Phase I study of vincristine, irinotecan, and 131I-MIBG for patients with relapsed or refractory neuroblastoma: A New Approach to Neuroblastoma Therapy (NANT) study.

Abstract

9513 Background: 131I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical with activity in neuroblastoma. Irinotecan is a radiosensitizer with activity in neuroblastoma. This phase I study aimed to determine the recommended phase II dose (RP2D) of MIBG together with vincristine and irinotecan. Methods: Patients 1-30 years old with relapsed or refractory MIBG-avid neuroblastoma were eligible. All patients had autologous hematopoietic stem cells (PBSCs) available and met standard phase 1 requirements. Prior vincristine and irinotecan, but not prior MIBG, were allowed. Patients received cefixime (8 mg/kg/day) on days -5 to +21. Irinotecan (20 mg/m2/dose IV) was given on days 0-4 and 7-11, with vincristine (1.5 mg/m2) on days 0 and 7. MIBG was given on day 1 following a 3+3 phase I design with dose levels of 8, 12, 15, and 18 mCi/kg, with 6 additional patients treated at the RP2D. PBSCs were administered to 1 patient at 8 mCi/kg for myelosuppression and on day 13 for all patients at > 12 mCi/kg. Results: 24 evaluable patients (median age 6.7 years; range 1.9 – 24.8) received 33 courses. Myelosuppression and diarrhea were the most common toxicities. 70% of courses were associated with diarrhea (grade 3 in 6 courses). No dose limiting toxicities (DLTs) were seen at dose levels 8 and 12 mCi/kg. At 15 mCi/kg, 1 patient had DLT of grade 3 diarrhea. At 18 mCi/kg, 1 patient had DLT with hallucinations and hyponatremia. One patient had protocol-defined DLT with prolonged ALT elevation that was not deemed clinically dose limiting. 18 mCi/kg was declared the RP2D and 6 additional patients enrolled, with 1 DLT (ALT and AST elevation). 7 patients received 2-3 courses to cumulative doses of 24-36 mCi/kg without DLT. The objective response rate was 25% (95% CI: 11-46%), with 3 complete responses, 1 very good partial response, and 2 partial responses. The response rate among 12 patients treated with 18 mCi/kg was 25% (2 complete responses and 1 very good partial response). Conclusions: MIBG is tolerable and active at doses of 18 mCi/kg with vincristine and irinotecan. Further studies are planned to determine this regimen’s role in frontline therapy for high risk patients.