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

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.

• Authors: Abdul-Kader Souid, Ronald L Dubowy, Ashish M Ingle, Maureen G Conlan, Junfeng Sun, Susan M Blaney, Peter C Adamson
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 55 Issue 7 Pg. 1323-8 (Dec 15 2010) ISSN: 1545-5017 [Electronic] United States
• PMID: 20712019 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2010 Wiley-Liss, Inc.

Chemical References

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

Topics

• Adolescent
• Benzamides (administration & dosage, adverse effects, 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, adverse effects, pharmacokinetics)
• Young Adult