Vaccine Therapy With or Without Interleukin-2 After Chemotherapy and an Autologous White Blood Cell Infusion in Treating Patients With Metastatic Melanoma

Study Overview
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Brief Summary
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This randomized phase II trial is studying how well giving vaccine therapy with or without interleukin-2 after chemotherapy and an autologous white blood cell infusion works in treating patients with metastatic melanoma. Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. Giving vaccine therapy with interleukin-2, chemotherapy, and an autologous white blood cell infusion may be a more effective treatment for metastatic melanoma.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the ability of gp100 and MART-1 peptide vaccines with or without a high-dose interleukin-2 (IL-2), when administered after a nonmyeloablative, lymphodepleting preparative regimen and reinfusion of autologous CD25+ T-regulatory-depleted lymphocytes, to mediate tumor regression in patients with metastatic melanoma. SECONDARY OBJECTIVES: I. Determine the generation of antitumor lymphocytes and the rate of repopulation of CD25+ T-regulatory cells in patients treated with this regimen. II. Determine the toxicity of this treatment regimen. OUTLINE: This is a randomized study. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients undergo apheresis and in-vitro depletion of T-regulatory cells. Patients then receive a nonmyeloablative, lymphocyte-depleting preparative regimen comprising cyclophosphamide IV over 1 hour on days -8 and -7 and fludarabine IV over 15-30 minutes on days -6 to -2 followed by autologous T-regulatory-depleted lymphocytes IV over 20-30 minutes on day 0. Patients receive vaccination with gp100:209-217 (210M) and MART-1:27-35 peptides emulsified in Montanide ISA-51 subcutaneously (SC) on days 0-3, 20-23, 41-44, and 62-65. Patients also receive filgrastim (G-CSF) SC beginning on day 1 and continuing until blood counts recover. ARM II: Patients receive treatment as in arm I. Patients also receive high-dose IL-2 IV over 15 minutes every 8 hours on days 0-4, beginning after the lymphocyte infusion. IL-2 treatment repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 1-3 months.

Official Title
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A Phase II Study Using a Peptide Vaccine With or Without Aldesleukin Following a Lymphodepleting Chemotherapy and Reinfusion of Autologous Lymphocytes Depleted of T Regulatory Lymphocytes in Metastatic Melanoma

Conditions
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Recurrent Melanoma, Stage IV Melanoma

Intervention / Treatment
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* Drug: cyclophosphamide
* Drug: fludarabine phosphate
* Biological: therapeutic autologous lymphocytes
* Procedure: in vitro-treated peripheral blood stem cell transplantation
* Biological: gp100 antigen
* Biological: MART-1 antigen
* Biological: incomplete Freund's adjuvant
* Biological: filgrastim
* Biological: aldesleukin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of metastatic melanoma No tumor reactive cells available for cell transfer therapy Measurable disease Previously treated with interleukin-2 (IL-2) and meets 1 of the following criteria: No response (progressive disease) Recurrent disease HLA*0201 positive ECOG performance status 0 or 1 Absolute neutrophil count > 1,000/mm^3 Platelet count > 100,000/mm^3 Hemoglobin > 8.0 g/dL ALT and AST < 3 times upper limit of normal Bilirubin ≤ 2.0 mg/dL (< 3.0 mg/dL if Gilbert's disease is present) Creatinine ≤ 2.0 mg/dL Life expectancy ≥ 3 months Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for up to 4 months after receiving the preparative regimen No active systemic infections, coagulation disorders, or other major medical illnesses of the cardiovascular, respiratory, or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, or obstructive or restrictive pulmonary disease No autoimmune disease (e.g., autoimmune colitis or Crohn's disease) or primary immunodeficiency disease No HIV positivity No hepatitis B or C virus positivity No Epstein-Barr virus negativity Eligible to receive high-dose IL-2, as evidenced by the following: Patients ≥ 50 years of age must have a normal cardiac stress test (e.g., stress thallium, stress MUGA, dobutamine echocardiogram, or other stress test) AND LVEF ≥ 45% Patients with a history of EKG abnormalities, symptoms of cardiac ischemia, or arrhythmias must have a normal cardiac stress test AND LVEF ≥ 45% Patients with a prolonged history of cigarette smoking or symptoms of respiratory dysfunction must have a normal pulmonary function test, as evidenced by FEV 1 ≥ 60% of predicted At least 4 weeks since prior systemic therapy At least 6 weeks since prior nitrosourea therapy No concurrent systemic steroid therapy Recovered immune competence after prior chemotherapy or radiotherapy No prior gp100:209-217 or MART-1:27-35 peptide vaccine

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 |
| --- | --- |
| Experimental: Arm I<br>Patients undergo apheresis and in-vitro depletion of T-regulatory cells. Patients then receive a nonmyeloablative, lymphocyte-depleting preparative regimen comprising cyclophosphamide IV over 1 hour on days -8 and -7 and fludarabine IV over 15-30 minutes on days -6 to -2 followed by autologous T-regulatory-depleted lymphocytes IV over 20-30 minutes on day 0. Patients receive vaccination with gp100:209-217 (210M) and MART-1:27-35 peptides emulsified in Montanide ISA-51 subcutaneously (SC) on days 0-3, 20-23, 41-44, and 62-65. Patients also receive filgrastim (G-CSF) SC beginning on day 1 and continuing until blood counts recover. | Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Biological: therapeutic autologous lymphocytes<br>* Given IV<br>* Other names: autologous T cells;Procedure: in vitro-treated peripheral blood stem cell transplantation<br>* Undergo in vitro-treated peripheral blood stem cell transplantation<br>* Other names: peripheral blood progenitor cell transplantation, in vitro-treated;Biological: gp100 antigen<br>* Given SC<br>* Other names: gp100;Biological: MART-1 antigen<br>* Given SC<br>* Other names: MART-1 Tumor Antigen;Biological: incomplete Freund's adjuvant<br>* Given SC<br>* Other names: Montanide ISA 51;Biological: filgrastim<br>* Given SC<br>* Other names: Neupogen;|
| Experimental: Arm II<br>Patients receive treatment as in arm I. Patients also receive high-dose IL-2 IV over 15 minutes every 8 hours on days 0-4, beginning after the lymphocyte infusion. IL-2 treatment repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Biological: therapeutic autologous lymphocytes<br>* Given IV<br>* Other names: autologous T cells;Procedure: in vitro-treated peripheral blood stem cell transplantation<br>* Undergo in vitro-treated peripheral blood stem cell transplantation<br>* Other names: peripheral blood progenitor cell transplantation, in vitro-treated;Biological: gp100 antigen<br>* Given SC<br>* Other names: gp100;Biological: MART-1 antigen<br>* Given SC<br>* Other names: MART-1 Tumor Antigen;Biological: incomplete Freund's adjuvant<br>* Given SC<br>* Other names: Montanide ISA 51;Biological: filgrastim<br>* Given SC<br>* Other names: Neupogen;Biological: aldesleukin<br>* Given IV<br>* Other names: recombinant interleukin-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective clinical response (CR or PR) |  | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of anti-tumor T cells |  | Up to 2 years | 
| Recovery of regulatory T cells |  | Up to 2 years | 
| Incidence of DLTs and SAEs graded according to CTCAE version 3.0 |  | Up to 2 years |