Humanized 3F8 Anti-G(D2) Monoclonal Antibody Dosing With Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Resistant Neuroblastoma A Phase 1 Clinical Trial

IMPORTANCE Chimeric and murine anti-G(D2) antibodies are active against neuroblastoma, but the development of neutralizing antibodies can compromise efficacy. To decrease immunogenicity, hu3F8, a humanized anti-G(D2) antibody, was constructed. OBJECTIVE To find the maximum-tolerated dose of hu3F8 with granulocyte-macrophage colony-stimulating factor. DESIGN, SETTING, AND PARTICIPANTS This phase 1 clinical trial used a 3 + 3 dose-escalation design in a single referral center (Memorial Sloan Kettering Cancer Center, New York, New York). Participantswere enrolled from December 24, 2012, through May 3, 2016, with follow-up and analyses through February 28, 2018. Eligibility criteria included older than 1 year and resistant or recurrent neuroblastoma regardless of the number or kinds of prior treatments. All 57 participants met the eligibility criteria, received treatment according to the protocol, andwere included in all analyses. INTERVENTIONS Treatmentcyclesweremonthly, ifhumanantihumanantibodyremainednegative. Each cycle comprised hu3F8 infused intravenously for 30minutes on Monday, Wednesday, and Friday aswell as granulocyte-macrophage colony-stimulating factor administered subcutaneously dailyfrom5days before infusionthroughthe lastdayof infusion. After cycle 2, hu3F8was increased to the highest dose level that had been confirmed as safe. MAIN OUTCOMES AND MEASURES Toxicity, pharmacokinetics, immunogenicity, and disease response. RESULTS Of the 57 participants, 34 (60%) were male and 23 (40%) were female (male-to-female ratio of 1.5), with a median (range) age of 6.8 (2.4-31.3) years at enrollment and a median (range) time of 3.1 (0.6-9.0) years since initial chemotherapy. Participants received a median (range) of 4 (1-15) cycles. Treatment was outpatient with reversible neuropathic pain and without unexpected toxic effects. No maximum-tolerated dose was identified. Dose escalation was associated with increased serum levels and proceeded through dosage of 9.6 mg/kg/cycle (approximately 288 mg/m(2)), which is more than 2.5 times higher than the standard dosage of 75 mg/m(2)/cycle or 100 mg/m(2)/cycle of dinutuximab and m3F8. Human antihuman antibody positivity developed in 5 of 57 patients (9%) after cycle 1, including in 1 of 10 patients (10%) not previously treated with anti-G(D2) antibody and in 4 of 47 patients (9%) previously exposed to 1 or 2 anti-G(D2) antibodies. Antineuroblastoma activity included major responses associated with higher dosing and prolonged progression-free survival despite a history of relapses. CONCLUSIONS AND RELEVANCE This phase 1 clinical trial found hu3F8 to be associated with modest toxic effects, low immunogenicity, and substantial antineuroblastoma activity; phase 2 trials are in progress.