Pediatric phase i trial design using maximum target inhibition as the primary endpoint

Holly Meany, Frank M. Balis, Alberta Aikin, Patricia Whitcomb, Robert F. Murphy, Seth M. Steinberg, Brigitte C. Widemann, Elizabeth Fox

Research output: Contribution to journalArticlepeer-review


The extent to which a drug inhibits a target responsible for a therapeutic effect is a more rational primary endpoint for dose-finding studies of more selective anticancer drugs than the conventional endpoint of dose-limiting toxicity (DLT) used for cytotoxic agents. An adaptive phase I trial design incorporating maximum target inhibition as the primary endpoint was developed to define the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in children with relapsed or refractory solid tumors. The relationship between dose and effect (percent inhibition of serum DPP-4) was assessed using a maximum effect model. Maximum target inhibition was defined as greater than 90% DPP-4 inhibition in five or more of six patients 24 hours post-dose. If DLT was to occur, the trial would adapt to a traditional phase I design with a more conservative dose escalation. At the 600 μg/m2 dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 μg/m2 of talabostat would maximally inhibit DPP-4. This adaptive trial design appears to be feasible, safe, and efficient and warrants further evaluation for development of molecularly targeted agents.

Original languageEnglish (US)
Pages (from-to)909-912
Number of pages4
JournalJournal of the National Cancer Institute
Issue number12
StatePublished - Jun 2010
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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