title: 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.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Steven G
authors.initials: SG
authors.lastname: DuBois
authors.affiliation: 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.
authors.forename: Araz
authors.initials: A
authors.lastname: Marachelian
authors.affiliation: 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.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.affiliation: 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.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Kudgus
authors.affiliation: 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.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.affiliation: 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.
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.affiliation: 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.
authors.forename: Jemily
authors.initials: J
authors.lastname: Malvar
authors.affiliation: 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.
authors.forename: Rochelle
authors.initials: R
authors.lastname: Bagatell
authors.affiliation: 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.
authors.forename: Lars
authors.initials: L
authors.lastname: Wagner
authors.affiliation: 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.
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.affiliation: 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.
authors.forename: Randall
authors.initials: R
authors.lastname: Hawkins
authors.affiliation: 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.
authors.forename: Jesse
authors.initials: J
authors.lastname: Courtier
authors.affiliation: 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.
authors.forename: Hollie
authors.initials: H
authors.lastname: Lai
authors.affiliation: 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.
authors.forename: Fariba
authors.initials: F
authors.lastname: Goodarzian
authors.affiliation: 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.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: 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.
authors.forename: Scarlett
authors.initials: S
authors.lastname: Czarnecki
authors.affiliation: 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.
authors.forename: Denice
authors.initials: D
authors.lastname: Tsao-Wei
authors.affiliation: 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.
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.affiliation: 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.
authors.forename: Yael P
authors.initials: YP
authors.lastname: Mosse
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001381:Azepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013607:Tablets; D000077204:Temozolomide; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D064096:Aurora Kinase A; D001381:Azepines; D002166:Camptothecin; D003606:Dacarbazine; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013607:Tablets; D000077204:Temozolomide; D000099148:UGT1A1 Enzyme; C550258:MLN 8237; C576917:AURKA protein, human