Phase 1 Study of the Hedgehog Pathway Inhibitor IPI-926 in Adult Patients with Solid Tumors
Mené sur 94 patients atteints d'une tumeur solide réfractaire aux traitements de référence, cet essai de phase I évalue la dose maximale tolérée et la toxicité d'un composé appelé IPI-926, un inhibiteur de la voie de signalisation Hedgehog
Purpose: To conduct a first-in-human Phase 1 study to determine the dose limiting toxicities (DLTs), characterize the pharmacokinetic profile, and document the antitumor activity of IPI-926, a new chemical entity that inhibits the Hedgehog pathway (HhP). Methods: Patients with solid tumors refractory to standard therapy were given IPI-926 once daily (QD) by mouth in 28-day cycles. The starting dose was 20 mg and an accelerated titration schedule was used until standard 3+3 dose escalation cohorts were implemented. Pharmacokinetics was evaluated on Day -7 and Day 22 of Cycle 1. Results: Ninety-four patients (32F, 62M; ages 39-87) received doses ranging from 20 mg to 210 mg QD. Dose levels up to and including 160 mg administered QD were well tolerated. Toxicities consisted of reversible elevations in AST, ALT and bilirubin, fatigue, nausea, alopecia, and muscle spasms. IPI-926 was not associated with hematologic toxicity. IPI-926 pharmacokinetics was characterized by a slow absorption (Tmax 2 to 8 hours) and a terminal half-life (t1/2) between 20 and 40 hours, supporting QD dosing. Of those HhP inhibitor-naïve patients with basal cell carcinoma (BCC) who received more than 1 dose of IPI-926 and had a follow-up clinical or RECIST assessment, nearly a third (8 of 28 patients) demonstrated a response to IPI-926 at doses ≥130 mg. Conclusions: IPI-926 was well tolerated up to 160 mg QD within 28-day cycles, which was established as the recommended Phase 2 dose and schedule for this agent. Single-agent activity of IPI-926 was observed in HhP inhibitor-naïve patients with BCC.