Abstract
PURPOSE: Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HR-NBL) remain dismal. Here, we investigate addition of the anti-GD2 monoclonal antibody, dinutuximab beta (dB), to temozolomide (T)-based chemotherapy. MATERIALS AND METHODS: Patients with RR-HR-NBL were randomly assigned in a 1:2 ratio to receive chemotherapy alone or chemotherapy with dB, given concurrently as a 7-day infusion (10 mg/m(2)/24 h). The trial had a factorial design, with some patients also randomly assigned between chemotherapy regimens (T v T-topotecan [TTo]). Crossover to dB with To/cyclophosphamide was allowed for patients randomly assigned to chemotherapy alone with disease progression (PD). The primary outcome was best objective response (complete or partial) rate (overall response rate [ORR]) during six cycles of treatment. Progression-free (PFS), overall survival (OS), and safety were secondary outcomes. RESULTS: Sixty-five patients were randomly assigned to chemotherapy alone (3 T, 19 TTo) or with dB (6 dBT, 37 dBTTo). The median age was 4 years; 28 and 37 patients had refractory and relapsed diseases, respectively. Baseline characteristics were balanced between arms. The ORR was 30.2% (13 of 43) and 18.2% (4 of 22) in dB and non-dB arms, the median PFS was 11.1 months (95% CI, 4.3 to 15.5) for dB patients and 3.8 months (95% CI, 1.9 to 7.9) for non-dB patients, respectively. The median OS was 25.7 months (95% CI, 11.4 to not reached [NR]) for dB patients and 17.1 months (95% CI, 7.6 to 54.6) for non-dB patients (upper 95% CI, NR in dB arm). Thirteen of 22 patients in the non-dB arm crossed over to dB with cyclophosphamide/To because of PD. Neurotoxicity was more common in the dB arm (grade 1 and 2: 26% v 9%, grade 3: 2.3% v 4.5%), but other toxicities were similar. CONCLUSION: Within a randomized phase II setting, results observed with addition of dB to T-based chemotherapy in RR-HR-NB warrant further evaluation.