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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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High Dose Interleukin-2 (IL-2) Therapy In Lymphodepleted Primed Patients With Metastatic Melanoma

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Biological: aldesleukin
* Biological: sargramostim
* Drug: cyclophosphamide
* Drug: fludarabine phosphate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IL-2, CTX, fludarabine, GM-CSF<br>Aldesleukin (IL-2), cyclophosphamide, fludarabine phosphate, sargramostim | Biological: aldesleukin<br>* ‡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<br>* Other names: Aldesleukin; IL-2; HD IL-2; Interleukin-2;Biological: sargramostim<br>* GM-CSF was given subcutaneously daily from day 8 until absolute granulocyte count exceeds 5,000 cells/mL for 2 consecutive days.<br>* Other names: GM-CSF; granulocyte-macrophage colony-stimulating factor;Drug: cyclophosphamide<br>* 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.<br>* Other names: cyclophosphamide,Cytoxan;Drug: fludarabine phosphate<br>* Fludarabine IV (25 mg/M2/day)-five daily doses from Day 3<br>* Other names: Fludara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of partiCIPANTS WITH OBJECTIVE RESPONSE AS MEASURED BY RECIST | Objective response as measured by radiological and physical examination using RECIST criteria. | Response at 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Lymphocyte Recovery as Measured by Blood Count | 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. | on days 1-15, weekly for 2 weeks, and then every 2-3 months | 
| Time to Progression as Measured by RECIST | Clinical outcome used the National Cancer Institute's Response Evaluation Criteria in Solid Tumors (RECIST)1.0. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent melanoma, stage IV melanoma