Pediatric phase I trial design using a pharmacodynamic marker as the primary endpoint

Abstract

10027 Background: The optimal dose of less toxic molecularly targeted agents should be defined by target modulation rather than toxicity. Talabostat is an inhibitor of dipeptidyl peptidase 4 (DPP-4) with minimal systemic toxicity in adults. We designed a dose finding trial of talabostat using serum DPP-4 inhibition as the primary endpoint. Methods: The cleavage rate of Ala-Pro-AFC to the fluorescent product, trifluoromethylcoumarin (AFC) was used to quantify plasma DPP-4 enzyme activity pre-dose and 1h and 24h after a daily oral dose of talabostat. The goal of the study was to identify a dose that inhibits DPP-4 continuously, throughout the 14 day dosing interval. Therefore, the optimal dose would inhibit >90% of pre-dose plasma DPP-4 activity at 24h. Talabostat (once daily × 14d) underwent intra- and inter-patient dose escalation by 70 to 100% over 4 dose levels with 2 patients enrolled per dose level. If <2 achieved >90% inhibition and neither had dose-limiting toxicity (DLT), the dose was escalated. If both achieved >90% inhibition, the cohort would expand to 6; and if ≥5/6 achieved >90% inhibition without DLT, the dose would be escalated 1 additional dose level to ensure that the optimal dose was on the plateau of the dose-response curve. If DLT occurred, the design would convert to a maximum tolerated dose primary endpoint with dose escalations in 40% increments. Results: Six patients (4.5–18 yr) were enrolled, 2 each at the first 3 dose levels, and 3 patients underwent intra-patient dose escalation. No DLTs were observed. DPP-4 activity was >90% inhibited 1h post-dose in 5/6 patients. Inhibition at 24h was dose-dependent, but Emax modeling of the dose-response curve predicted 90% inhibition would require doses >1,350 mcg/m2, which prompted a change to a twice daily dosing schedule. Conclusions: This trial design using a primary pharmacodynamic endpoint appeared to be feasible for determination of optimal drug dose and dosing schedule for talabostat. Subject Cycle Dose Level (mcg/m2/d) % DPP-IV inhibition 1h 24h 1 1 100 0 45 2 1 100 100 52 2 200 100 63 3 1 200 94 34 2 350 100 69 4 1 200 100 72 5 1 350 96 65 6 1 350 100 63 2 600 100 85 3 600 100 85 No significant financial relationships to disclose.