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

Abstract

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 microg/m(2) dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 microg/m(2) 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.

• Authors: Holly Meany, Frank M Balis, Alberta Aikin, Patricia Whitcomb, Robert F Murphy, Seth M Steinberg, Brigitte C Widemann, Elizabeth Fox
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 102 Issue 12 Pg. 909-12 (Jun 16 2010) ISSN: 1460-2105 [Electronic] United States
• PMID: 20460632 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Antineoplastic Agents
• Boronic Acids
• Dipeptides
• Dipeptidyl-Peptidase IV Inhibitors
• Membrane Proteins
• Endopeptidases
• Serine Endopeptidases
• fibroblast activation protein alpha
• Gelatinases
• talabostat

Topics

• Administration, Oral
• Adolescent
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Area Under Curve
• Boronic Acids (administration & dosage, adverse effects, pharmacokinetics)
• Child
• Child, Preschool
• Confounding Factors, Epidemiologic
• Dipeptides (administration & dosage, adverse effects, pharmacokinetics)
• Dipeptidyl-Peptidase IV Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Endopeptidases
• Female
• Gelatinases (antagonists & inhibitors)
• Humans
• Male
• Membrane Proteins (antagonists & inhibitors)
• Neoplasms (drug therapy)
• Research Design
• Serine Endopeptidases