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.

Figures

Fig. 1

Lymphocyte counts. Columns, mean lymphocyte counts of all 28 patients in all four courses of immunocytokine therapy based on blood samples before treatment on the indicated days; bars, SE.

Fig. 2

Correlation of boost in lymphocyte counts on day 8 (lymphocyte count on day 8 lymphocyte count on day 0) of course 1 and dose level. The boost in lymphocyte count on day 8 shows a positive correlation with the dose of immunocytokine given (P = 0.002).

Fig. 3

Correlation of peak concentration of hu14.18-IL2 detected on day 1 and on day 3 with the boost in lymphocyte count detected on day 8 (value for day 8 value for day 0) for course 1. Spearman’s rank correlation analysis was done to correlate a change from baseline to day 8 lymphocyte counts versus peak concentration of hu14.18-IL2 on day 1 or 3. There is a significant positive correlation between these variables with P = 0.001 for hu14.18-IL2 levels on day 1 (A) and P = 0.0006 for the hu14.18-IL2 level on day 3 (B).

Fig. 4

sIL2R levels on various days of each course of treatment. Columns, average serum sIL2R levels obtained for serum samples from all patients for each of the designated courses; bars, SE.

Fig. 5

Correlation between sIL2 receptor levels and peak concentration of immunocytokine. AUC of serum sIL2R levels measured from days 0 to 22, during course 1 was computed using the trapezoid rule for each subject. Spearman’s rank correlation coefficient was calculated between sIL2r AUC and peak concentration of immunocytokine for day 1 of course 1. There is a positive correlation between these two variables (P = 0.009). Therefore, a higher sIL2r AUC is associated with higher peak concentrations of hu14.18-IL2.