Cyclophosphamide, Fludarabine, and Total-Body Irradiation Followed By Cellular Adoptive Immunotherapy, Autologous Stem Cell Transplantation, and 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. Radiation therapy uses high-energy x-rays to damage tumor cells. Biological therapies, such as cellular adoptive immunotherapy, work in different ways to stimulate the immune system and stop tumor cells from growing. Autologous stem cell transplant may be able to replace immune cells that were destroyed by chemotherapy and radiation therapy. Interleukin-2 may stimulate a person's lymphocytes to kill tumor cells. Combining chemotherapy, radiation therapy, and biological therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving cyclophosphamide and fludarabine together with radiation therapy followed by cellular adoptive immunotherapy, autologous stem cell transplant, and interleukin-2 works in treating patients with metastatic melanoma.

Detailed Description
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OBJECTIVES: Primary Determine complete clinical tumor regression in patients with metastatic melanoma treated with a myeloablative lymphoid-depleting preparative regimen comprising cyclophosphamide, fludarabine, and total body irradiation followed by autologous tumor-reactive tumor-infiltrating lymphocyte infusion, autologous CD34+ stem cell transplantation, and low-dose or high-dose interleukin-2. Evaluate the safety of this regimen in these patients. Secondary Determine the survival of the infused lymphocytes by analyzing the sequence of the variable region of the T-cell receptor or flow cytometry in patients treated with this regimen. OUTLINE: Autologous stem cell collection: Patients receive filgrastim (G-CSF) subcutaneously (SC) twice daily for 8 days. Beginning on day 5 of G-CSF, patients undergo apheresis daily for up to 3 days. Patients may receive 1 additional course of G-CSF and apheresis or use stem cells stored from a prior stem cell harvest in order to obtain an adequate number of cells. Lymphocyte-depleting myeloablative preparative regimen: Patients receive cyclophosphamide intravenous (IV) over 1 hour on days -5 and -6 and fludarabine IV over 15-30 minutes on days -6 to -2. Patients also undergo total body irradiation on day -1. Autologous lymphocyte infusion: Patients receive autologous tumor-reactive tumor-infiltrating lymphocytes IV over 20-30 minutes on day 0* followed by G-CSF SC once daily until blood counts recover. Autologous stem cell transplantation: Patients receive autologous CD34+ stem cells IV on day 2. Interleukin therapy: Patients are assigned to 1 of 2 cohorts, depending on whether they have received prior high-dose interleukin-2 (IL-2). Cohort 1 (patients who received prior high-dose IL-2): Beginning on day 0*, patients receive high-dose IL-2 IV over 15 minutes 3 times daily for up to 5 days (maximum of 15 doses). Cohort 3 (patients who have not received prior high-dose IL-2): Patients receive treatment as in cohort 1. NOTE: *Day 0 is 1-4 days after the last dose of fludarabine. Patients are evaluated at 4-6 weeks. PROJECTED ACCRUAL: A total of 116 patients will be accrued for this study.

Official Title
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Treatment of Patients With Metastatic Melanoma Using a Transplant of Autologous Lymphocytes Reactive With Tumor Following a Myeloablative Lymphocyte Depleting Regimen of Chemotherapy, Total Body Irradiation and Reconstitution With CD34+ Cells

