Background: ¹³¹I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical active in neuroblastoma. A previous study demonstrated that MIBG (18 mCi/kg) could be combined with vincristine and irinotecan (20 mg/m²/dose for 5 days/week x 2 weeks) as a radiation sensitizer. However, 25% of courses were associated with grade 3 diarrhea. To reduce the incidence of diarrhea, the current study evaluated MIBG together with vincristine and 5 days of higher-dose irinotecan, a standard schedule in recent pediatric trials. This report describes the experience with this regimen at maximum tolerated MIBG dose of 18 mCi/kg. Methods: Patients < 30 with relapsed or refractory MIBG-avid neuroblastoma were eligible for this multicenter trial (NCT01313936). Prior MIBG therapy was allowed if > 6 months from prior MIBG and < 18 mCi/kg cumulative prior dose. Patients received cefixime on days -1 to +6, irinotecan (50 mg/m²/dose IV) on days 0-4, and vincristine (2 mg/m²) on day 0. MIBG (18 mCi/kg) was given on day 1 and peripheral blood stem cells on day 13. Up to two courses of therapy were allowed. Response was assessed at day 42 and was the primary endpoint of this phase II portion. Consenting patients provided germline DNA for UGT1A1 genotyping. Results: 26 patients received 37 courses of therapy. Myelosuppression was the most common toxicity, with 55% of patients with grade 4 thrombocytopenia and 65% of patients with grade 4 neutropenia in course 1. No patients had failure to engraft. Only 4.5% of first courses were associated with grade 3 diarrhea. Correlation of UGT1A1 genotype with toxicity is ongoing. Centrally reviewed best response after course 1 is available for 17 patients at the time of this submission. Of these, the overall response rate was 23.5% (2 CR and 2 PR). The response rate by MIBG scan was 37.5%, including 4 CR. Conclusions: MIBG at doses of 18 mCi/kg with vincristine and 5 days of irinotecan is tolerable and active. This regimen is now being compared to single-agent MIBG in a randomized phase II trial. Clinical trial information: NCT01313936.