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 C_max 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.