Cancer Therapy : Clinical Phase I Study of Vincristine , Irinotecan , and 131 I-Metaiodobenzylguanidine for Patients with Relapsed or Refractory Neuroblastoma : A New Approaches to Neuroblastoma Therapy Trial

Purpose: I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical with activity in patients with relapsed or refractory neuroblastoma. Irinotecan is a known radiosensitizer with activity in neuroblastoma. This phase I study aimed to determine the recommended phase 2 dose of MIBG together with fixed doses of vincristine and irinotecan. Experimental Design: Patients 1 to 30 years old with relapsed or refractory neuroblastoma and MIBGavid tumors were eligible. All patients had autologous hematopoietic stem cells (PBSC) available and met standardphase I organ function requirements. Irinotecan (20mg/m/dose IV)was givenondays 0 to4and7 to 11, with vincristine (1.5 mg/m IV) on days 0 and 7. MIBG was given on day 1 following a 3þ 3 phase I dose escalation design starting at 8 mCi/kg MIBG. PBSCs were administered at dose level 8 mCi/kg for prolonged myelosuppression and for all patients at 12 mCi/kg or more. Results: Twenty-four patients evaluable for dose escalation (median age, 6.7 years; range, 1.9–26.8 years) received 1 (n1⁄4 17), 2 (n1⁄4 5), or 3 (n1⁄4 2) cycles of therapy. Myelosuppression and diarrhea were the most common toxicities. Twoof 6patients at the 18mCi/kg dose level haddose-limiting toxicity (DLT), including onewith protocol-definedDLTwith prolongedmild aspartate aminotransferase elevation. EighteenmCi/kg was the recommended phase 2 dose. Six additional patients were treated at 18mCi/kg, with one additional DLT. Responses (2 complete and 4 partial responses) occurred in 6 of 24 (25%) evaluable patients. Conclusions: MIBG is tolerable and active at 18 mCi/kg with standard doses of vincristine and irinotecan. Clin Cancer Res; 18(9); 1–8. 2012 AACR.