Phase II Trial Of Extended Dose Anti-CTLA-4 Antibody Ipilimumab (formerly MDX-010) With A Multi-peptide Vaccine For Resected Stages IIIC And IV Melanoma
Background: Ipilimumab is a human anti-CTLA-4 antibody shown to have clinical activity in melanoma and renal cancer that is associated with inflammatory-type adverse events termed immune breakthrough events (IBEs). Methods: 25 patients with resected stages IIIC/IV melanoma received MART-1/gp100/tyrosinase peptides with adjuvant Montanide ISA 51 12 times injected subcutaneously with Ipilimumab at 3 mg/kg intravenously every eight weeks for 12 months. The primary endpoints were toxicity and the achievement of a 40% rate of tolerable IBEs, and 20% or less rate of intolerable adverse events. Immune responses measured by ELISPOT and peptide-tetramer assays, and time to relapse were also assessed. The three melanoma peptides differed from wild type by one amino acid modification to increase HLA binding, and were administered at 1000 mcg/dose each. Results: Median age was 55, with 13 men and 12 women. 15 patients had stage IV, and 10 had stage IIIC resected disease. Thus far, 12/25 (48%) patients had grades 2–3 IBEs; 5 (20%) were dose limiting; 7 had GI toxicity, of which 2 were dose limiting; four had skin toxicity, of which 2 were dose limiting; one patient had hypopituitarism, which was also dose limiting. No patient with dose limiting toxicity required hospitalization and all returned to baseline status with the use of systemic steroids. Serologic assays of IBD-related microbial and auto-antibodies showed that seven of eight patients tested had increases in ANCA IgG or I2 IgA, and 5/8 had increases in ASCA IgA. Four of 25 patients have relapsed with a median of 10 months of follow-up. Two were again rendered NED surgically. The two remaining patients were treated with biochemotherapy, with one CR and one PR. All 25 patients are alive, one with disease. No patient with grade 2–3 IBEs has relapsed. ELISPOT assays showed that 10/11 patients tested responded in fresh PBMC to MART-1 and gp100. Conclusions: These data suggest that IBEs are associated with clinical benefit in patients with resected high-risk melanoma receiving Ipilimumab at 3 mg/kg with a peptide vaccine, and support testing the current regimen in a larger randomized trial.
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