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Biological: aldesleukin
* Biological: filgrastim
* Biological: therapeutic tumor infiltrating lymphocytes
* Drug: cyclophosphamide
* Drug: fludarabine phosphate
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of metastatic melanoma Measurable disease Resected or stable brain metastases are allowed PATIENT CHARACTERISTICS: Age 18 and over Performance status Eastern Cooperative Oncology Group (ECOG) 0-1 Life expectancy At least 3 months Hematopoietic See Immunologic Absolute neutrophil count > 1,000/mm^3 (without support of filgrastim [G-CSF]) Platelet count > 100,000/mm^3 Hemoglobin ≥ 8 g/dL (transfusion allowed) No coagulation disorders Hepatic Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 times upper limit of normal Bilirubin ≤ 2 mg/dL (< 3 mg/dL in patients with Gilbert's syndrome) No hepatitis B or C Renal Creatinine ≤ 1.6 mg/dL Cardiovascular Left ventricular ejection fraction (LVEF) ≥ 45% by cardiac stress test* No active major cardiovascular illness as evidenced by stress thallium or other comparable test No myocardial infarction No cardiac arrhythmias NOTE: *For patients ≥ 50 years of age receiving high-dose interleukin-2 (IL-2) OR patients with a history of electrocardiogram (EKG) abnormalities, symptoms of cardiac ischemia, or arrhythmias Pulmonary Forced expiratory volume 1 (FEV_1) ≥ 60% of predicted by pulmonary function test in patients with prolonged history of cigarette smoking or symptoms of respiratory dysfunction* No active major respiratory illness No obstructive or restrictive pulmonary disease NOTE: *For patients receiving high-dose IL-2 only Immunologic No active major immunologic illness No active systemic infections No primary or secondary immunodeficiency Fully recovered immune competence after prior chemotherapy or radiotherapy as evidenced by both of the following: Absolute neutrophil count > 1,000/mm^3 No opportunistic infections Human Immunodeficiency virus (HIV) negative Epstein-Barr virus positive Other Not pregnant or nursing Fertile patients must use effective contraception during and for 4 months after study treatment PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics Chemotherapy At least 6 weeks since prior nitrosourea therapy No prior cyclophosphamide and fludarabine as part of a preparative regimen on National Cancer Institute (NCI) Surgery Branch adoptive cell therapy studies unless sufficient numbers of CD34+ stem cells (more than 2 x10^6/kg patient weight) have been obtained prior to the administration of chemotherapy Endocrine therapy No concurrent systemic steroid therapy Radiotherapy Not specified Surgery See Disease Characteristics Prior minor surgery within the past 3 weeks allowed if recovered Other Recovered from all prior therapy At least 30 days since prior systemic therapy No other concurrent experimental agents

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: TBI 200cGy + TIL +HD IL-2, prior IL-2<br>Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator. Lymphocytes that that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient. | Biological: aldesleukin<br>* high dose: 720,000 IU/kg intravenously over 15 minutes every 8 hours for up to 5 days (maximum 5 doses) or low dose: 250,000 IU/kg subcutaneously daily for 5 days, after a two day rest, 125,000 IU/kg subcutaneously daily for 5 days for five weeks (2 days rest per week)<br>* Other names: Interleukin-2;Biological: filgrastim<br>* 10 mcg/kg/day daily subcutaneously until neutrophil count >1x10^9/1.<br>* Other names: GCSF;Biological: therapeutic tumor infiltrating lymphocytes<br>* Lymphocytes that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient.<br>Drug: cyclophosphamide<br>* 60 mg/kg/day x 2 days intravenously over 1 hour<br>* Other names: Cytoxan;Drug: fludarabine phosphate<br>* 25 mg/m^2/day intravenous piggyback daily over 15-20 minutes for 5 days<br>* Other names: Fludara;Radiation: radiation therapy<br>* Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator.<br>* Other names: total body irradiation;|
| Other: TBI 200cGy + TIL +HD IL-2, No prior IL-2<br>Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator. Lymphocytes that that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient. | Biological: aldesleukin<br>* high dose: 720,000 IU/kg intravenously over 15 minutes every 8 hours for up to 5 days (maximum 5 doses) or low dose: 250,000 IU/kg subcutaneously daily for 5 days, after a two day rest, 125,000 IU/kg subcutaneously daily for 5 days for five weeks (2 days rest per week)<br>* Other names: Interleukin-2;Biological: filgrastim<br>* 10 mcg/kg/day daily subcutaneously until neutrophil count >1x10^9/1.<br>* Other names: GCSF;Biological: therapeutic tumor infiltrating lymphocytes<br>* Lymphocytes that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient.<br>Drug: cyclophosphamide<br>* 60 mg/kg/day x 2 days intravenously over 1 hour<br>* Other names: Cytoxan;Drug: fludarabine phosphate<br>* 25 mg/m^2/day intravenous piggyback daily over 15-20 minutes for 5 days<br>* Other names: Fludara;Radiation: radiation therapy<br>* Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator.<br>* Other names: total body irradiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Tumor Regression | Tumor regression is defined as a complete response (CR) or partial response (PR) and was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is the disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. | Every 4-6 weeks for up to 1 year, and then every 6 months for up to 5 years. | 
| Safety | Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module. | 4 years | 

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