Vaccine Therapy in Treating Patients With Stage III or Stage IV Melanoma That Cannot Be Removed With Surgery

Randomized, Open Phase II Study of Immunization With the Recombinant MAGE-3 Protein Combined With Adjuvant AS02B or AS15 in Patients With Unresectable and Progressive Metastatic Cutaneous Melanoma

RATIONALE: Vaccines may make the body build an immune response to kill tumor cells.

PURPOSE: This randomized phase II trial is studying two different regimens of vaccine therapy and comparing them to see how well they work in treating patients with stage III or stage IV melanoma that cannot be removed with surgery.

OBJECTIVES:

Primary

• Compare the objective response rate (complete and partial response) in patients with unresectable stage III or stage IV M1a cutaneous melanoma immunized with vaccine comprising D1/3-MAGE-3-His fusion protein and SB-AS02B adjuvant vs SB-AS15 adjuvant.
• Compare the activity of SB-AS02B adjuvant vs SB-AS15 adjuvant, in terms of maximizing the antigenicity of MAGE-3, in patients treated with these regimens.
• Compare the rate of grade 3/4 vaccine-related toxicity in patients treated with these regimens.

Secondary

• Compare progression-free survival in patients treated with these regimens.

OUTLINE: This is a randomized, open label, parallell-group, multicenter study. Patients are stratified according to disease stage (III in transit vs other stage III vs IV), presence of lesion ≥ 20 mm (yes vs no), and participating center. Patients are randomized to 1 of 2 treatment arms.

• Induction therapy

  • Arm I: Patients receive immunization comprising D1/3-MAGE-3-His fusion protein and SB-AS02B adjuvant intramuscularly (IM) once weekly on weeks 1, 3, 5, 7, 9, and 11.
  • Arm II: Patients receive immunization comprising D1/3-MAGE-3-His fusion protein SB-AS15 adjuvant IM once weekly on weeks 1, 3, 5, 7, 9, and 11.

Patients achieving a clinical complete response (CR), partial response (PR), stable disease (SD), or slow progressive disease (SPD) proceed to maintenance therapy.

• Maintenance therapy: Patients in both arms receive immunization (according to their randomized arm) once weekly on weeks 15, 18, 21, 24, 27, 30, 34, 40, 46, and 52.

Patients maintaining a CR, PR, or SD proceed to long-term treatment.

• Long-term treatment: Beginning 3 months after completion of maintenance therapy, patients in both arms receive immunization (according to their randomized arm) once every 3 months for 4 courses and then once every 6 months for 4 courses.

Treatment continues in both arms in the absence of disease progression that does not correspond to SPD status, unacceptable toxicity, or the diagnosis of an autoimmune disease.

Patients are followed every 12 weeks.

PROJECTED ACCRUAL: A total of 68 patients (34 patients per treatment arm) will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed cutaneous melanoma

  • Unresectable stage III OR stage IV M1a disease

• Documented progressive disease within the past 12 weeks

• Measurable disease

• Skin, soft tissue, or lymph node metastasis allowed provided the disease is not amenable to curative treatment with surgery

• Tumor must express the MAGE-3 gene by reverse transcription polymerase chain reaction analysis (more than 1% of the positive MAGE-3 control included in the assay)

• No visceral metastases within the past 56 days by imaging

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Hemoglobin ≥ lower limit of normal (LLN)
• WBC ≥ LLN
• Lymphocyte count ≥ LLN
• Platelet count ≥ LLN
• No bleeding disorders

Hepatic

• Bilirubin ≤ upper limit of normal (ULN)
• Lactic dehydrogenase ≤ ULN
• AST and ALT ≤ 2 times ULN
• PT and aPTT normal
• Hepatitis B surface antigen negative (antibody test may be positive)
• Hepatitis C antibody negative

Renal

• Creatinine ≤ ULN

Cardiovascular

• No clinically significant heart disease (CTC grade III or IV)

Immunologic

• No autoimmune disease (vitiligo allowed)
• No anti-nuclear antibody titer ≥ 1/320 OR equal to 1/160 AND auto-antibodies directed against specific auto-antigens
• No immunodeficiency
• No active infection requiring antibiotic therapy
• HIV negative

Other

• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study participation
• No other malignancy within the past 5 years except surgically cured basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No other serious acute or chronic illness requiring concurrent medications
• No psychological, familial, sociological, or geographical condition that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• More than 8 weeks since prior adjuvant vaccine therapy
• No prior vaccine therapy containing a MAGE-3 antigen
• No prior vaccine therapy for metastatic melanoma
• No concurrent immunomodulating agents (e.g., BCG)

Chemotherapy

• No prior systemic chemotherapy
• No concurrent chemotherapy

Endocrine therapy

• No concurrent corticosteroids

  • Concurrent prednisone or equivalent allowed provided the dose is ≤ 40 mg/day and treatment duration is for no more than 3 weeks
  • Concurrent inhaled and topical steroids are allowed

Radiotherapy

• No prior radiotherapy to the spleen

• No concurrent radiotherapy to > 20% of all existing lesions (i.e., target lesions, non-target lesions, and nonmeasurable lesions)

  • Concurrent local low-dose (≤ 20 Grays) radiotherapy allowed

Surgery

• Recovered from prior surgery or biopsy
• No prior organ allograft
• No prior splenectomy
• Concurrent surgery to a limited number of lesions allowed for patients with a complete response, partial response, or stable disease after at least 3 courses of study therapy

Other

• No prior systemic anticancer therapy
• More than 4 weeks since prior isolated limb perfusion therapy
• No other concurrent anticancer therapy
• No other concurrent immunosuppressive agents