TY - JOUR
T1 - Phase I dose-escalation study of taselisib, an oral PI3K inhibitor, in patients with advanced solid tumors
AU - Juric, Dejan
AU - Krop, Ian
AU - Ramanathan, Ramesh K.
AU - Wilson, Timothy R.
AU - Ware, Joseph A.
AU - Sanabria Bohorquez, Sandra M.
AU - Savage, Heidi M.
AU - Sampath, Deepak
AU - Salphati, Laurent
AU - Lin, Ray S.
AU - Jin, Huan
AU - Parmar, Hema
AU - Hsu, Jerry Y.
AU - Von Hoff, Daniel D.
AU - Baselga, José
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/7
Y1 - 2017/7
N2 - 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 preclinical PIK3CA-mutant tumor xenograft models. Confirmed response rate was 36% for PIK3CA-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 known PIK3CA hotspot mutations (0/15). Significance: Preliminary data consistent with preclinical data indicate increased antitumor activity of taselisib in patients with PIK3CA -mutant tumors (in comparison with patients with tumors without known activating PIK3CA hotspot mutations) starting at the lowest dose tested of 3 mg, thereby supporting higher potency for taselisib against PIK3CA -mutant tumors.
AB - 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 preclinical PIK3CA-mutant tumor xenograft models. Confirmed response rate was 36% for PIK3CA-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 known PIK3CA hotspot mutations (0/15). Significance: Preliminary data consistent with preclinical data indicate increased antitumor activity of taselisib in patients with PIK3CA -mutant tumors (in comparison with patients with tumors without known activating PIK3CA hotspot mutations) starting at the lowest dose tested of 3 mg, thereby supporting higher potency for taselisib against PIK3CA -mutant tumors.
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U2 - 10.1158/2159-8290.CD-16-1080
DO - 10.1158/2159-8290.CD-16-1080
M3 - Article
C2 - 28331003
AN - SCOPUS:85018510810
SN - 2159-8274
VL - 7
SP - 704
EP - 715
JO - Cancer discovery
JF - Cancer discovery
IS - 7
ER -