Monoclonal Antibody Therapy and Interleukin-2 in Treating 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).

Eligibility Criteria:
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)