Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors.
Taselisib is a potent and selective tumor growth inhibitor through PI3K pathway suppression. Thirty-four patients with locally advanced or metastatic solid tumors were treated (phase I study, modified 3+3 dose escalation; 5 cohorts; 3-16 mg taselisib once-daily capsule). Taselisib pharmacokinetics were dose-proportional; mean half-life was 40 hours. Frequent dose-dependent, treatment-related adverse events included diarrhea, hyperglycemia, decreased appetite, nausea, rash, stomatitis, and vomiting. At 12 and 16 mg dose levels, dose-limiting toxicities (DLT) were observed, with an accumulation of higher-grade adverse events after the cycle 1 DLT assessment window. Pharmacodynamic findings showed pathway inhibition at ≥3 mg in patient tumor samples, consistent with preclinicalPIK3CA-mutant tumor xenograft models. Confirmed response rate was 36% forPIK3CA-mutant tumor patients with measurable disease [5/14: 4 breast cancer (3 patients at 12 mg); 1 non-small cell lung cancer], where responses started at 3 mg, and 0% in patients with tumors without knownPIK3CAhotspot mutations (0/15).Significance:Preliminary data consistent with preclinical data indicate increased antitumor activity of taselisib in patients withPIK3CA-mutant tumors (in comparison with patients with tumors without known activatingPIK3CAhotspot mutations) starting at the lowest dose tested of 3 mg, thereby supporting higher potency for taselisib againstPIK3CA-mutant tumors.Cancer Discov; 7(7); 704-15. ©2017 AACR.See related commentary by Rodon and Tabernero, p. 666This article is highlighted in the In This Issue feature, p. 653.
Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Dejan
D
Juric
Dana-Farber Cancer Institute, Boston, Massachusetts.
Ian
I
Krop
Mayo Clinic, Scottsdale, Arizona.
Ramesh K
RK
Ramanathan
Genentech, Inc., South San Francisco, California.
Timothy R
TR
Wilson
Genentech, Inc., South San Francisco, California.
Joseph A
JA
Ware
Genentech, Inc., South San Francisco, California.
Sandra M
SM
Sanabria Bohorquez
Genentech, Inc., South San Francisco, California.
Heidi M
HM
Savage
Genentech, Inc., South San Francisco, California.
Deepak
D
Sampath
Genentech, Inc., South San Francisco, California.
Laurent
L
Salphati
Genentech, Inc., South San Francisco, California.
Ray S
RS
Lin
Genentech, Inc., South San Francisco, California.
Huan
H
Jin
Genentech, Inc., South San Francisco, California.
Hema
H
Parmar
Genentech, Inc., South San Francisco, California.
Jerry Y
JY
Hsu
Virginia G. Piper Cancer Center Honor Health, Scottsdale, Arizona.
Daniel D
DD
Von Hoff
Memorial Sloan Kettering Cancer Center, New York, New York. baselgaj@mskcc.org.
José
J
Baselga
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C582924:2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide; D007093:Imidazoles; D010077:Oxazepines; D047428:Protein Kinase Inhibitors; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human