A Multicenter Phase I Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors

• DOI: 10.1158/1078-0432.ccr-12-0714
• Publication Date: 2012-06-13T04:30:48Z
• Authors: David S. Hong; Daniel W. Bowles; Gerald S. Falchook; Wells A. Messersmith; Goldy C. George; Cindy L. O'Bryant; Alex C. H. Vo; Kevin Klucher; Roy S. Herbst; S. Gail Eckhardt; Scott Peterson; Diana F. Hausman; Razelle Kurzrock; Antonio Jimeno
• Keywords: Adult; Aged, 80 and over; Diarrhea; Male; Dose-Response Relationship, Drug; Metabolic Clearance Rate; Administration, Oral; Nausea; Gonanes; Middle Aged; Drug Administration Schedule; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Area Under Curve; Neoplasms; Mutation; Disease Progression; Humans; Female; Enzyme Inhibitors; Fatigue; Aged

Abstract Purpose: The objectives of the study were to evaluate the maximum tolerated dose (MTD), safety, pharmacodynamics, pharmacokinetics, and antitumor activity of PX-866 in patients with incurable cancers. Experimental Design: This was a phase I, 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 substudy. 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 12 and 8 mg for arm 1 and 2, respectively. The dose-limiting toxicities (DLT) consisted of grade III diarrhea (n = 3) and grade III elevated aspartate aminotransferase (AST; n = 1). The pharmacokinetics profile was dose proportional, with no evidence of drug accumulation. PX-866–associated inhibition of platelet pAKTSER473 was observed at the arm 2 MTD. The best response per Response Evaluation Criteria in Solid Tumors (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 shows that PX-866, an irreversible small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), was well tolerated and was associated with prolonged stable disease, particularly when using a continuous dosing schedule. Clin Cancer Res; 18(15); 4173–82. ©2012 AACR.