title: A Phase 1 Trial of TPI 287 as a Single Agent and in Combination With Temozolomide in Patients with Refractory or Recurrent Neuroblastoma or Medulloblastoma.
abstract: BACKGROUND
  The primary aim of this Phase I study was to determine the maximum tolerated dose (MTD) of TPI 287 and the safety and tolerability of TPI 287 alone and in combination with temozolomide (TMZ) in pediatric patients with refractory or recurrent neuroblastoma or medulloblastoma. The secondary aims were to evaluate the pharmacokinetics of TPI 287 and the treatment responses.
  
  
  METHODS
  Eighteen patients were enrolled to a phase I dose escalation trial of weekly intravenous infusion of TPI 287 for two 28-day cycles with toxicity monitoring to determine the MTD, followed by two cycles of TPI 287 in combination with TMZ. Samples were collected to determine the pharmacokinetic parameters C(max), AUC(0-24), t(1/2), CL, and Vd on day 1 of cycles 1 (TPI 287 alone) and 3 (TPI 287 + TMZ) following TPI 287 infusion. Treatment response was evaluated by radiographic (CT or MRI) and radionuclide (MIBG) imaging for neuroblastoma.
  
  
  RESULTS
  We determined the MTD of TPI 287 alone and in combination with temozolomide to be 125 mg/m(2). The non-dose-limiting toxicities at this dose were mainly anorexia and pain. The dose-limiting toxicities (DLTs) of two patients at 135 mg/m(2) were grade 3 hemorrhagic cystitis and grade 3 sensory neuropathy.
  
  
  CONCLUSIONS
  Overall, TPI 287 was well tolerated by pediatric patients with refractory and relapsed neuroblastoma and medulloblastoma at a dose of 125 mg/m(2) IV on days 1, 8, and 15 of a 28 day cycle.
authors.affiliation: Helen DeVos Children's Hospital, Grand Rapids, Michigan.|Michigan State University College of Human Medicine, Grand Rapids, Michigan.
authors.forename: Deanna
authors.initials: D
authors.lastname: Mitchell
authors.affiliation: Helen DeVos Children's Hospital, Grand Rapids, Michigan.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Bergendahl
authors.affiliation: Cardinal Glennon Children's Medical Center, Saint Louis University School of Medicine, Saint Louis, Missouri.
authors.forename: William
authors.initials: W
authors.lastname: Ferguson
authors.affiliation: Rady Children's Hospital, University of California San Diego School of Medicine, San Diego, California.
authors.forename: William
authors.initials: W
authors.lastname: Roberts
authors.affiliation: Department of Radiology, University of Vermont Medical Center, Burlington, Vermont.
authors.forename: Timothy
authors.initials: T
authors.lastname: Higgins
authors.affiliation: Medical Biostatistics and Biometry Facility, University of Vermont College of Medicine, Burlington, Vermont.
authors.forename: Takamaru
authors.initials: T
authors.lastname: Ashikaga
authors.affiliation: Medical Biostatistics and Biometry Facility, University of Vermont College of Medicine, Burlington, Vermont.
authors.forename: Mike
authors.initials: M
authors.lastname: DeSarno
authors.affiliation: Levine Children's Hospital, Charlotte, North Carolina.
authors.forename: Joel
authors.initials: J
authors.lastname: Kaplan
authors.affiliation: Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Kraveka
authors.affiliation: Arnold Palmer Hospital for Children, Orlando, Florida.
authors.forename: Don
authors.initials: D
authors.lastname: Eslin
authors.affiliation: Helen DeVos Children's Hospital, Grand Rapids, Michigan.
authors.forename: Alyssa Vander
authors.initials: AV
authors.lastname: Werff
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Gina K
authors.initials: GK
authors.lastname: Hanna
authors.affiliation: Helen DeVos Children's Hospital, Grand Rapids, Michigan.|Michigan State University College of Human Medicine, Grand Rapids, Michigan.
authors.forename: Giselle L Saulnier
authors.initials: GL
authors.lastname: Sholler
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008527:Medulloblastoma / Q000188:drug therapy*; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma / Q000188:drug therapy*; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D000077204:Temozolomide
chemical_list: C578069:TPI-287; D043823:Taxoids; D003606:Dacarbazine; D000077204:Temozolomide
keywords: TPI 287; brain tumors; medulloblastoma; neuroblastoma; pediatric hematology/oncology; phase I clinical trials