Fludarabine Followed by Vaccine Therapy and White Blood Cell Infusions in Treating Patients With Unresectable or Metastatic Melanoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as fludarabine, work in different ways to stop tumor cells from dividing so they stop growing or die. Vaccines made from peptides may make the body build an immune response to kill tumor cells. Infusions of a person's white blood cells may be able to replace immune cells that were destroyed by chemotherapy. Combining fludarabine with vaccine therapy and white blood cell infusions may kill more tumor cells. PURPOSE: This randomized phase I trial is studying the side effects of giving vaccine therapy together with fludarabine and white blood cell infusions and to see how well it works in treating patients with unresectable or metastatic melanoma.

Detailed Description
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OBJECTIVES: Primary Determine the toxicity and immune effects of vaccination comprising modified gp100 peptide (gp100:209-217[210M]), Montanide ISA-51, and keyhole limpet hemocyanin followed by peripheral blood mononuclear cell reinfusion after treatment-induced lymphopenia with fludarabine in patients with unresectable or metastatic melanoma. Determine the induction of antigen-specific T-cell responses in patients treated with this regimen. Determine the kinetics and duration of immune response in patients treated with this regimen. Compare the immunologic effects of this regimen in these patients with historical results. Secondary Compare 2 different dosing schedules of fludarabine, in terms of induction of lymphopenia and granulocytopenia and on the induction of a specific immune response to this vaccine, in these patients. OUTLINE: This is a pilot, randomized study. Patients are randomized to 1 of 2 treatment arms. Within 2 weeks before the start of fludarabine, all patients undergo leukapheresis over 4-6 hours for the collection of peripheral blood mononuclear cells (PBMCs). Arm I: Patients receive fludarabine IV over 30 minutes on days 1-5. Arm II: Patients receive fludarabine as in arm I on days 1, 3, and 5. In both arms, patients receive autologous PBMCs IV over approximately 30 minutes on day 8 and vaccination comprising gp100:209-217(210M) peptide, Montanide ISA-51, and keyhole limpet hemocyanin subcutaneously on days 8, 22, 36, 50, and 64. Patients with stable or responding disease continue to receive vaccination on day 78 and then every 28-31 days for up to 1 year. Patients are followed every 3 months. PROJECTED ACCRUAL: A total of 20 patients (10 per treatment arm) will be accrued for this study within 2 years.

Official Title
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A Pilot Trial of Therapeutic Vaccination With a Modified gp100 Melanoma Peptide (gp100:209-217(210M)), Montanide ISA 51, and KLH With Reconstitution After Chemotherapy to Induce Lymphopenia in Patients With Metastatic Melanoma

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Biological: gp100 antigen
* Biological: incomplete Freund's adjuvant
* Biological: keyhole limpet hemocyanin
* Drug: fludarabine phosphate
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed malignant melanoma Metastatic or unresectable disease Measurable disease HLA-A2 positive Received at least 1 prior immunotherapy and/or chemotherapy regimen for metastatic disease (first 6 patients only) No known brain metastases unless previously treated with radiotherapy and/or surgery AND is stable for at least 1 month after treatment PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-2 OR Karnofsky 60-100% Life expectancy More than 3 months Hematopoietic WBC ≥ 3,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Absolute lymphocyte count ≥ 500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 10 g/dL (transfusions allowed) Hematocrit ≥ 24% No other active bleeding Hepatic Bilirubin < 2 times upper limit of normal (ULN) (unless due to Gilbert's disease) AST and ALT < 3 times ULN Hepatitis B surface antigen negative Hepatitis C antibody negative Renal Creatinine < 2 mg/dL No uncontrolled hypercalcemia Cardiovascular No uncontrolled symptomatic congestive heart failure No unstable angina pectoris No uncontrolled cardiac arrhythmia No uncontrolled hypertension Pulmonary No uncontrolled bronchospasm No hemoptysis Immunologic Negative serology for all of the following: HIV-1 and HIV-2 HTLV-1 and -2 Syphilis Rheumatoid factor < 43 units/μL Anti-nuclear antibody < 11 units/μL No history of multiple sclerosis, systemic lupus erythematosus, or myasthenia gravis No primary or secondary immunodeficiency No active infection No allergy to seafood or shellfish that would preclude study participation Other No active gastrointestinal bleeding No uncontrolled hyperglycemia No other medical or psychiatric condition or social situation that would preclude study compliance No other uncontrolled illness Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3-4 months after study participation PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics No prior immunization with gp100:209-217(210M) peptide Chemotherapy See Disease Characteristics More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) Endocrine therapy More than 2 weeks since prior steroid therapy except replacement steroids or inhaled steroids No concurrent corticosteroids except replacement steroids No concurrent dexamethasone Radiotherapy See Disease Characteristics More than 2 weeks since prior radiotherapy Surgery See Disease Characteristics Recovered from prior surgery Other No other concurrent investigational agents No other concurrent anticancer 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
Allocation: Randomized


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: gp100 antigen|nan|
|Biological: incomplete Freund's adjuvant|nan|
|Biological: keyhole limpet hemocyanin|nan|
|Drug: fludarabine phosphate|nan|
|Procedure: peripheral blood stem cell transplantation|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity by clinical and laboratory observation at 1 month |  |  | 
| Antigen-specific T-cell responses by tetramer analysis, ELISPOT, and cytokine flow cytometry periodically |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare 2 different dosing schedules of fludarabine in terms of lymphocyte recovery using a complete blood count periodically |  |  | 
| Tumor regression by standard imaging at study completion |  |  | 

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