Phase I study of the aurora A kinase inhibitor alisertib in combination with irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma: A nant (new approaches to neuroblastoma therapy) trial

Steven G. DuBois, Araz Marachelian, Elizabeth Fox, Rachel A. Kudgus, Joel M Reid, Susan Groshen, Jemily Malvar, Rochelle Bagatell, Lars Wagner, John M. Maris, Randall Hawkins, Jesse Courtier, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, Denice Tsao-Wei, Katherine K. Matthay, Yael P. Mosse

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Abstract

Purpose: Alisertib is an oral Aurora A kinase inhibitor with preclinical activity in neuroblastoma. Irinotecan and temozolomide have activity in patients with advanced neuroblastoma. The goal of this phase I study was to determine the maximum tolerated dose (MTD) of alisertib with irinotecan and temozolomide in this population. Patients and Methods: Patients age 1 to 30 years with relapsed or refractory neuroblastoma were eligible. Patients received alisertib tablets at dose levels of 45, 60, and 80 mg/m2 per day on days 1 to 7 along with irinotecan 50 mg/m2 intravenously and temozolomide 100 mg/m2 orally on days 1 to 5. Dose escalation of alisertib followed the rolling six design. Samples for pharmacokinetic and pharmacogenomic testing were obtained. Results: Twenty-three patients enrolled, and 22 were eligible and evaluable for dose escalation. A total of 244 courses were administered. The MTD for alisertib was 60 mg/m2, with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea. Thrombocytopenia and neutropenia of any grade were seen in the majority of courses (84% and 69%, respectively). Diarrhea in 55% of courses and nausea in 54% of courses were the most common nonhematologic toxicities. The overall response rate was 31.8%, with a 50% response rate observed at the MTD. The median number of courses per patient was eight (range, two to 32). Progression-free survival rate at 2 years was 52.4%. Pharmacokinetic testing did not show evidence of drug-drug interaction between irinotecan and alisertib. Conclusion: Alisertib 60 mg/m2 per dose for 7 days is tolerable with a standard irinotecan and temozolomide backbone and has promising response and progression-free survival rates. A phase II trial of this regimen is ongoing.

Original languageEnglish (US)
Pages (from-to)1368-1375
Number of pages8
JournalJournal of Clinical Oncology
Volume34
Issue number12
DOIs
StatePublished - Apr 20 2016

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

DuBois, S. G., Marachelian, A., Fox, E., Kudgus, R. A., Reid, J. M., Groshen, S., Malvar, J., Bagatell, R., Wagner, L., Maris, J. M., Hawkins, R., Courtier, J., Lai, H., Goodarzian, F., Shimada, H., Czarnecki, S., Tsao-Wei, D., Matthay, K. K., & Mosse, Y. P. (2016). Phase I study of the aurora A kinase inhibitor alisertib in combination with irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma: A nant (new approaches to neuroblastoma therapy) trial. Journal of Clinical Oncology, 34(12), 1368-1375. https://doi.org/10.1200/JCO.2015.65.4889