Format

Send to

Choose Destination
J Clin Oncol. 2016 Apr 20;34(12):1368-75. doi: 10.1200/JCO.2015.65.4889. Epub 2016 Feb 16.

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.

Author information

1
Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY. steven_dubois@dfci.harvard.edu.
2
Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY.

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/m(2) per day on days 1 to 7 along with irinotecan 50 mg/m(2) intravenously and temozolomide 100 mg/m(2) 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/m(2), 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/m(2) 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.

PMID:
26884555
PMCID:
PMC4872349
[Available on 2017-02-20]
DOI:
10.1200/JCO.2015.65.4889
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center