SURVIVAL BENEFIT IN PATIENTS WITH SOLID TUMORS WITH ELEVATED C-REACTIVE PROTEIN LEVELS

• US 20150065447A1
• Filed: 08/19/2014
• Published: 03/05/2015
• Est. Priority Date: 08/20/2013
• Status: Abandoned Application

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation
• Inventors: Sandor, Victor
• Application Number:
  US14/463,232
• Publication Number:
  US 20150065447A1
• Time in Patent Office: Days
• US Class Current: 514/49
• 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 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/14 Ortho-condensed systems
• CPC Class Codes: G01N 2333/4737 C-reactive protein
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/57496 involving intracellular compounds

Abstract

This application relates to methods of increasing survival or progression-free survival in a patient with a solid tumor, wherein the patient has an elevated serum concentration of C-reactive protein (CRP), by administering a JAK inhibitor or an inhibitor of IL-6 signaling to the patient, as well as methods of predicting survival benefit in these patients from such therapy.

Claims

1. A method of increasing survival or progression-free survival in a patient that has a solid tumor, wherein the patient has elevated serum concentrations of C-reactive protein (CRP), comprising administering a JAK inhibitor or an inhibitor of IL-6 signaling to the patient, wherein the administering increases survival or progression-free survival of the patient.

2. The method of claim 1, wherein the method further comprises selecting a patient with an elevated serum concentration of C-reactive protein prior to said administering.

3. The method of claim 1, wherein the method further comprises

selecting a patient having the solid tumor with a serum concentration of C-reactive protein (CRP) that is equal to or greater than a median baseline serum concentration of CRP for a population of patients with the solid tumor.

4. The method of claim 1, wherein the method further comprises

selecting a patient having the solid tumor with a serum concentration of C-reactive protein (CRP) that is equal to or greater than about 10 μ

g/mL.

7. The method of claim 1, wherein the serum concentration of CRP is equal to or greater than about 13 μ

g/mL.

9. The method of claim 1, wherein the method further comprises

selecting a patient having the solid tumor with a modified Glasgow Prognostic Score of 1 or 2.

5-6. -6. (canceled)

8. A method of treating a solid tumor or diffuse large B-cell lymphoma in a patient in need thereof, wherein the patient modified Glasgow Prognostic Score (mGPS) of 1 or 2, comprising administering a Janus Kinase (JAK) inhibitor or an inhibitor of IL-6 signaling to the patient.

10. The method of claim 8, wherein the method is a method of treating a solid tumor.

11. The method of claim 8, wherein the method is a method of treating diffuse large B-cell lymphoma.

12. The method of claim 10, wherein the solid tumor is prostate cancer, renal cancer, hepatic cancer, colon cancer, rectal cancer, renal cancer, colorectal cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi'"'"'s sarcoma, melanoma, oesophageal cancer, gastro-oesophageal cancer, cervical cancer, hepatocellular carcinoma, endometrial cancer, urothelial cancer, or ovarian cancer.

13. The method of claim 10, wherein the solid tumor is prostate cancer, pancreatic cancer, gastric cancer, colon cancer, or lung cancer.

14. The method of claim 10, wherein the solid tumor is pancreatic cancer.

15. The method of claim 10, wherein the solid tumor is endometrial cancer.

16. The method of claim 10, wherein the solid tumor is the solid tumor is non-small cell lung cancer.

17. The method of claim 10, wherein the method comprises administering a JAK inhibitor to the patient.

18. The method of claim 10, wherein the method comprises administering an inhibitor of IL-6 signaling to the patient.

19. The method of claim 10, wherein the JAK inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof.

20. The method of claim 10, wherein the method comprises administering from about 15 mg to about 25 mg BID on a free base basis of ruxolitinib, or pharmaceutically acceptable salt thereof, to the patient.

21. The method of claim 10, wherein the method further comprises administering to the patient one or more additional chemotherapeutic agents.

22. The method of claim 21, wherein the one or more chemotherapeutic agents are selected from antimetabolite agents, topoisomerase 1 inhibitors, platinum analogs, taxanes, and anthracyclines, EGFR inhibitors, and combinations thereof.

