title: 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.affiliation: Department of Hematology/Oncology, Children's National Medical Center, 111 Michigan Ave NW, Washington, DC 20010, USA. hmeany@cnmc.org
authors.forename: Holly
authors.initials: H
authors.lastname: Meany
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Alberta
authors.initials: A
authors.lastname: Aikin
authors.forename: Patricia
authors.initials: P
authors.lastname: Whitcomb
authors.forename: Robert F
authors.initials: RF
authors.lastname: Murphy
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D015986:Confounding Factors, Epidemiologic; D004151:Dipeptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D010450:Endopeptidases; D005260:Female; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy*; D012107:Research Design; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C514044:talabostat
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