Cyclophosphamide, Fludarabine, and High-Dose Interleukin-2 in Treating Patients With Metastatic Melanoma

OBJECTIVES:

Primary

• Determine the objective response rate in lymphodepleted patients with metastatic melanoma treated with cyclophosphamide, fludarabine, and high-dose interleukin-2.
• Determine the feasibility of this regimen in these patients.

Secondary

• Determine the quality and quantity of lymphocyte recovery in these patients during and after treatment with this regimen.
• Determine time to disease progression and survival in patients treated with this regimen.

OUTLINE: This is an open-label, multicenter study.

Patients receive lymphodepleting therapy comprising cyclophosphamide IV over 1 hour on days 1 and 2 and fludarabine IV over 30 minutes on days 3-7. Patients then receive high-dose interleukin-2 IV every 8 hours (14 doses) on days 8-12 and 22-26. Patients also receive sargramostim (GM-CSF) subcutaneously beginning on day 8 and continuing until blood counts recover. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 18-33 patients will be accrued for this study.

Inclusion criteria

• Histologically confirmed melanoma
• Metastatic disease
• Measurable disease
• No history of brain metastases
• Over 18
• Karnofsky 60-100%
• Life expectancy At least 12 weeks
• Hematopoietic
• Absolute neutrophil count ≥ 1,000/mm^3
• Platelet count ≥ 75,000/mm^3
• Hemoglobin ≥ 8.5 g/dL
• aspartate aminotransferase ≤ 2 times upper limit of normal (ULN) (5 times ULN if liver metastases are present)
• Bilirubin ≤ 2 times ULN (except for patients with Gilbert's syndrome)
• Hepatitis B and C negative
• Creatinine ≤ 2.0 times ULN
• Creatinine clearance ≥ 50 mL/min
• Cardiovascular
• Ejection fraction ≥ 50%
• No evidence of congestive heart failure
• No symptoms of coronary artery disease
• No serious cardiac arrhythmias
• No myocardial infarction within the past 6 months
• Cardiac stress test negative or of low probability for patients > 40 years of age OR who have had prior myocardial infarction > 6 months ago
• Pulmonary Forced expiratory volume 1 ≥ 2.0 liters OR at least 75% of predicted for height and age
• Diffusing capacity of lung for carbon monoxide ≥ 60%
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative

Exclusion criteria

• No uncontrolled diabetes
• No history of autoimmune disease
• No active infection
• No other concurrent significant illness that would preclude study participation
• No other malignancy within the past 5 years except nonmelanoma skin cancer or non-invasive cancer (e.g., carcinoma in situ of the cervix, superficial bladder cancer without local recurrence, or carcinoma in situ of the breast)
• At least 4 weeks since prior immunotherapy and recovered
• No other concurrent anticancer biologic agents
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) and recovered
• No concurrent chemotherapy
• At least 4 weeks since prior steroid therapy
• No concurrent corticosteroids
• At least 4 weeks since prior radiotherapy and recovered
• No concurrent radiotherapy
• At least 4 weeks since prior surgery and recovered
• No concurrent immunosuppressive therapy