A pediatric phase I trial and pharmacokinetic study of ispinesib: a Children's Oncology Group phase I consortium study

Pediatr Blood Cancer. 2010 Dec 15;55(7):1323-8. doi: 10.1002/pbc.22609. Epub 2010 Aug 13.

Abstract

Purpose: To determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of the kinesin spindle protein inhibitor ispinesib in pediatric patients with recurrent or refractory solid tumors.

Subjects and methods: Ispinesib was administered as 1-hr intravenous infusion weekly × 3, every 28 days. Cohorts of 3-6 patients were enrolled at 5, 7, 9, and 12 mg/m(2) /dose. Serial plasma samples for pharmacokinetic analyses were obtained after the first dose.

Results: Twenty-four (13 females) patients with a median (range) age of 10 years (1-19) were enrolled in the study. At the 12 mg/m(2) dose level dose-limiting neutropenia occurred in 2/6 patients and hyperbilirubinemia in 1/6 patients, while at the 9 mg/m(2) dose level 1/6 patients had dose-limiting neutropenia. There were no objective responses, but three patients (diagnoses of anaplastic astrocytoma, alveolar soft part sarcoma, and ependymoblastoma) had stable disease for 4-7 courses. There was substantial interpatient variation in drug disposition. The median (range) terminal elimination half-life was 16 (8-44) hr and the plasma drug clearance was 5 (1-14) L/hr/m(2) .

Conclusions: The maximum tolerated and recommended phase II dose for ispinesib administered weekly × 3 every 28 days for children with solid tumors is 9 mg/m(2) /dose. Plans for a phase II trial in select pediatric solid tumors are in development.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Benzamides / administration & dosage*
  • Benzamides / adverse effects
  • Benzamides / pharmacokinetics
  • Child
  • Child, Preschool
  • Drug Administration Schedule
  • Female
  • Humans
  • Hyperbilirubinemia / chemically induced
  • Infant
  • Infusions, Intravenous
  • Kinesins / antagonists & inhibitors*
  • Maximum Tolerated Dose
  • Neoplasms / drug therapy*
  • Neutropenia / chemically induced
  • Quinazolines / administration & dosage*
  • Quinazolines / adverse effects
  • Quinazolines / pharmacokinetics
  • Young Adult

Substances

  • Benzamides
  • KIF11 protein, human
  • Quinazolines
  • ispinesib
  • Kinesins