Evaluation of the Impact of Adjuvants Accompanying Peptide Immunization in High-Risk Melanoma

Background: A previous clinical trial has been conducted in the Surgery Branch National Cancer Institute (NCI) in which gp100 immunizations have been administered to patients with melanoma in the adjuvant setting. In this prior protocol, the peptide emulsified in Incomplete Freund's Adjuvant was administered subcutaneously using several different schedules and was well tolerated except for mild and transient erythema at the site of injection. Each of the schedules provided successful immunization although the q3w schedule was the best tolerated locally and three courses of immunization appeared to be sufficient using this regimen. An important finding from the adjuvant protocol however was the significant increase in immune precursors specifically reactive against peptide and tumor that occurred with increasing courses of immunization. These findings have encouraged us to now further explore the optimal methods for generating immune precursors using the gp100:209-217(210M) peptide by testing the impact of an additional immune adjuvant, imiquimod, reported to increase the immunizing potential of antigens as well as evaluate an alternate route of injection, intradermal administration. Objectives: The primary objective of this trial is to evaluate the immunologic activity of immunization with four different preparations of the gp100:209-217(210M) melanoma antigen peptide and potentially select one for further study. Eligibility: HLA-A 0201 patients, age greater than or equal 16 years, with primary melanomas with lesions that are ulcerated and greater than or equal 2mm, or any lesions that are greater than or equal 4.0 mm in thickness, or greater than or equal 1 positive lymph node, or local recurrence, or resected metastatic disease, within 6 months of surgical resection will be considered. Patients who have ocular or mucosal melanoma or who require systemic steroid therapy will be excluded. The following patients will also be excluded: have previously been immunized with gp100; have known hypersensitivity to any of the agents used in this study; have previously received chemotherapy for treatment of melanoma; or who are undergoing or have undergone in the past 3 weeks any systemic therapy except surgery for their cancer. Design: Patients will be randomized into one of the following four arms: 1. gp100:209-217(210M) peptide emulsified in MONTANIDE ISA-51 or Montanide ISA 51 VG injected subcutaneously on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks). 2. gp100:209-217(210M) peptide emulsified in MONTANIDE ISA-51 or Montanide ISA 51 VG injected subcutaneously on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks); following the injection patients will apply imiquimod to the skin at the site of injection daily for 5 days. 3. gp100:209-217(210M) in 0.9% Sodium Chloride Injection injected intradermally on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks). 4. gp100:209-217(210M) peptide in 0.9% Sodium Chloride Injection injected intradermally on day one every three weeks (1 cycle) for a total of twelve cycles (33 weeks); following the injection patients will apply imiquimod to the skin at the site of the injection daily for 5 days. Immunizations will be administered on an outpatient basis unless side effects or the patient's clinical condition warrants hospitalization. Patients will receive full clinical evaluation three weeks after 8 cycles and 12 cycles. Each of the arms will be conducted using a two-stage optimal design Since the primary objective is to select one regimen from among the four on the basis of the immune response, this design allows there to be greater than 80% probability of correctly selecting the superior arm if there is either a tie in the number of immune responses, or if there is at least one more immune response on one arm than the other three arms, and if the true response rates are 15%, 15%, 15% and 35%. Initially, 19 patients will be enrolled in each arm and evaluated; if 0 to 3 of 19 in an arm have an immune response to T2 cells pulsed with 0.01 M peptide after the 4th, 8th, and 12th cycles, no further patients would be randomized to receive the peptide on that arm. If at least four immunologic responses are noted after the 8th cycle, then accrual to 33 patients would take place. If all four arms need to be completed and 33 patients need to be completed in each arm, a total of 132 patients are required.