancer;

or a hematological malignancy, e.g., a lymphoma or leukemia, wherein Rad-001 is ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R)-1,18-dihydroxy-12-{(1R)-2-[(1S, 3R, 4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone).

36. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with an HDM2 ligase inhibitor.

37. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with CGM097 to treat a cancer or disorder described in Table 1, e.g., a solid tumor, wherein CGM097 is (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}phenyl)-1,4-dihydro-2H-isoquinolin-3one.

38. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with a PIM kinase inhibitor.

39. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with LGH447 to treat a cancer or disorder described in Table 1, e.g., hematological malignancy, e.g., multiple myeloma, myelodysplastic syndrome, myeloid leukemia, or non-Hodgkin lymphoma, wherein LGH447 is N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridine-3-yl)-6-(2,6-difluorophenyl)-3-fluoropicolinamide.

40. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with a HER3 kinase inhibitor.

41. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with a LJM716 to treat a cancer or disorder described in Table 1, e.g., a solid tumor, e.g. a gastric cancer, an esophageal cancer, a breast cancer, a head and neck cancer, a stomach cancer, or a digestive/gastrointestinal cancer therapy, wherein LJM716 is an anti-HER3 monoclonal antibody or antigen binding fragment thereof, that comprises a VH of SEQ ID NO:

141 and VL of SEQ ID NO;

140, as described in U.S. Pat. No. 8,735,551.

42. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with an HDAC inhibitor.

43. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with LBH589 to treat a cancer or disorder described in Table 1, e.g., a solid tumor, e.g., a bone cancer, a small cell lung cancer, a respiratory/thoracic cancer a prostate cancer, a non-small cell lung cancer (NSCLC), a nerologic cancer, a gastric cancer, a melanoma, a breast cancer, a pancreatic cancer, a colorectal cancer, a renal cancer, or a head and neck cancer, or a liver cancer;

or a hematological malignancy, e.g., multiple myeloma, a hematopoeisis disorder, myelodysplastic syndrome, lymphoma (e.g., non-Hodgkin lymphoma), or leukemia (e.g., myeloid leukemia), wherein LBH589 is (E)-N-hydroxy-3-(4-(((2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylamide.

44. The use of any of claim 1-2 or 6-30, or the method of any of claims 23-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with a Janus kinase inhibitor.

45. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with INC424 to treat a cancer or disorder described in Table 1, e.g., a solid tumor, e.g., a prostate cancer, a lung cancer, a breast cancer, a pancreatic cancer, a colorectal cancer;

or a hematological malignancy, e.g., multiple myeloma, lymphoma (e.g., non-Hodgkin lymphoma), or leukemia (e.g., myeloid leukemia, lymphocytic leukemia), wherein INC424 is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile.

46. The use or method of claim 45, wherein the cancer has, or is identified as having, a JAK mutation, e.g., a JAK2 V617F mutation.

47. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with an FGF receptor inhibitor.

48. The use of any of claim 1-2 or 6-30, or the method of any of claims 3-30, wherein the immunomodulator is Nivolumab, Pembrolizumab, or MSB0010718C used in combination with BUW078 to treat a cancer described in Table 1, e.g., a solid tumor, e.g., a digestive/gastrointestinal cancer;

or a hematological cancer, wherein BUW078 is 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl)-amide.

2. A combination comprising an immunomodulator and a second therapeutic agent for use in treating a cancer in a subject, wherein:

(i) the immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a costimulatory molecule, or a combination thereof,

wherein the inhibitor of an immune checkpoint molecule is chosen from an inhibitor of one or more of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR beta, and

wherein the activator of the costimulatory molecule is chosen from an agonist of one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand; and

(ii) the second therapeutic agent is chosen from one or more of;

1) (S)—

N—

((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide;

2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R)-1,18-dihydroxy-12-{(1R)-2-[(1S, 3R, 4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);

3) (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}phenyl)-1,4-dihydro-2H-isoquinolin-3one;

4)N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide;

5) anti-HER3 monoclonal antibody or antigen binding fragment thereof, that comprises a VH of SEQ ID NO;

141 and VL of SEQ ID NO;

140, as described in U.S. Pat. No. 8,735,551;

6) (E)-N-hydroxy-3-(4-(((2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylamide;

7) (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile; and

/or

8) 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl)-amide.

3. A method of treating a cancer in a subject, comprising administering to the subject an immunomodulator and a second therapeutic agent, wherein:

(i) the immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a costimulatory molecule, or a combination thereof

wherein the inhibitor of an immune checkpoint molecule is chosen from an inhibitor of one or more of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR beta, and

wherein the activator of the costimulatory molecule is chosen from an agonist of one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand; and

(ii) the second therapeutic agent is chosen from one or more of

     1) an IAP inhibitor;

     2) a TOR kinase inhibitor;

     3) a HDM2 ligase inhibitor;

     4) a PIM kinase inhibitor;

     5) a HER3 kinase inhibitor;

     6) a Histone Deacetylase (HDAC) inhibitor;

     7) a Janus kinase inhibitor;

or

     8) an FGF receptor inhibitor, as provided in Table 1,

thereby treating the cancer.

