A phase II trial of nifurtimox combined with topotecan and cyclophosphamide for refractory or relapsed neuroblastoma and medulloblastoma

• Published in: International journal of cancer 2023-09, Vol.153 (5), p.1026-1034
• Main Authors: Eslin, Don, Zage, Peter E., Bergendahl, Genevieve, Lewis, Elizabeth, Roberts, William, Kraveka, Jacqueline, Mitchell, Deanna, Isakoff, Michael S., Rawwas, Jawhar, Wada, Randal K., Fluchel, Mark, Brown, Valerie I., Ginn, Kevin, Higgins, Timothy, BeeravallyNagulapally, Abhinav, Dykema, Karl, Hanna, Gina, Ferguson, William, Saulnier Sholler, Giselle L.
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - adverse effects; Cancer; Cerebellar Neoplasms; Child; Cyclophosphamide; Humans; Medical research; Medulloblastoma; Medulloblastoma - drug therapy; Myelosuppression; Neoplasm Recurrence, Local - pathology; Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - etiology; Neurological complications; Nifurtimox; Nifurtimox - therapeutic use; Response rates; Solid tumors; Topotecan; Topotecan - adverse effects
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.34569

Children with relapsed/refractory (R/R) neuroblastoma (NB) and medulloblastoma (MB) have poor outcomes. We evaluated the efficacy of nifurtimox (Nfx) in a clinical trial for children with R/R NB and MB. Subjects were divided into three strata: first relapse NB, multiply R/R NB, and R/R MB. All patients received Nfx (30 mg/kg/day divided TID daily), Topotecan (0.75 mg/m2/dose, days 1‐5) and Cyclophosphamide (250 mg/m2/dose, days 1‐5) every 3 weeks. Response was assessed after every two courses using International Neuroblastoma Response Criteria and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. One hundred and twelve eligible patients were enrolled with 110 evaluable for safety and 76 evaluable for response. In stratum 1, there was a 53.9% response rate (CR + PR), and a 69.3% total benefit rate (CR + PR + SD), with an average time on therapy of 165.2 days. In stratum 2, there was a 16.3% response rate, and a 72.1% total benefit rate, and an average time on study of 158.4 days. In stratum 3, there was a 20% response rate and a 65% total benefit rate, an average time on therapy of 105.0 days. The most common side effects included bone marrow suppression and reversible neurologic complications. The combination of Nfx, topotecan and cyclophosphamide was tolerated, and the objective response rate plus SD of 69.8% in these heavily pretreated populations suggests that this combination is an effective option for patients with R/R NB and MB. Although few objective responses were observed, the high percentage of stabilization of disease and prolonged response rate in patients with multiply relapsed disease shows this combination therapy warrants further testing. What's new? Outcomes remain poor for children with relapsed and refractory neuroblastoma and medulloblastoma. This single‐arm, Phase II, open‐label, multicenter clinical trial shows that the combination of the novel agent nifurtimox with topotecan and cyclophosphamide is tolerated in children with relapsed or refractory neuroblastoma and medulloblastoma. The observed response rate and the high percentage of children with disease stabilization and prolonged responses suggest that the drug combination may be an option for these heavily pretreated patients with multiply relapsed disease. The findings demonstrate the feasibility and tolerability of the drug combination, supporting the need for further testing.