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

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.

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