PARENTERAL LOW DOSE TYPE 1 INTERFERONS FOR BLADDER CANCER

Abstract

Novel methods and drug products for treating superficial bladder cancer (SBC) are disclosed, which involve parenteral administration of low doses of a type 1 interferon. The doses used are subtherapeutic for other solid tumors. Use of the novel methods and products in combination with other therapies for SBC is also described.

Description

Claims

1. A method of treating a patient diagnosed with superficial bladder cancer (SBC), which comprises parenterally administering to the patient a type 1 interferon using a dosing regimen that provides an amount of the type 1 interferon that is within a pre-defined range for the type 1 interferon, wherein the lower limit of the range is the amount sufficient to achieve at least half maximal binding of the interferon α/β receptors on immune cells in the bloodstream for at least 1 day and the upper limit of the range is a subtherapeutic dose of the type 1 interferon for other solid tumors.

2. The method of claim 1, wherein the type 1 interferon is an interferon alpha.

3. The method of claim 2, wherein the lower limit of the range is the amount sufficient to achieve at least half maximal binding of the interferon α/β receptors on immune cells in the bloodstream for at least 3 days and the interferon alpha is a pegylated interferon alpha.

4. The method of claim 3, wherein the pegylated interferon alpha is PEG12,000-interferon alpha 2a or PEG12,000-interferon alpha 2b and the dosing regimen comprises a single injection of a dose of 0.1 μg/kg≦4.0 μg/kg.

5. The method of claim 4, wherein the pegylated interferon alpha is PEG12,000-interferon alpha 2b and the dosing regimen comprises a single subcutaneous injection of a dose of 0.1 μg/kg<1.0 μg/kg.

6. The method of claim 5, wherein the dose is 0.1 μg/kg≦0.5 μg/kg.

7. The method of claim 6, wherein the dose is 0.1 μg/kg≦0.25 μg/kg.

8. The method of claim 5, wherein the dose is 0.25 μg/kg≦0.5 μg/kg.

9. The method of claim 3, wherein the pegylated interferon alpha is U-PEG40,000-interferon alpha 2a or U-PEG40,000-interferon alpha 2b and the dosing regimen comprises a single subcutaneous injection of a dose of 1.0<180 μg.

10. The method of claim 9, wherein the pegylated interferon alpha is U-PEG40,000-interferon alpha 2a and the dosing regimen comprises a single subcutaneous injection of a dose of 1.0<135 μg.

11. The method of claim 10, wherein the dose is 5.0≦90 μg.

12. The method of claim 10, wherein the dose is 25.0≦50 μg.

13. The method of claim 1, further comprising repeating the dosage regimen every week for a time period of 1 to 260 weeks.

14. The method of claim 13, wherein the time period is 2 to 130 weeks.

15. The method of claim 14, wherein the time period is 4 to 65 weeks.

16. The method of claim 1, further comprising administering to the patient a therapeutically effective dose of a different antitumor agent.

17. The method of claim 16, wherein the different antitumor agent is an immunomodulator administered to the bladder between 24 hours before and 24 hours after administration of the first dose of the type 1 interferon.

18. The method of claim 16, wherein the type 1 interferon is a pegylated interferon α and the antitumor agent is an immunomodulator administered to the bladder between 24 hours before and 168 hours after administration of the first dose of the type 1 interferon.

19. The method of claim 18, wherein pegylated interferon α is selected from the group consisting of PEG12,000-interferon alpha 2a, PEG12,000-interferon alpha 2b, U-PEG40,000-interferon alpha 2a and U-PEG40,000-interferon alpha 2b.

20. The method of any of claims 17-19, wherein the immunomodulator is bacille Calmette Guerin (BCG).

21. The method of claim 20, wherein the BCG is administered in a dose less than 1×106 CFU.

22. The method of any of claims 17-19, wherein the immunomodulator is a bladder tumor vaccine.

23. The method of claim 16, wherein the different antitumor agent is a chemotherapeutic agent administered to the bladder between 24 hours before and 24 hours after administration of the first dose of the type 1 interferon.

24. The method of claim 16, wherein the type 1 interferon is a pegylated interferon α and the different antitumor agent is a chemotherapeutic agent administered to the bladder between 24 hours before and 168 hours after administration of the first dose of the type 1 interferon.

25. The method of claim 1, wherein the patient has had at least one bladder tumor surgically removed.

26. The method of any of claim 1, wherein the patient has carcinoma in situ of the bladder.

27. The method of claim 1, wherein the patient has superficial carcinoma of the bladder with high grade pathological characteristics.

28. The method of claim 1, wherein the patient is a treatment-naive patient.

29. The method of claim 1, wherein the patient is a treatment-experienced patient.

30. The method of claim 29, wherein the patient relapsed after prior treatment with intravesical interferon and intravesical BCG.

31. The method of claim 1, wherein the type 1 interferon is a sustained release formulation of an unmodified interferon alpha.

32. The method of claim 31, wherein the sustained release formulation comprises a biodegradable polymer matrix.

33. The method of claim 1, wherein the type 1 interferon is a fusion protein comprising human serum albumin fused to an interferon alpha.

