Originally published as JCO Early Release 10.1200/JCO.2004.11.035 on October 13 2004

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Phase I Clinical Trial of the Immunocytokine EMD 273063 in Melanoma Patients

From the University of Wisconsin, Madison, WI; Departments of Medicine, Human Oncology, Surgery, Pathology, Biostatistics, Pediatrics, and Genetics, Ohio State University, Columbus, OH; The Scripps Research Institute, La Jolla CA; and EMD-Lexigen Research Center, Billerica, MA

Address reprint requests to Mark R. Albertini MD, 600 Highland Avenue, K4/414 CSC, Madison, WI 53792; e-mail: mralbert{at}facstaff.wisc.edu

PURPOSE: To evaluate the safety, toxicity, in vivo immunologic activation, and maximum-tolerated dose (MTD) of EMD 273063 (hu14.18-IL-2) in patients with metastatic melanoma.

PATIENTS AND METHODS: Thirty-three patients were treated with EMD 273063, a humanized anti-GD2 monoclonal antibody (mAb) linked to interleukin-2 (IL-2). EMD 273063 was given as a 4-hour intravenous infusion on days 1, 2, and 3 of week 1. Patients with stabilization or regression of disease could receive a second course of treatment at week 5. Dose levels evaluated were 0.8, 1.6, 3.2, 4.8, 6.0, and 7.5 mg/m²/d.

RESULTS: Nineteen of 33 patients completed course 1 with stable disease and went on to receive course 2. Eight patients had stable disease on completion of course 2. Grade 3 adverse events included hypophosphatemia (11 patients), hyperglycemia (three patients), hypotension (two patients), thrombocytopenia (one patient), hypoxia (three patients), elevated hepatic transaminases (two patients), and hyperbilirubinemia (one patient). Opioids were required for treatment-associated arthralgias and/or myalgias during 17 of 52 treatment courses. No grade 4 adverse events were observed. Dose-limiting toxicities at the MTD included hypoxia, hypotension, and elevations in AST/ALT. Grade 3 toxicities were anticipated based on prior studies of IL-2 or anti-GD2 mAbs, and all resolved. Immune activation was induced, as measured by lymphocytosis, increased peripheral-blood natural killer activity, and cell numbers, and increased serum levels of the soluble alpha chain of the IL-2 receptor complex.

CONCLUSION: Treatment with the immunocytokine EMD 273063 induced immune activation and was associated with reversible clinical toxicities at the MTD of 7.5 mg/m²/d in melanoma patients.

Supported by grant Nos. CA32685, CA14520, CA87025, CA81403, and RR03186 from the National Institutes of Health and a grant from the Midwest Athletes for Childhood Cancer Fund. Partial personnel support was provided by EMD for data management required by EMD for this study, which was beyond the clinical research and data monitoring required for this National Cancer Institute–supported study.

Work previously presented in part at the 35th Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999; the 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 20-23, 2000; the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002; American Association for Cancer Research Annual Meeting, Washington DC, July 11-15, 2003; and Society for Biologic Therapy Annual Meetings, Bethesda, MD, November 8-10, 2001, and San Diego, CA, November 7-9, 2002.

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

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