Monoclonal Antibody Therapy and Interleukin-2 in Treating Patients With Metastatic Melanoma

MDX-CTLA4 Combined With IL-2 for Patients With Metastatic Melanoma

RATIONALE: Biological therapies, such as MDX-010, work in different ways to stimulate the immune system and stop tumor cells from growing. Interleukin-2 may stimulate a person's white blood cells to kill tumor cells. Combining monoclonal antibody therapy with interleukin-2 may kill more tumor cells.

PURPOSE: Phase I/II trial to study the effectiveness of combining monoclonal antibody therapy with interleukin-2 in treating patients who have metastatic melanoma.

OBJECTIVES:

• Determine the maximum tolerated dose (MTD) of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-CTLA4) in combination with high-dose interleukin-2 (IL-2) in patients with metastatic melanoma. (Phase I is closed to accrual as of 4/13/2004).
• Determine the activity of MDX-CTLA4 administered at the MTD with high-dose IL-2 in these patients.
• Determine whether the administration of IL-2 alters the pharmacokinetics of MDX-CTLA4 in these patients.
• Determine the safety and adverse event profile of this regimen in these patients.

OUTLINE: This is an open-label, dose-escalation study of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-CTLA4).

• Phase I: Patients receive MDX-CTLA4 IV on days 0, 21, and 42. Patients also receive high-dose interleukin-2 (IL-2) IV over 15 minutes every 8 hours for up to 15 doses beginning on days 22 and 43. Treatment repeats every 63 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients with an ongoing partial response and no greater than grade 1 toxicity may receive additional courses of therapy. Patients who require discontinuation of MDX-CTLA4 due to toxicity may continue receiving IL-2 at the discretion of the investigator.

Cohorts of 3-6 patients receive escalating doses of MDX-CTLA4 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. (Phase I is closed to accrual as of 4/13/2004).

• Phase II: Patients receive treatment as in phase I at the MTD of MDX-CTLA4. Patients who achieve a partial or complete response and later develop recurrent or progressive disease may be retreated at the same dose.

Patients are followed at 3 weeks, every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 3-51 patients (3-18 for phase I and 19-33 for phase II) will be accrued for this study within 1 year. (Phase I is closed to accrual as of 4/13/2004).

DISEASE CHARACTERISTICS:

• Histologically confirmed stage IV melanoma

  • Mucosal or ocular melanoma also eligible

• Clinically evaluable disease

  • At least 1 site of measurable disease

PATIENT CHARACTERISTICS:

Age

• 16 and over

Performance status

• ECOG 0-1

Life expectancy

• At least 3 months

Hematopoietic

• WBC at least 2,500/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 10 g/dL
• Hematocrit at least 30%

Hepatic

• Bilirubin no greater than upper limit of normal (ULN)* (less than 3.0 mg/dL in patients with Gilbert's syndrome)
• AST no greater than 3 times ULN*
• Hepatitis B surface antigen negative
• Hepatitis C antibody nonreactive
• No evidence or history of significant hepatic disease that would preclude safe administration of high-dose IL-2 NOTE: *Unless attributable to disease

Renal

• Creatinine no greater than 2.0 mg/dL
• No evidence or history of significant renal disease that would preclude safe administration of high-dose IL-2

Cardiovascular

• No evidence or history of significant cardiac disease that would preclude safe administration of high-dose IL-2
• Thallium stress test normal (for patients over 50 years of age or with a history of cardiovascular disease)

Pulmonary

• No evidence or history of significant pulmonary disease that would preclude safe administration of high-dose IL-2

Immunologic

• HIV negative
• No autoimmune disease (including uveitis and autoimmune inflammatory eye disease)
• No active infection

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix
• No evidence or history of significant gastrointestinal disease that would preclude safe administration of high-dose IL-2
• No evidence or history of psychiatric disease that would preclude safe administration of high-dose IL-2
• No other underlying medical condition that would make the administration of the study drug hazardous or obscure the interpretation of adverse events
• No other concurrent medical condition that would preclude study entry

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 3 weeks since prior immunotherapy for melanoma and recovered
• No prior anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-CTLA4)
• No prior high-dose (at least 600,000 IU/kg every 8 hours) interleukin-2 (IL-2)

Chemotherapy

• At least 3 weeks since prior chemotherapy for melanoma and recovered
• No concurrent chemotherapy

Endocrine therapy

• At least 3 weeks since prior hormonal therapy for melanoma and recovered
• At least 4 weeks since prior corticosteroids
• No concurrent systemic or topical corticosteroids

Radiotherapy

• At least 3 weeks since prior radiotherapy for melanoma and recovered

Surgery

• Not specified

Other

• No concurrent immunosuppressive agents (e.g., cyclosporine or its analog)