A novel anti-GD2 monoclonal antibody (mAb), hu14.18K322A, in children with refractory or recurrent neuroblastoma: Early-phase evaluation.
9523 Background: Immunotherapy, including combination anti-GD2 mAb ch14.18 and cytokines, improves the outcome of patients with advanced neuroblastoma. Dose escalation of antibodies targeting GD2 antigen on neuroblastoma cells has been limited by toxicities which may be partially mediated by complement activation. Hu14.18K332A is a humanized anti-GD2 mAb with a single point mutation (K322A) reducing complement-dependent lysis. We report the preliminary results of a phase I trial to determine the maximum tolerated dose (MTD) and toxicity profile of hu14.18K322A. METHODS: Cohorts of 3-6 eligible patients with refractory or recurrent neuroblastoma received a 4-hour daily IV infusion of escalating doses of hu14.18K322A (2, 4, 6, 10, 20, 40, 50, and 60 mg/m(2)/dose) for 4 consecutive days every 28 days (1 course). Patients were allowed to receive up to 4 courses in the absence of progressive disease or unacceptable toxicity. RESULTS: A total of 32 patients (22 males, median age 6.5 years) received a total of 71 courses. Patients received a median of 2 courses. Dose-limiting grade 3 toxicities occurred in 2 of 29 evaluable patients and were characterized by cough and asthenia. The most common grade 3 or 4 toxicities were pain (65% of patients), fever (19%) and hyponatremia (13%). Pain was well managed and predominately occurred on the first day of course 1. Grade 1 or 2 ocular abnormalities were noted in 13 patients and appear to be dose related. No objective responses by RECIST have been observed; however, 9 patients completed the maximum of 4 courses allowed by protocol. CONCLUSIONS: Hu14.18K322A is well tolerated at the doses tested which exceed the dosages of similar GD2 mAbs used in other trials. MTD has not been defined and the study continues to accrue patients at higher doses.
Navid, F; Barfield, RC; Handgretinger, R; Sondel, PM; Shulkin, BL; Kaufman, R; Billups, C; Wu, J; Furman, WL; McGregor, LM; Otto, M; Gillies, S; Santana, VM
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