A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors.

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.

• 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 15 Pg. 4173-82 (Aug 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22693357 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Gonanes
• PX-866
• Phosphoinositide-3 Kinase Inhibitors

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Area Under Curve
• Diarrhea (chemically induced)
• Disease Progression
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Enzyme Inhibitors (adverse effects, pharmacokinetics, therapeutic use)
• Fatigue (chemically induced)
• Female
• Gonanes (administration & dosage, pharmacokinetics, therapeutic use)
• Humans
• Male
• Metabolic Clearance Rate
• Middle Aged
• Mutation
• Nausea (chemically induced)
• Neoplasms (drug therapy, metabolism, pathology)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Treatment Outcome
• Vomiting (chemically induced)