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Three Phase II Cytokine Working Group Trials of gp100 (210M) Peptide Plus High-Dose Interleukin-2 in Patients With HLA-A2–Positive Advanced Melanoma

Jeffrey A. Sosman, Carole Carrillo, Walter J. Urba, Lawrence Flaherty, Michael B. Atkins, Joseph I. Clark, Janet Dutcher, Kim A. Margolin, James Mier, Jarod Gollob, John M. Kirkwood, David J. Panka, Nancy A. Crosby, Kevin O'Boyle, Bonnie LaFleur, Marc S. Ernstoff

From the Vanderbilt University Medical Center, Nashville, TN; Earle A. Chiles Research Institute, Portland, OR; Wayne State University, Detroit, MI; Beth Israel Deaconess Medical Center, Boston, MA; Loyola University Medical Center, Maywood, IL; Our Lady of Mercy Medical Center, Bronx, NY; City of Hope Medical Center, Duarte, CA; University of Pittsburgh Medical Center, Pittsburgh, PA; and Dartmouth Hitchcock Medical Center, Lebanon, NH

Corresponding author: Jeffrey A. Sosman, MD, Vanderbilt-Ingram Cancer Center Vanderbilt, University Medical Center, Section of Hematology/Oncology, 777 Preston Research Bldg, Nashville, TN 37232-6307; e-mail: jeff.sosman{at}vanderbilt.edu

Purpose: High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2–restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial.

Patients and Methods: In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment.

Results: From 1998 to 2003, 131 patients with HLA-A2–positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at 30 months. Immune studies including assays of CD3- expression and numbers of CD4⁺/CD25⁺/FoxP3⁺ regulatory T cells, CD15⁺/CD11b⁺/CD14^– immature myeloid-derived cells, and CD8⁺gp100 tetramer-positive cells in the blood did not correlate with clinical benefit.

Conclusion: The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.

Supported by a research grant from Chiron Pharmaceuticals (Emeryville, CA); support from Cancer Therapy Evaluation Program–National Cancer Institute, which held the Investigation New Drug Applications for gp100:209-217(210M) (NSC 683472) and Montanide ISA-51 (NSC 675756); and K24 Grant No. 5K24-CA097588 (J.A.S.).

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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