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A Phase I Trial of SD-9427 (Progenipoietin) with a Multipeptide Vaccine for Resected Metastatic Melanoma¹

Department of Medicine, Divisions of Hematology [V. P.] and Medical Oncology [R. S., R. L., J. S., S. S., J. S. W.] and Department of Preventive Medicine [S. G., C. G.] Keck School of Medicine, University of Southern California, Los Angeles, California 90033; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California 94305 [P. P. L., V. R.], and Pharmacia, St. Louis, Missouri 63198 [S. L. W., R. A. W.]

Purpose: The melanoma tumor antigen epitope peptides MART-1_{26–35 (27L)}, gp100_{209–217 (210M)},and tyrosinase_{368–376 (370D)} were emulsified with incomplete Freund’s adjuvant and administered with SD-9427 (progenipoietin), an agonist of granulocyte colony-stimulating factor and the FLT-3 receptor, to evaluate the toxicities of and immune responses to this regimen as primary end points and time to relapse and survival as secondary end points.

Experimental Design: Fifteen patients with high-risk resected stage III and IV melanoma were enrolled. Each patient received peptides + incomplete Freund’s adjuvant with SD-9427 at doses of either 10, 20, or 40 µg/kg s.c. for 3 days before and 7 days after each vaccination. Immunizations were administered every month for 6 months and then administered once 6 months later. A leukapheresis to obtain peripheral blood mononuclear cells for immune analyses as well as skin testing with peptides and recall antigens was performed before and after vaccination. IFN- release assay, ELISPOT, and MHC-peptide tetramer analysis were performed using peripheral blood mononuclear cells collected before and after vaccination to evaluate peptide-specific cytotoxic T-cell responses.

Results: Local pain and granuloma formation and fatigue of grade I or II were the most common side effects. One patient developed antibody-mediated leukopenia and transient grade III neutropenia that resolved after stopping SD-9427. Six of 12 patients tested developed a positive skin test response to one or more of the peptides. Seven of 10 patients tested demonstrated an immune response to at least one peptide when evaluated by IFN- release assay and ELISPOT assay after vaccination, as did 11 of 12 patients analyzed by MHC-peptide tetramer assay. Four of 15 patients have relapsed with a median follow-up of 20 months, and 1 patient in this high-risk group has died of disease.

Conclusions: SD-9427 with a multipeptide vaccine was generally well tolerated, although one patient developed reversible antibody-mediated neutropenia. These data suggest that the majority of patients with resected melanoma mount an antigen-specific immune response against a multipeptide vaccine administered with SD-9427.

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