TETRAHYDROFOLATES IN COMBINATION WITH EGFR-INHIBITORS

• US 20150017158A1
• Filed: 01/18/2013
• Published: 01/15/2015
• Est. Priority Date: 01/20/2012
• Status: Active Grant

• Current Assignee: Isofol Medical AB
• Original Assignee: Isofol Medical AB
• Inventors: Gustavsson, Bengt, Carlsson, Bjrn
• Granted Patent: US 9,675,617 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• 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 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4704 2-Quinolinones, e.g. carbostyril
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators

Abstract

The present invention relates a pharmaceutical composition comprising an EGFR inhibitor and methylene-tetrahydrofolate, tetrahydrofolate or methyl-tetrahydrofolate, for use in the treatment of cancer. The methylene-tetrahydrofolate, tetrahydrofolate or methyl-tetrahydrofolate enhances the anticancer efficacy of the EGFR inhibitor. The cancers that may be treated include breast cancer, gastric cancer, gastrointestinal cancer, gall bladder cancer, bile duct cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, head and neck cancer, esophageal cancer, mesothelioma cancer, lung cancer including non-small-cell lung cancer, ovarian cancer, endometrial cancer, cervical cancer, peripheral T-cell lymphoma (PTCL), melanoma, brain tumors, adenocarcinoma, esophageal cancer, and osteosarcoma

Claims

1. A pharmaceutical composition comprising as components:

a. methylene-tetrahydrofolate, tetrahydrofolate or methyl-tetrahydrofolate; and

b. an EGFR inhibitor;

for use in the treatment of cancer.

2. The pharmaceutical composition for use according to claim 1, wherein said composition is for administration in isolation of 5-fluorouracil.

3. The pharmaceutical composition for use according to claim 2, wherein said composition is for administration in isolation of analogues, prodrugs and/or metabolites of 5-fluorouracil.

4. The pharmaceutical composition for use according to claim 3, wherein said 5-fluoruracil, and/or said analogues, prodrugs and/or metabolites of 5-fluoruracil are metabolized to FdUMP.

5. The pharmaceutical composition for use according to claim 1, wherein said treatment of cancer is inhibition of tumor growth.

6. The pharmaceutical composition for use according to claim 1, wherein said treatment of cancer is reduction of the volume of a tumor.

7. The pharmaceutical composition for use according to claim 1, wherein component b) is selected from the EGFR inhibitors listed in Table 1, and gefitinib, erlotinib and lapatinib, and polyclonal or monoclonal antibody EGFR inhibitors such as cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, or combinations thereof.

8. The pharmaceutical composition for use according to claim 7, wherein component b) is a monoclonal antibody EGFR inhibitor.

9. The pharmaceutical composition for use according to claim 8, wherein component b) is cetuximab and/or panitumumab.

10. The pharmaceutical composition for use according to claim 1, wherein component a) is methylene-tetrahydrofolate.

11. The pharmaceutical composition for use according to claim 1, wherein component a) is for administration no later than 24 hours before the administration of 5-FU and/or an analogue, prodrug and/or metabolite thereof.

12. The pharmaceutical composition for use according to claim 1, wherein component a) is for administration no later than 36 hours before the administration of 5-FU and/or an analogue, prodrug and/or metabolite thereof.

13. The pharmaceutical composition for use according to claim 1, wherein component a) is for administration no later than 48 hours before the administration of 5-FU and/or an analogue, prodrug and/or metabolite thereof.

14. The pharmaceutical composition for use according to claim 1, wherein component a) is for administration at the earliest 6 hours after the administration of 5-FU and/or an analogue, prodrug and/or metabolite thereof.

15. The pharmaceutical composition for use according to claim 1, wherein component a) is for administration at the earliest 24 hours after the administration of 5-FU and/or an analogue, prodrug and/or metabolite thereof.

16. The pharmaceutical composition for use according to claim 1, wherein component a) is for administration at the earliest 48 hours after the administration of 5-FU and/or an analogue, prodrug and/or metabolite thereof.

17. The pharmaceutical composition for use according to claim 1, wherein component a) is for administration at the earliest one week after the administration of 5-FU and/or an analogue, prodrug and/or metabolite thereof.

18. The pharmaceutical composition for use according to claim 1, wherein component a) is for administration at the earliest 12 days after the administration of 5-FU and/or an analogue, prodrug and/or metabolite thereof.

19. The pharmaceutical composition for use according to claim 1, wherein said composition is for administration no later than one week before the administration of 5-FU and/or an analogue, prodrug and/or metabolite thereof.

20. The pharmaceutical composition for use according to claim 1, wherein said composition is for administration at the earliest one week after the administration of 5-FU and/or an analogue, prodrug and/or metabolite thereof.

21. The pharmaceutical composition for use according to claim 1, wherein said composition is for administration in isolation from 5-FU and/or an analogue, prodrug and/or metabolite thereof during a time period of at least 3 months.

22. The pharmaceutical composition for use according to claim 1, wherein component a) and component b) are formulated in different pharmaceutical compositions.

23. The pharmaceutical composition for use according to claim 1, wherein component a) and component b) are formulated in a common pharmaceutical composition.

24. The pharmaceutical composition for use according to claim 1, wherein component b) is cetuximab and is for administration in an amount of at least 50 mg/m², preferably at least 100 mg/m², and more preferably at least 250 mg/m², 400 mg/m² or 500 mg/m², and at maximum 1000 mg/m².

25. The pharmaceutical composition for use according to claim 1, wherein component a) is for administration in an amount of at least 10 mg/m², preferably at least 20 mg/m², more preferably at least 50 mg/m², most preferably at least 100 mg/m², 200 mg/m² or 500 mg/m², and at maximum 5 g/m².

26. The pharmaceutical composition for use according to claim 1, wherein said cancer is selected from breast cancer, gastric cancer, gastrointestinal cancer, gall bladder cancer, bile duct cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, head and neck cancer, esophageal cancer, mesothelioma cancer, lung cancer including non-small-cell lung cancer, ovarian cancer, endometrial cancer, cervical cancer, peripheral T-cell lymphoma (PTCL), melanoma, brain tumors, adenocarcinoma, esophageal cancer, and osteosarcoma.