Lymphocyte-Depleting Nonmyeloablative Preparative Chemotherapy Followed By Autologous Lymphocyte Infusion, Peptide Vaccine Plus Montanide ISA-51, 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. Treating a person's lymphocytes in the laboratory and reinfusing them may replace immune cells destroyed by chemotherapy. Vaccines made from peptides may make the body build an immune response to kill tumor cells. Giving a vaccine with Montanide ISA-51 may cause a stronger immune response and kill more tumor cells. Interleukin-2 may stimulate a person's lymphocytes to kill tumor cells. PURPOSE: This phase II trial is studying how well lymphocyte-depleting nonmyeloablative (not damaging to bone marrow) chemotherapy followed by autologous lymphocyte infusion, peptide vaccine plus Montanide ISA-51, and interleukin-2 works in treating patients with metastatic melanoma.

Detailed Description
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OBJECTIVES: Primary Determine the clinical tumor regression in patients with metastatic melanoma treated with a lymphocyte-depleting nonmyeloablative preparative chemotherapy regimen followed by autologous lymphocyte infusion, ESO-1 peptide vaccination comprising ESO-1:157-165 (165V) and Montanide ISA-51, and interleukin-2. Secondary Determine the survival of the infused lymphocytes in patients treated with this regimen. Determine the long-term immune status of patients treated with this regimen. OUTLINE: Patients are stratified according to type of lymphocyte infusion (ESO-1-reactive tumor-infiltrating lymphocytes [TIL] vs ESO-1 reactive peripheral blood lymphocytes [PBL]). Autologous lymphocyte collection and expansion: Autologous PBL or TIL are collected from patients during leukapheresis or biopsy. The cells are sensitized in vitro with ESO-1:157-165 (165V) melanoma antigen and expanded. Lymphocyte-depleting nonmyeloablative preparative chemotherapy: Patients receive lymphocyte-depleting nonmyeloablative preparative chemotherapy comprising cyclophosphamide IV over 1 hour on days -7 and -6 and fludarabine IV over 15-30 minutes on days -5 to -1. Autologous lymphocyte infusion: Autologous PBL or TIL are reinfused on day 0*. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 1 and continuing until blood counts recover. ESO-1 peptide vaccination: Patients receive ESO-1 peptide vaccination comprising ESO-1:157-165 (165V) peptide emulsified in Montanide ISA-51 SC on days 0*-4, 11, 18, and 25. Interleukin therapy: Patients receive interleukin-2 IV over 15 minutes 3 times daily on days 0*-4. NOTE: *Day 0 is 1-4 days after the last dose of fludarabine. Patients achieving stable disease or partial response may receive up to 1 retreatment course. Patients with progressive disease after infusion of PBL may receive retreatment with TIL, if available. Patients are followed at 4-5 weeks, every 3-4 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 24-74 patients (12-37 per stratum) will be accrued for this study within 2-3 years.

Official Title
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Treatment Of Patients With Metastatic Melanoma Using Nonmyeloablative But Lymphocyte Depleting Regimen Followed By The Administration Of In Vitro Sensitized Lymphocytes Reactive With ESO-1 Antigen

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Biological: NY-ESO-1 peptide vaccine
* Biological: aldesleukin
* Biological: filgrastim
* Biological: incomplete Freund's adjuvant
* Biological: therapeutic autologous lymphocytes
* Drug: cyclophosphamide
* Drug: fludarabine phosphate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of metastatic melanoma that is refractory to standard therapy (including high-dose interleukin-2) Measurable disease HLA-A*0201 positive Epstein-Barr virus positive ESO-1-expressing disease by reverse transcription polymerase chain reaction amplified tissue OR presence of ESO-1 serum antibody PATIENT CHARACTERISTICS: Age 16 and over Performance status ECOG 0-1 Life expectancy More than 3 months Hematopoietic Absolute neutrophil count > 1,000/mm^3 Platelet count > 100,000/mm^3 Hemoglobin > 8.0 g/dL Hepatic Hepatitis B surface antigen negative Hepatitis C antibody negative AST and ALT < 3 times upper limit of normal Bilirubin ≤ 2.0 mg/dL (< 3.0 mg/dL for patients with Gilbert's syndrome) No coagulation disorders Renal Creatinine ≤ 2.0 mg/dL Cardiovascular No prior myocardial infarction No major cardiovascular illness by stress thallium or comparable test No cardiac arrhythmias LVEF ≥ 45% Normal cardiac stress test required for the following conditions: Prior EKG abnormalities Symptoms of cardiac ischemia Arrhythmias Age 50 and over Pulmonary FEV_1 > 60% of predicted (for patients with a prolonged history of cigarette smoking or symptoms of respiratory dysfunction) No obstructive or restrictive pulmonary disease No other major respiratory illness Immunologic HIV negative No active systemic infection No opportunistic infection No major immune system illness No form of primary or secondary immunodeficiency No known hypersensitivity to study agents Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for at least 4 months after study participation PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics Prior ESO-1-based vaccination allowed Chemotherapy At least 6 weeks since prior nitrosoureas and recovered Endocrine therapy No concurrent systemic steroid therapy Radiotherapy Recovered from prior radiotherapy Surgery Not specified Other At least 4 weeks since prior systemic therapy

Ages Eligible for Study
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Minimum Age: 16 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
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: NY-ESO-1 peptide vaccine|nan|
|Biological: aldesleukin|nan|
|Biological: filgrastim|nan|
|Biological: incomplete Freund's adjuvant|nan|
|Biological: therapeutic autologous lymphocytes|nan|
|Drug: cyclophosphamide|nan|
|Drug: fludarabine phosphate|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical tumor regression |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival of infused lymphocytes |  |  | 
| Long-term immune status |  |  | 

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