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


METHODS
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.
MD Anderson Cancer Center, Houston, Texas, USA.
David S
DS
Hong
Daniel W
DW
Bowles
Gerald S
GS
Falchook
Wells A
WA
Messersmith
Goldy C
GC
George
Cindy L
CL
O'Bryant
Alex C H
AC
Vo
Kevin
K
Klucher
Roy S
RS
Herbst
S Gail
SG
Eckhardt
Scott
S
Peterson
Diana F
DF
Hausman
Razelle
R
Kurzrock
Antonio
A
Jimeno
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D003967:Diarrhea / Q000139:chemically induced; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006067:Gonanes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009154:Mutation; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
D004791:Enzyme Inhibitors; D006067:Gonanes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C496788:PX-866