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A Phase I Clinical Trial of the hu14.18-IL2 (EMD 273063) as a Treatment for Children with Refractory or Recurrent Neuroblastoma and Melanoma: a Study of the Children's Oncology Group

Authors' Affiliations: ¹ The University of Wisconsin-Madison, Madison, Wisconsin; ² Children's Hospital of Los Angeles, Los Angeles, California; ³ University of California-San Francisco, San Francisco, California; ⁴ Stanford University, Stanford, California; ⁵ Children's Oncology Group, Arcadia, California; ⁶ Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; ⁷ The Scripps Research Institute, La Jolla, California; and ⁸ EMD Lexigen Research Center, Billerica, Massachusetts

Requests for reprints: Paul M. Sondel, K4/448 UWCCC, 600 Highland Avenue, Madison, WI 53792, Phone: 608-263-9069; Fax: 608-263-4226; E-mail: pmsondel{at}humonc.wisc.edu.

Purpose: Evaluate the clinical safety, toxicity, immune activation/modulation, and maximal tolerated dose of hu14.18-IL2 (EMD 273063) in pediatric patients with recurrent/refractory neuroblastoma and other GD2-positive solid tumors.

Experimental Design: Twenty-seven pediatric patients with recurrent/refractory neuroblastoma and one with melanoma were treated with a humanized anti-GD2 monoclonal antibody linked to human interleukin 2 (IL-2). Cohorts of patients received hu14.18-IL2, administered i.v. over 4 hours for three consecutive days, at varying doses. Patients with stable disease, partial, or complete responses were eligible to receive up to three additional courses of therapy.

Results: Most of the clinical toxicities were anticipated and similar to those reported with IL-2 and anti-GD2 monoclonal antibody therapy and to those noted in the initial phase I study of hu14.18-IL2 in adults with metastatic melanoma. The maximal tolerated dose was determined to be 12 mg/m²/d, with agent-related dose-limiting toxicities of hypotension, allergic reaction, blurred vision, neutropenia, thrombocytopenia, and leukopenia. Three patients developed dose-limiting toxicity during course 1; seven patients in courses 2 to 4. Two patients required dopamine for hypotension. There were no treatment-related deaths, and all toxicity was reversible. Treatment with hu14.18-IL2 led to immune activation/modulation as evidenced by elevated serum levels of soluble IL-2 receptor (sIL2R) and lymphocytosis. The median half-life of hu14.18-IL2 was 3.1 hours. There were no measurable complete or partial responses to hu14.18-IL2 in this study; however, three patients did show evidence of antitumor activity.

Conclusion: Hu14.18-IL2 (EMD 273063) can be administered safely with reversible toxicities in pediatric patients at doses that induce immune activation. A phase II clinical trial of hu14.18-IL2, administered at a dose of 12 mg/m²/d x 3 days repeated every 28 days, will be done in pediatric patients with recurrent/refractory neuroblastoma.

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