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Ispinesib effective in pediatric solid tumors
Ispinesib, a highly specific inhibitor of kinesin spindle protein, was well-tolerated in pediatric patients with refractory solid tumors, according to data presented at the 2008 ASCO Annual Meeting.
In a phase-I consortium trial, researchers from the Children’s Oncology Group assessed the efficacy of ispinesib administered in a one-hour IV infusion weekly times three, every twenty-eight days in pediatric patients with refractory solid tumors.
Nineteen of 24 patients enrolled were evaluable for toxicity and 23 of 24 were evaluable for response. The median age of patients was 10 years.
Patients were divided into cohorts and assigned to 5 mg/m2/dose, 7 mg/m2/dose, 9 mg/m2/dose or 12 mg/m2/dose.
The researchers reported no dose-limiting toxicities at 5 mg/m2/dose. One patient at 7 mg/m2/dose presented with elevated transaminases, which was initially attributed to disease and retrospectively determined to be dose-limiting. Neutropenia and hepatotoxicity were dose-limiting toxicities in the 9 mg/m2/dose (n=1) and 12 mg/m2/dose (n=2) groups.
The researchers concluded that the maximum tolerated dose and recommended phase-2 dose in this setting is 9 mg/m2 – by Stacey L. Adams.
Kinesin spindle proteins have been a topic of a lot of discussion, particularly in the medical oncology world, and are clearly a concept we value highly, particularly in the treatment of pediatric leukemias, as well as solid tumors (with the use of vincristine). There is evidence of preclinical activity with this compound in Wilms’ tumors and rhabdoid tumors and eRMS xenograph models. Overall, the dose limiting toxicities were defined, which were neutropenia and hepatotoxicity, and the recommended phase-2 dose was described. There was minimal activity noted in this study for a relatively short number of cycles.
The PK data established in this study to date appear similar to the adult data; however, they are limited due to the few number of samples measured per dose level. It is very hard to make assessments based on two samples, particularly with the range they presented. The maximum tolerated dose in children does appear to match the adults, and the next question is where is it going? When we think of mechanism of action, we think about how we currently use vincristine and whether or not this would be an acceptable swap or substitute.
– Lia Gore, MD
Assistant Professor of Pediatrics, University of Colorado at Denver and Health Sciences Center
For more information:
- Souid A. Pediatric phase I trial and pharmacokinetic (PK) study of ispinesib (SB715992): A Children’s Oncology Group phase I consortium study. Presented at: 2008 ASCO Annual Meeting; May 30-June 3, 2008; Chicago.