A phase 1 study of nifurtimox in patients with relapsed/refractory neuroblastoma.
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.
Department of Pediatrics, Vermont Children's Hospital, Burlington, VT, USA. Giselle.Sholler@uvm.edu
Giselle L
GL
Saulnier Sholler
Genevieve M
GM
Bergendahl
Laurent
L
Brard
Ajay P
AP
Singh
Barry W
BW
Heath
Peter M
PM
Bingham
Taka
T
Ashikaga
Barton A
BA
Kamen
Alan C
AC
Homans
Marni A
MA
Slavik
Shannon R
SR
Lenox
Timothy J
TJ
Higgins
William S
WS
Ferguson
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009447:Neuroblastoma / Q000188:drug therapy* / Q000517:prevention & control; D009547:Nifurtimox / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012008:Recurrence; D019772:Topotecan / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
D019772:Topotecan; D003520:Cyclophosphamide; D009547:Nifurtimox