A Phase 1 Study of Nifurtimox in Patients With Relapsed/Refractory Neuroblastoma

Abstract

The primary aim of this phase 1 study was to determine the maximum tolerated dose (MTD) and evaluate the safety of nifurtimox alone and in combination with cyclophosphamide and topotecan in multiple relapsed/refractory neuroblastoma pediatric patients. The secondary aim was to evaluate the pharmacokinetics of nifurtimox and the treatment response. To these ends, we performed a phase 1 dose escalation trial of daily oral nifurtimox with toxicity monitoring to determine the MTD, followed by 3 cycles of nifurtimox in combination with cyclophosphamide and topotecan. Samples were collected to determine the pharmacokinetic parameters maximum concentration, time at which maximum concentration is reached, and area under the curve between 0 and 8 hours. Treatment response was evaluated by radiographic and radionuclide (I-metaiodobenzylguanidine) imaging, measurement of urinary catecholamines, and clearance of bone marrow disease. We determined the MTD of nifurtimox to be 30 mg/kg/d. The non-dose-limiting toxicities were mainly nausea and neuropathy. The dose-limiting toxicities of 2 patients at 40 mg/kg/d were a grade 3 pulmonary hemorrhage and a grade 3 neuropathy (reversible). Overall, nifurtimox was well tolerated by pediatric patients at a dose of 30 mg/kg/d, and tumor responses were seen both as a single agent and in combination with chemotherapy. A Phase 2 study to determine the antitumor efficacy of nifurtimox is currently underway.

Overview and recent advances in the treatment of neuroblastoma

“…Nifurtimox is a nitrofuran compound that has been used since the 1970s as a primary form of therapy for Chagas' disease, a parasitic infection caused by Trypanosoma cruzi [132,133]. Preclinical studies have shown that nifurtimox inhibits neuroblastoma cell growth in vitro and in vivo [134,135], and in early-phase clinical trials tumor responses were seen in patients treated with nifurtimox at a dose of 30 mg/kg/day both as a single agent and in combination with chemotherapy [136], leading to an ongoing national phase II trial (NCT00601003).…”

Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells

“…Recent research and clinical trials led to innovative new drugs and targeted therapies against NB (10)(11)(12). Targeted therapies also consider the use of redox-modulating drugs.…”

Nifurtimox reduces N-Myc expression and aerobic glycolysis in neuroblastoma

“…24 It could be shown that these two compounds induce the formation of reactive oxygen species (ROS) in neuroblastoma cells and thus lead to apoptotic cell death. 25,26 In a phase I dose escalation study, the maximum tolerated dose of nifurtimox in patients with relapsed or refractory high-risk neuroblastoma and medulloblastoma was determined to 30 27 Nifurtimox plasma trough concentrations of 3 -6 mg/mL are recommended for the treatment of trypanosomiasis. 29,30 A multi-center phase II study on the efficacy of nifurtimox with a planned enrollment of 100 patients with relapsed or refractory neuroblastoma and medulloblastoma is currently being performed (estimated primary completion date: December 2016).…”