A Phase I New Approaches to Neuroblastoma Therapy Study of Buthionine Sulfoximine and Melphalan With Autologous Stem Cells for Recurrent/Refractory High‐Risk Neuroblastoma

Background Myeloablative therapy for high-risk neuroblastoma commonly includes melphalan. Increased cellular glutathione (GSH) can mediate melphalan resistance. Buthionine sulfoximine (BSO), a GSH synthesis inhibitor, enhances melphalan activity against neuroblastoma cell lines, providing the rationale for a Phase 1 trial of BSO-melphalan. Procedures Patients with recurrent/resistant high-risk neuroblastoma received BSO (3 gram/m2 bolus, then 24 grams/m2/day infusion days −4 to −2), with escalating doses of intravenous melphalan (20–125 mg/m2) days −3 and −2, and autologous stem cells day 0 using 3 + 3 dose escalation. Results Among 28 patients evaluable for dose escalation, one dose-limiting toxicity occurred at 20 mg/m2 melphalan (grade 3 aspartate aminotransferase/alanine aminotransferase) and one at 80 mg/m2 (streptococcal bacteremia, grade 4 hypotension/pulmonary/hypocalcemia) without sequelae. Among 25 patients evaluable for response, there was one partial response (PR) and two mixed responses (MRs) among eight patients with prior melphalan exposure; one PR and three MRs among 16 patients without prior melphalan; one stable disease with unknown melphalan history. Melphalan pharmacokinetics with BSO were similar to reports for melphalan alone. Melphalan Cmax for most patients was below the 10 μM concentration that showed neuroblastoma preclinical activity with BSO. Conclusions BSO (75 gram/m2) with melphalan (125 mg/m2) is tolerable with stem cell support and active in recurrent/refractory neuroblastoma. Further dose escalation is feasible and may increase responses.