23. The method of claim 21, wherein the one or more additional chemotherapeutic agents are selected from capecitabine, gemcitabine, Abraxane®

(paclitaxel protein-bound particles for injectable suspension), docetaxel, fluorouracil (5-FU), oxaliplatin, cisplatin, carboplatin, irinotecan, topotecan, paclitaxel, leucovorin, doxorubicin, and combinations thereof.

24. The method of claim 21, wherein the one or more additional chemotherapeutic agents is capecitabine.

48. The method of claim 10, wherein the JAK inhibitor is a selective JAK1 inhibitor.

49. The method of claim 48, wherein said selective JAK1 inhibitor is selected from:

3-[1-(6-chloropyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-(1-[1,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

4-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl)carbonyl]-3-fluorobenzonitrile;

4-[(4-{3-cyano-2-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propyl}piperazin-1-yl)carbonyl]-3-fluorobenzonitrile;

{1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide;

[3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile;

[trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile;

{trans-3-(4-{[4-[(3-hydroxyazetidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

4-(4-{3-[(dimethylamino)methyl]-5-fluorophenoxy}piperidin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

5-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide;

4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

5-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide;

{1-(cis-4-{[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{trans-3-(4-{[4-({[(1S)-2-hydroxy-1-methylethyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-({[(2R)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-({[(2S)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile; and

4-[3-(cyanomethyl)-3-(3′

,5′

-dimethyl-1H,1′

H-4,4′

-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

or a pharmaceutically acceptable salt of any of the aforementioned.

50. The method of claim 48, wherein the selective JAK1 inhibitor is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.

51. The method of claim 48, wherein the selective JAK1 inhibitor is 4-[3-(cyanomethyl)-3-(3′

,5′

-dimethyl-1H, 1′

H-4,4′

-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

52. The method of claim 48, wherein the selective JAK1 inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.

53. The method of claim 10, further comprising administering one or more nonsteroidal anti-inflammatory drugs (NSAIDs) to said patient.

54. The method of claim 53, wherein the NSAIDs are selected from aspirin, diflunisal, salsalate, ibuprofen, naproxen, fenoprofen, ketoprofen, oxaprozin, Indomethicin, tolmetin, sulindac, etodolac, ketodolac, piroxicam, meloxicam, tenoxicam, acetaminophen, celecoxib and combinations thereof.

55. The method of claim 10, wherein the administering increases survival in a patient.

56. The method of claim 10, wherein the administering increases progression-free survival of the patient.

25. A method of predicting a benefit to a patient having a solid tumor of treatment using a JAK inhibitor or an inhibitor of IL-6 signaling, comprising comparing said serum concentration of C-reactive protein (CRP) of the patient to a baseline serum concentration of CRP of a population of patients having the solid tumor, wherein the serum CRP concentration in the patient of equal to or greater than the baseline serum concentration is indicative of a benefit to the patient of the treatment using the JAK inhibitor or an inhibitor of IL-6 signaling.

26. The method of claim 25, wherein the method further comprises measuring the serum concentration of CRP of the patient using a CRP assay prior to said comparing.

27. The method of claim 25, wherein the method further comprises prescribing a JAK inhibitor or an inhibitor of IL-6 signaling for said patient.

28. The method of claim 25, wherein said benefit is improvement in overall survival of the patient.

29. The method of claim 25, wherein said benefit is improvement in progression-free survival of the patient.

30-39. -39. (canceled)

40. A method of predicting a benefit to a pancreatic cancer patient of treatment using ruxolitinib, or a pharmaceutically acceptable salt thereof, comprising comparing serum concentration of C-reactive protein (CRP) of the patient to a baseline serum concentration of CRP of a population of patients having the solid tumor, wherein the serum CRP concentration in the patient of equal to or greater than the baseline serum concentration is indicative of a benefit to the patient of the treatment using the inhibitor of ruxolitinib, or a pharmaceutically acceptable salt thereof.

41-47. -47. (canceled)