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.