34. The method of claim 1, wherein the lower limit of the range is the amount sufficient to achieve at least half maximal binding of the interferon α/β receptors on immune cells in the bloodstream for at least 2 days, the type 1 interferon comprises an unmodified interferon alpha and the dosing regimen comprises a subcutaneous injection of 0.005 million international units (MIU)<1.5 MIU once every twenty-four hours for a period of at least 48 hours.

35. The method of claim 1, wherein the lower limit of the range is the amount sufficient to achieve at least half maximal binding of the interferon α/β receptors on immune cells in the bloodstream for at least 7 days, the type 1 interferon comprises an unmodified interferon alpha and the dosing regimen comprises a subcutaneous injection of 0.005 million international units (MIU)<1.5 MIU once every twenty-four hours for a period of at least 7 days.

36. The method of claim 1, wherein the lower limit of the range is the amount sufficient to achieve at least half maximal binding of the interferon α/β receptors on immune cells in the bloodstream for at least 2 days the type 1 interferon is an unmodified interferon alpha and the dosing regimen comprises administering a total dose of 0.01 MIU<3.0 MIU by continuous subcutaneous infusion over a period of 48 hours.

37. A manufactured drug product for treating superficial bladder cancer (SBC), which comprises: a pharmaceutical formulation comprising a type 1 interferon; andproduct information which comprises instructions for administering the pharmaceutical formulation to SBC patients according to a dosing regimen that provides an amount of the type 1 interferon that is within a pre-defined range for the type 1 interferon, wherein the lower limit of the range is the amount sufficient to achieve at least half maximal binding of the interferon α/β receptors on immune cells in the bloodstream for at least 1 day and the upper limit of the range is a subtherapeutic dose of the type 1 interferon for other solid tumors.

38. The drug product of claim 37, wherein the type 1 interferon is an interferon alpha.

39. The drug product of claim 38, wherein the interferon alpha is a pegylated interferon alpha.

40. The drug product of claim 39, wherein the pegylated interferon alpha is PEG12,000-interferon alpha 2a or PEG12,000-interferon alpha 2b and the dosing regimen comprises a single injection of a dose of 0.1 μg/kg<1.0 μg/kg.

41. The drug product of claim 40, wherein the pharmaceutical formulation is a lyophilized powder and the drug product further comprises a solvent for reconstitution of the powder.

42. The drug product of claim 40, wherein the dosing regimen comprises a single injection of a dose of 0.1 μg/kg<0.75 μg/kg.

43. The drug product of claim 39, wherein the pegylated interferon alpha is U-PEG40,000 interferon alpha 2a or U-PEG40,000 interferon alpha 2b and the dosing regimen comprises a single subcutaneous injection of a dose of 1.0<180 μg.

44. The drug product of claim 43, wherein the pegylated interferon alpha is U-PEG40,000 interferon alpha 2a and the dosing regimen comprises a single subcutaneous injection of a dose of 1.0<135 μg.

45. The drug product of claim 37, further comprising a second pharmaceutical formulation which comprises a different anti-tumor agent, and the product information further comprises a dosage regimen for intravesical administration of the different anti-tumor agent.

46. The drug product of claim 45, wherein the different anti-tumor agent is a BCG substrain.

47. A method of treating a patient diagnosed with superficial bladder cancer (SBC), which comprises parenterally administering to the patient a pegylated interferon alpha between 4 and 12 hours prior to intravesical BCG installation, wherein the pegylated interferon alpha is administered using a dosing regimen that provides an amount of the pegylated interferon alpha that is within a pre-defined range for the pegylated interferon alpha, wherein the lower limit of the range is the amount sufficient to achieve at least half maximal binding of the interferon α/β receptors on immune cells in the bloodstream for at least 3 days and the upper limit of the range is a subtherapeutic dose of the pegylated interferon alpha for other solid tumors.

48. The method of claim 47, wherein the pegylated interferon alpha is PEG12,000-interferon alpha 2a or PEG12,000-interferon alpha 2b and the dosing regimen comprises a single subcutaneous injection of a dose of 0.1 μg/kg<1.0 μg/kg.

49. The method of claim 47, wherein the pegylated interferon alpha is U-PEG40,000-interferon alpha 2a or U-PEG40,000-interferon alpha 2b and the dosing regimen comprises a single subcutaneous injection of a dose of 1.0<180 μg.

50. A method of manufacturing a drug product for treating superficial bladder cancer (SBC), the method comprising: combining in a package a pharmaceutical formulation comprising a type 1 interferon andprescribing information, which comprises instructions for parenterally administering the formulation to a patient diagnosed with SBC using a specific dosage regimen,wherein the dosing regimen is capable of providing an amount of the type 1 interferon that is within a pre-defined range for that interferon, wherein the lower limit of the range is the amount sufficient to achieve at least half maximal binding of the interferon α/β receptors on immune cells in the bloodstream for at least 1 day and the upper limit of the range is a dose that is subtherapeutic for other solid tumors.