4. A method of treating a cancer in a subject, comprising administering to the subject an immunomodulator and a second therapeutic agent, wherein:

(i) the immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a costimulatory molecule, or a combination thereof

wherein the inhibitor of an immune checkpoint molecule is chosen from an inhibitor of one or more of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR beta, and

wherein the activator of the costimulatory molecule is chosen from an agonist of one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand; and

(ii) the second therapeutic agent is chosen from one or more of;

1) (S)—

N—

((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide;

2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R)-1,18-dihydroxy-12-{(1R)-2-[(1S, 3R, 4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);

3) (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}phenyl)-1,4-dihydro-2H-isoquinolin-3one;

4)N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide;

5) anti-HER3 monoclonal antibody or antigen binding fragment thereof, that comprises a VH of SEQ ID NO;

141 and VL of SEQ ID NO;

140, as described in U.S. Pat. No. 8,735,551;

6) (E)-N-hydroxy-3-(4-(((2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylamide;

7) (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile; and

/or

8) 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl)-amide,

thereby treating the cancer.

5. A method of reducing growth, survival, or viability, or all, of a cancer cell, comprising contacting the cell with an immunomodulator and a second therapeutic agent, wherein:

(i) the immunomodulator is an inhibitor of an immune checkpoint molecule or an activator of a costimulatory molecule, or a combination thereof,

wherein the inhibitor of an immune checkpoint molecule is chosen from an inhibitor of one or more of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR beta, and

wherein the activator of the costimulatory molecule is chosen from an agonist of one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand; and

(ii) the second therapeutic agent is chosen from one or more of

     1) an IAP inhibitor;

     2) a TOR kinase inhibitor;

     3) a HDM2 ligase inhibitor;

     4) a PIM kinase inhibitor;

     5) a HER3 kinase inhibitor;

     6) a Histone Deacetylase (HDAC) inhibitor;

     7) a Janus kinase inhibitor;

or

     8) an FGF receptor inhibitor, as provided in Table 1,

thereby reducing the growth, survival, or viability of the cancer cell.

49. A combination comprising an anti-PD-1 antibody or an anti-TIM-3 antibody and a second therapeutic agent for use in treating a cancer in a subject, wherein:

(i) the PD-1 inhibitor is chosen from Nivolumab, Pembrolizumab, or Pidilizumab; and

(ii) the second therapeutic agent is chosen from one or more of;

1) (S)—

N—

((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide;

2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R)-1,18-dihydroxy-12-{(1R)-2-[(1S, 3R, 4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);

3) (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}phenyl)-1,4-dihydro-2H-isoquinolin-3one;

4)N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide;

5) anti-HER3 monoclonal antibody or antigen binding fragment thereof, that comprises a VH of SEQ ID NO;

141 and VL of SEQ ID NO;

140, as described in U.S. Pat. No. 8,735,551;

6) (E)-N-hydroxy-3-(4-(((2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylamide;

7) (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile; and

/or

8) 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl)-amide.

50. A method of treating a cancer in a subject, comprising administering to the subject an anti-PD-1 antibody or an anti-TIM-3 antibody and a second therapeutic agent, wherein:

(i) the PD-1 inhibitor is chosen from Nivolumab, Pembrolizumab, or Pidilizumab; and

(ii) the second therapeutic agent is chosen from one or more of;

1) (S)—

N—

((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide;

2) ((1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R)-1,18-dihydroxy-12-{(1R)-2-[(1S, 3R, 4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone);

3) (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}phenyl)-1,4-dihydro-2H-isoquinolin-3one;

4)N-(4-((1R,3S,55)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide;

5) anti-HER3 monoclonal antibody or antigen binding fragment thereof, that comprises a VH of SEQ ID NO;

141 and VL of SEQ ID NO;

140, as described in U.S. Pat. No. 8,735,551;

6) (E)-N-hydroxy-3-(4-(((2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylamide;

7) (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile; and

/or

8) 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (4-dimethylaminomethyl-1H-imidazol-2-yl)-amide,

thereby treating the cancer.

51. A composition (e.g., one or more compositions or dosage forms), comprising an immunomodulator (e.g., one or more of:

an activator of a costimulatory molecule or an inhibitor of an immune checkpoint molecule) and a second therapeutic agent, e.g., a second therapeutic agent chosen from one or more of

     1) an IAP inhibitor;

     2) a TOR kinase inhibitor;

     3) a HDM2 ligase inhibitor;

     4) a PIM kinase inhibitor;

     5) a HER3 kinase inhibitor;

     6) a Histone Deacetylase (HDAC) inhibitor;

     7) a Janus kinase inhibitor;

or

     8) an FGF receptor inhibitor, as provided in Table 1.