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

• Number of Participants With Lymphocyte Recovery as Measured by Blood Count [ Time Frame: on days 1-15, weekly for 2 weeks, and then every 2-3 months ] [ Designated as safety issue: No ]
  Lymphocyte recovery to a greater than 1000 cells/mcL was determined by differential peripheral blood cell counts on sequential days as noted in time frame.
• Time to Progression as Measured by RECIST [ Time Frame: From date of randomization until the first date of documented progression or date of death from any cause, which ever came first, assessed up till 100 months ] [ Designated as safety issue: No ]
  Clinical outcome used the National Cancer Institute's Response Evaluation Criteria in Solid Tumors (RECIST)1.0.

RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide and fludarabine, work in different ways to stop tumor cells from dividing so they stop growing or die. Interleukin-2 may stimulate a person's white blood cells to kill tumor cells and may help a person's immune system recover from the side effects of chemotherapy.

PURPOSE: This phase II trial is studying how well giving cyclophosphamide and fludarabine together with high-dose interleukin-2 works 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.

• Biological: aldesleukin
  ‡Interleukin-2 (aldesleukin) IV (600,000 U/kg; Chiron, Emeryville, CA): two 5-day courses on days 8 and 22. Interleukin-2 was given over 15 minutes every 8 hours. Goal is 14 doses/5-day course
  Other Name: Aldesleukin; IL-2; HD IL-2; Interleukin-2
• Biological: sargramostim
  GM-CSF was given subcutaneously daily from day 8 until absolute granulocyte count exceeds 5,000 cells/mL for 2 consecutive days.
  Other Name: GM-CSF; granulocyte-macrophage colony-stimulating factor
• Drug: cyclophosphamide
  Cyclophosphamide (60 mg/kg/d; Baxter, Deerfield, IL) intravenously (IV) for 2 days with sodium 2- mercaptoethanesulfonate (Mesna; Sicor, Irvine, CA) at 20% of cyclophosphamide dose IV 15 minutes before and 40% of the cyclophosphamide dose orally at 2 and 6 hours after the initiation of chemotherapy.
  Other Name: cyclophosphamide,Cytoxan
• Drug: fludarabine phosphate
  Fludarabine IV (25 mg/M2/day)-five daily doses from Day 3
  Other Name: Fludara

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