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.

Abstract

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 alpha (sIL2Ralpha) 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.

• Authors: Kaci L Osenga, Jacquelyn A Hank, Mark R Albertini, Jacek Gan, Adam G Sternberg, Jens Eickhoff, Robert C Seeger, Katherine K Matthay, C Patrick Reynolds, Clare Twist, Mark Krailo, Peter C Adamson, Ralph A Reisfeld, Stephen D Gillies, Paul M Sondel, Children's Oncology Group
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 6 Pg. 1750-9 (Mar 15 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16551859 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Antibodies, Monoclonal
• Interleukin-2
• lorukafusp alfa

Topics

• Adolescent
• Anemia (chemically induced)
• Antibodies (blood)
• Antibodies, Monoclonal (adverse effects, pharmacokinetics, therapeutic use)
• Area Under Curve
• Child
• Child, Preschool
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Female
• Fever (chemically induced)
• Humans
• Hypotension (chemically induced)
• Infusions, Intravenous
• Interleukin-2 (adverse effects, pharmacokinetics, therapeutic use)
• Male
• Melanoma (drug therapy, pathology)
• Metabolic Clearance Rate
• Neoplasm Recurrence, Local
• Neuroblastoma (drug therapy, pathology)
• Treatment Outcome