METHODS OF TREATMENT FOR SOLID TUMORS

• US 20110044942A1
• Filed: 04/20/2010
• Published: 02/24/2011
• Est. Priority Date: 04/20/2009
• Status: Active Grant

• Current Assignee: Gilead Calistoga LLC (Gilead Sciences Inc.)
• Original Assignee: Gilead Calistoga LLC (Gilead Sciences Inc.)
• Inventors: PURI, Kamal D., Evarts, Jerry B., Giese, Neill A., Lannutti, Brian
• Granted Patent: US 8,546,409 B2
• Time in Patent Office: Days
• US Class Current: 424/85.2
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine

Abstract

The invention provides methods that relate to a novel therapeutic strategy for the treatment of hematological malignancies and inflammatory diseases. In particular, the method comprises administration of a compound of formula I,

• • or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such compound admixed with at least one pharmaceutically acceptable excipient.

Claims

1. A method of treating a solid tumor in a subject comprising administering to said subject an optically active compound of formula I

2. The method of claim 1, wherein the solid tumor is selected from the group consisting of pancreatic cancer;

bladder cancer;

colorectal cancer;

breast cancer;

prostate cancer;

renal cancer;

hepatocellular cancer;

lung cancer;

ovarian cancer;

cervical cancer;

gastric cancer;

esophageal cancer;

head and neck cancer;

melanoma;

neuroendocrine cancers;

CNS cancers;

brain tumors;

bone cancer; and

soft tissue sarcoma.

3. The method of claim 1, wherein the solid tumor is selected from non-small cell lung cancer, small-cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer.

4. The method of claim 1, wherein the S-enantiomer predominates over the R enantiomer by a ratio of at least about 9:

1.

5. The method of claim 1, wherein the S-enantiomer predominates over the R enantiomer by a ratio of at least about 19:

1.

6. The method of claim 1, wherein the compound is administered orally.

7. The method of claim 1, wherein the compound is administered in solid form.

8. The method of claim 7, wherein the solid form comprises the optically active compound of Formula I admixed with at least one pharmaceutically acceptable excipient.

9. The method of claim 7, wherein the solid tumor is ovarian, renal, breast, lung, colon or prostate cancer.

10. The method of claim 1 wherein the subject is refractory to chemotherapy treatment, or in relapse after treatment with chemotherapy.

11. The method of claim 1 wherein the compound of formula I is administered at a dose of 20-500 mg/day.

12. The method of claim 1 wherein the compound of formula I is administered at a dose of 50-250 mg/day.

13. The method of claim 1 wherein the compound of formula I is administered at a dose of 50-150 mg twice per day.

14. The method of claim 1 wherein a compound of formula I is administered at least twice daily.

15. The method of claim 1, further comprising reducing the level of PI3Kδ

activity in said subject.

16. The method of claim 1, wherein the subject is a human subject.

17. The method of claim 16, wherein the concentration of the compound in the blood is between 40-3000 ng/mL over a 12 hour period from the time of administration.

18. The method of claim 16, wherein the concentration of the compound in the blood is between about 100 nM and 2000 nM in the treated subject.

19. The method of claim 1, wherein the agent is administered orally, intravenously or by inhalation.

20. The method of claim 1, further comprising administering in addition to a compound of formula Ito said subject, a therapeutically effective amount of at least one therapeutic agent and/or therapeutic procedure selected to treat said solid tumor in said subject.

21. The method of claim 20, wherein said therapeutic agent is selected from the following group consisting of Docetaxel, Mitoxantrone, Prednisone, Estramustine, Anthracyclines, (doxorubicin (Adriamycin), epirubicin (Ellence), and liposomal doxorubicin (Doxil)), Taxanes (docetaxel (Taxotere), paclitaxel (Taxol), and protein-bound paclitaxel (Abraxane)), Cyclophosphamide (Cytoxan), Capecitabine (Xeloda) and 5 fluorouracil (5 FU), Gemcitabine (Gemzar), methotrexate, Vinorelbine (Navelbine), an EGFR inhibitor such as erlotinib, Trastuzumab, Herceptin, Avastin, Platins (cisplatin, carboplatin), Temazolamide, Interferon alpha, and IL-2.

22. The method of claim 20, wherein in said therapeutic agent is selected from the group consisting of an EGFR inhibitor, an mTOR inhibitor, a platin, and a taxane.

23. The method of claim 20, wherein said therapeutic procedure is selected from the group consisting of peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, immunohistochemistry staining method, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, high-dose chemotherapy and nonmyeloablative allogeneic hematopoietic stem cell transplantation.

24. The method of claim 1 further comprising obtaining a biological sample from said subject;

and analyzing said biological sample with an analytical procedure selected from the group consisting of blood chemistry analysis, chromosomal translocation analysis, needle biopsy, fluorescence in situ hybridization, laboratory biomarker analysis, immunohistochemistry staining method, flow cytometry or a combination thereof.

25. The method of claim 24, wherein the compound is administered twice daily for about 28 days, and is then discontinued for at least 7 days.