Background: The rationale for studying the combination of bevacizumab plus irinotecan and temozolomide (BIT) in neuroblastoma is based on: (a) Vascular endothelial growth factor (VEGF) expression is associated with aggressive phenotype. (b) Anti-VEGF antibody bevacizumab enhances irinotecan-mediated suppression of xenografts. (c) Irinotecan+temozolomide (IT) is a standard salvage chemotherapy. (d) Bevacizumab safety was established in pediatric phase I studies.
Methods: We completed a phase II study to evaluate tumor responses to BIT in patients with measurable/evaluable refractory or relapsed high-risk neuroblastoma (www.clinicaltrials.gov NCT01114555). Each cycle consisted of bevacizumab (15mg/kg intravenously) (days 1 and 15) plus irinotecan (50mg/m2/day intravenously) and temozolomide (150mg/m2/day orally) (days 4-8). Patients could have previously received but not relapsed on IT. Patients were monitored for toxicity and response assessed after every two cycles; cycles could be repeated every four weeks after reversal of toxicities, and if progressive disease (PD) was not observed. An early stopping rule for efficacy mandated continuing study therapy only if >5/27 evaluable patients achieved partial (PR) or complete response (CR) based on INRC after 4 cycles.
Results: 33 heavily-pretreated (25 previously received IT) patients (9 primary refractory; 24 relapsed) received 1 (n=7 patients), 2 (n=7), 3 (n=1), 4 (n=10), 5 (n=1), 6 (n=5), 7 (n=1) or 8 (n=1) cycles respectively. All toxicities were expected and transient. Grade 4 toxicities were neutropenia (n=11, 30%), thrombocytopenia (n=8; 24%) and proteinuria (n=2; 6%). Grade 3 toxicities included hepatic transaminitis (n=5;15%) and diarrhea (n=1;3%). Overall responses were: 3 CR (all in prior IT-treated patients with relapsed disease), 12 PD and 18 no response. Only 1/23 patients assessable for early stopping rule regarding efficacy achieved CR/PR. Median progression-free and overall survival post-BIT was 7.7±1.7 and 31.5±5.6 months respectively; all patients received further anti-neuroblastoma therapy post-BIT.
Conclusion: Although BIT was well tolerated, the addition of bevacizumab did not improve response rates in relapsed or refractory neuroblastoma compared to historical data for IT. The study was terminated due to lack of efficacy of the combination.