Monoclonal Antibody With or Without gp100 Peptides Plus Montanide ISA-51 in Treating Patients With Stage IV Melanoma

OBJECTIVES:

Primary

• Determine the clinical response in patients with stage IV melanoma treated with escalating doses of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010) with or without gp100 peptides emulsified in Montanide ISA-51.

Secondary

• Determine the safety and toxicity profile of these regimens in these patients.
• Determine the immunologic response in patients treated with these regimens.
• Determine the pharmacokinetics of these regimens in these patients.
• Determine, in HLA-A*0201-positive patients, the differences in responses between patients previously vaccinated with gp100 peptides and patients not previously vaccinated.

OUTLINE: This is a 2-part, partially randomized study.

• Part I (closed as of 3/7/2005):

• HLA-A*0201-negative patients: Patients receive anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010) IV over 90 minutes on day 1. Treatment repeats every 3 weeks for up to 6 doses (3 courses of 3 escalating doses) in the absence of disease progression or unacceptable toxicity.
• HLA-A*0201-positive patients: Patients are stratified according to prior exogenous gp100 peptide immunization (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive MDX-010 in the same manner as the HLA-A*0201-negative patients.
• Arm II: Patients receive MDX-010 as in arm I. Patients also receive gp100:209-217 and gp100:280-288 peptides emulsified in Montanide ISA-51 subcutaneously immediately after each MDX-010 infusion.
• Part II:

• HLA-A*0201-negative patients (closed as of 3/7/2005): Patients receive MDX-010 as in part I. Treatment repeats every 3 weeks for up to 4 doses (2 courses of 2 escalating doses, beginning with a higher dose level than in part I) in the absence of disease progression or unacceptable toxicity.
• HLA-A*0201-positive patients: Patients are stratified and randomized as in part I.

• Arm I: Patients receive MDX-010 in the same manner as the HLA-A*0201-negative patients.
• Arm II: Patients receive MDX-010 as in arm I. Patients also receive gp100:209-217 and gp100:280-288 peptides emulsified in Montanide ISA-51 subcutaneously immediately after each MDX-010 infusion.

In both parts, patients with stable disease or a complete response (CR) after completing all courses of MDX-010 may receive 1 additional course of therapy in the absence of unacceptable toxicity. Patients achieving a partial response may continue to recieve treatment with MDX-010 at the same dose, in the absence of unacceptable toxicity, until CR or until tumor is no longer shrinking.

Patients are followed at 3 weeks, every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 35-179 patients (up to 35 for part I [closed as of 3/7/05] and 69-141 [23-47 per arm (arm I closed as of 3/7/05)] for part II) will be accrued for this study within 3-4 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed stage IV melanoma
• Clinically evaluable or measurable disease
• No mucosal or ocular melanoma

PATIENT CHARACTERISTICS:

Age

• 16 and over

Performance status

• ECOG 0-2

Life expectancy

• At least 6 months

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9 g/dL
• Hematocrit ≥ 28%
• WBC ≥ 2,500/mm^3

Hepatic

• AST ≤ 3 times upper limit of normal (ULN)
• Bilirubin ≤ ULN (< 3 mg/dL for patients with Gilbert's syndrome)
• Hepatitis B surface antigen negative
• Hepatitis C virus antibody negative

Renal

• Creatinine < 2 mg/dL

Immunologic

• HIV negative
• No history of any of the following:

• Inflammatory bowel disease
• Regional enteritis
• Connective tissue disorders (e.g., systemic lupus erythematosus)
• Rheumatoid arthritis
• Autoimmune inflammatory eye disease
• Sjögren's syndrome
• Inflammatory neurologic disorder (e.g., multiple sclerosis)
• No active infection
• No active autoimmune disease that may cause life-threatening symptoms or severe organ/tissue damage

• Vitiligo, autoimmune thyroiditis, or skin rashes associated with prior therapy are allowed if patient has recovered to grade 1 or less toxicity
• No systemic hypersensitivity to study agents

• Prior local reaction (e.g., delayed hypersensitivity or glaucomatous reactions) to Montanide ISA-51 or gp100 injections allowed
• No autoimmune disease requiring active therapy with any form of steroid or immunosuppressant

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No concurrent underlying medical condition that would preclude study participation
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody
• Prior therapy with gp100 peptides or any other immunotherapy allowed

Chemotherapy

• At least 6 weeks since prior nitrosoureas and recovered (toxicity no greater than grade 1)
• No concurrent chemotherapy

Endocrine therapy

• At least 4 weeks since prior steroids
• No concurrent systemic, inhaled, optical, or topical corticosteroids

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• At least 3 weeks since prior systemic therapy for melanoma and recovered (toxicity no greater than grade 1)
• No concurrent immunosuppressive agents (e.g., cyclosporine)