A Multicenter Phase 1 Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors
Mené sur 84 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la toxicité et l'activité antitumorale d'un composé appelé PX-866, un inhibiteur de PI3K
Purpose: The objectives of the study were to evaluate the maximum tolerated dose (MTD), safety, pharmacodynamics, pharmacokinetics (PK), and antitumor activity of PX-866 in patients with incurable cancers. Patients and Methods: This was a phase 1, open-label, dose-escalation study. Drug was administered orally once per day either on an intermittent (Arm 1; days 1-5 and 8-12 of a 28-day cycle) or continuous (Arm 2; days 1-28 of a 28-day cycle) schedule. Additional patients were treated at the Arm 2 MTD in a food effects sub-study. Results: Eighty-four patients were treated in the Arm 1 (n=51), Arm 2 (n=20) and food effects (n = 13) cohorts. The most frequent study drug-related adverse events were gastrointestinal disorders (69.0%), with diarrhea being the most common (48.8%). The MTD was 12mg and 8mg for Arm 1 and 2, respectively. The dose-limiting toxicities (DLTs) consisted of grade 3 (g3) diarrhea (n=3) and g3 elevated AST (n=1). The PK profile was dose proportional, with no evidence of drug accumulation. PX-866-associated inhibition of platelet P-AKT SER473 was observed at the Arm 2 MTD. The best response per RECIST was stable disease in 22% of evaluable patients in Arm 1, 53% in Arm 2, and 11% in the food effects cohort. Eight patients were on study for 4 or more months. Conclusions: This first-in-human study demonstrates that PX-866, an irreversible small molecule inhibitor of PI-3K, was well tolerated and was associated with prolonged stable disease, particularly when using a continuous dosing schedule.