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


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.
Souid
Abdul-Kader
AK
State University of New York, Health Science Center, Syracuse, New York, USA.
Dubowy
Ronald L
RL
Ingle
Ashish M
AM
Conlan
Maureen G
MG
Sun
Junfeng
J
Blaney
Susan M
SM
Adamson
Peter C
PC
D000293:Adolescent; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced; D007223:Infant; D007262:Infusions, Intravenous; D016547:Kinesins / Q000037:antagonists & inhibitors*; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
D001549:Benzamides; C470243:KIF11 protein, human; D011799:Quinazolines; C508757:ispinesib; D016547:Kinesins