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Updated: Jun 13, 2026
10:49
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Pediatric phase I trial design using maximum target inhibition as the primary endpoint
Holly Meany1, Frank M Balis, Alberta Aikin
1Department of Hematology/Oncology, Children's National Medical Center, 111 Michigan Ave NW, Washington, DC 20010, USA. hmeany@cnmc.org
Journal of the National Cancer Institute
|May 13, 2010
Summary
Maximum target inhibition, not dose-limiting toxicity, is a better primary endpoint for selective anticancer drugs. An adaptive trial for talabostat in children showed this approach is feasible and efficient for finding optimal doses.
Area of Science:
- Pediatric Oncology
- Pharmacodynamics
- Clinical Trial Design
Background:
- Selective anticancer agents require novel dose-finding endpoints beyond dose-limiting toxicity (DLT).
- Maximum target inhibition offers a more rational primary endpoint for molecularly targeted therapies.
Purpose of the Study:
- To develop and evaluate an adaptive phase I trial design using maximum target inhibition as the primary endpoint.
- To determine the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in pediatric patients with relapsed or refractory solid tumors.
Main Methods:
- An adaptive phase I trial design was implemented with maximum serum DPP-4 inhibition as the primary endpoint.
- A maximum effect model assessed the dose-response relationship.
- Maximum target inhibition was defined as >90% DPP-4 inhibition in at least five of six patients 24 hours post-dose.
Main Results:
- At 600 microg/m(2), talabostat achieved 85% serum DPP-4 inhibition.
- No talabostat-related dose-limiting toxicity (DLT) was observed.
- The maximum effect model predicted 1200 microg/m(2) would achieve maximal DPP-4 inhibition.
Conclusions:
- The adaptive trial design incorporating maximum target inhibition is feasible, safe, and efficient for pediatric oncology.
- This approach warrants further evaluation for dose optimization of molecularly targeted anticancer agents.
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