A safety and feasibility trial of 131 I-MIBG in newly diagnosed high-risk neuroblastoma: A Children's Oncology Group study

Abstract

Introduction: 131 I-meta-iodobenzylguanidine (131 I-MIBG) is effective in relapsed neuroblastoma. The Children's Oncology Group (COG) conducted a pilot study (NCT01175356) to assess tolerability and feasibility of induction chemotherapy followed by 131 I- MIBG therapy and myeloablative busulfan/melphalan (Bu/Mel) in patients with newly diagnosed high-risk neuroblastoma.

Methods: Patients with MIBG-avid high-risk neuroblastoma were eligible. After the first two patients to receive protocol therapy developed severe sinusoidal obstruction syndrome (SOS), the trial was re-designed to include an 131 I-MIBG dose escalation (12, 15, and 18 mCi/kg), with a required 10-week gap before Bu/Mel administration. Patients who completed induction chemotherapy were evaluable for assessment of 131 I-MIBG feasibility; those who completed 131 I-MIBG therapy were evaluable for assessment of 131 I-MIBG + Bu/Mel feasibility.

Results: Fifty-nine of 68 patients (86.8%) who completed induction chemotherapy received 131 I-MIBG. Thirty-seven of 45 patients (82.2%) evaluable for 131 I-MIBG + Bu/Mel received this combination. Among those who received 131 I-MIBG after revision of the study design, one patient per dose level developed severe SOS. Rates of moderate to severe SOS at 12, 15, and 18 mCi/kg were 33.3%, 23.5%, and 25.0%, respectively. There was one toxic death. The 131 I-MIBG and 131 I-MIBG+Bu/Mel feasibility rates at the 15 mCi/kg dose level designated for further study were 96.7% (95% CI: 83.3%-99.4%) and 81.0% (95% CI: 60.0%-92.3%).

Conclusion: This pilot trial demonstrated feasibility and tolerability of administering 131 I-MIBG followed by myeloablative therapy with Bu/Mel to newly diagnosed children with high-risk neuroblastoma in a cooperative group setting, laying the groundwork for a cooperative randomized trial (NCT03126916) testing the addition of 131 I-MIBG during induction therapy.

Keywords: Bu/Mel; MIBG; high risk; neuroblastoma.

Conflict of interest statement

Conflict of Interest: The authors have no known competing financial interests/personal relationships to declare.

© 2021 Wiley Periodicals LLC.

Figures

Figure 1.

Figure 1A. Treatment Schema Patients received 2 cycles of topotecan (1.2 mg/m2/dose × 5 days) and cyclophosphamide (400 mg/m2/dose × 5 days) (each cycle lasting 21 days assuming blood count recovery), followed by PBSC harvest; cycle 3 of cisplatin (50 mg/m2/dose × 4 days) and etoposide (200 mg/m2/dose × 3 days); cycle 4 of cyclophosphamide (2100 mg/m2/dose × 2 days), doxorubicin (25 mg/m2/dose × 3 days) and vincristine (the lower dose of 0.67 mg/m2/dose OR 0.022 mg/kg/dose × 3 days) followed by tumor imaging and MIBG scan and attempted surgical resection; and cycle 5 cisplatin and etoposide. Patients on the first iteration of the protocol (Iteration 1) then received 131I-MIBG at 18 mCi/kg along with vincristine (2 mg/m2/dose × 1 day; max 2 mg) and irinotecan (50 mg/m2/dose × 5 days; max 100 mg) followed 2 weeks later by ASCR, then 5 weeks later by myeloablative Bu/Mel consolidation plus ASCR. Patients enrolled on Iteration 2 received 131I-MIBG (3–6 weeks from the start of cycle 5) at either 12 mCi/kg, 15 mCi/kg, or 18 mCi/kg (without vincristine or irinotecan) using a modified rolling six design, followed by ASCR 2 weeks later. A mandatory break of 10–12 weeks from 131I-MIBG infusion was required prior to myeloablative Bu/Mel consolidation plus ASCR. Patients received intravenous busulfan every six hours for 16 doses from Day −6 to Day −3 (with mandatory pharmacokinetic (PK) guided dosing), and melphalan (140 mg/m2) on Day −1. After recovery from acute toxicities, patients received external beam radiation therapy (21.6 Gy) to the primary site and up to five MIBG-avid sites, followed by post-consolidation therapy of the investigator’s choice, though anti-GD2 antibody therapy was recommended.

Figure 1B.

Dose escalation plan The initial cohort of patients in Iteration 2 received 15 mCi/kg 131I-MIBG followed by Bu/Mel. While determining safety at this dose, subsequent patients received 131I-MIBG at a dose of 12 mCi/kg upon completion of induction chemotherapy. Once 15 mCi/kg 131I-MIBG was determined to be safe, a dose of 18 mCi/kg 131I-MIBG was similarly assessed. While toxicities associated with 18 mCi/kg 131I-MIBG followed by Bu/Mel were being evaluated, subsequent patients received a dose of 15 mCi/kg. A maximum of 18 patients were to be treated with 131I-MIBG plus Bu/Mel on any dose level. While therapy tolerability was being assessed, up to 18 patients could receive 12 mCi/kg of 131I-MIBG, or the highest proven tolerable dose.

Figure 2.

Consort diagram for ANBL09P1 Feasibility evaluations included eligible patients from Iteration 1 (n=11) and Iteration 2 (n=87). Tolerability evaluations only included patients from Iteration 2. Of eligible patients, 68 were evaluable for feasibility of 131I-MIBG (3 from Iteration 1 and 65 from Iteration 2) and 45 for feasibility of 131I-MIBG + Bu/Mel (2 from iteration 1 and 43 from Iteration 2). Patients from Iteration 2 evaluable for tolerability were: 131I-MIBG (n=53); 131I-MIBG + Bu/Mel (n=35).