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Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors
Dejan Juric1, Ian Krop2, Ramesh K Ramanathan3
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Abstract:
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. 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.
Insights
Taselisib effectively inhibits tumor growth by targeting the PI3K pathway. This potent inhibitor showed higher antitumor activity in patients with PIK3CA-mutant tumors, even at the lowest tested dose.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Taselisib is a potent inhibitor of the phosphoinositide 3-kinase (PI3K) pathway, a critical regulator of tumor growth.
- The PI3K pathway is frequently dysregulated in various solid tumors, making it a promising therapeutic target.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of taselisib in patients with advanced solid tumors.
- To investigate the antitumor activity of taselisib in relation to PIK3CA mutation status.
Main Methods:
- Phase I, modified 3+3 dose escalation study involving 34 patients with advanced solid tumors.
- Taselisib was administered orally once daily at doses ranging from 3 to 16 mg.
- Pharmacokinetic, pharmacodynamic (PI3K pathway inhibition in tumor samples), and response assessments were performed.
Main Results:
- Taselisib exhibited dose-proportional pharmacokinetics with a mean half-life of 40 hours.
- Common dose-dependent adverse events included diarrhea, hyperglycemia, and nausea.
- A confirmed response rate of 36% was observed in patients with PIK3CA-mutant tumors, with responses noted from 3 mg, compared to 0% in patients with wild-type PIK3CA tumors.
Conclusions:
- Taselisib demonstrates PI3K pathway inhibition in patients, consistent with preclinical findings.
- Preliminary data suggest enhanced antitumor activity of taselisib in patients with PIK3CA-mutant tumors.
- These findings support further investigation of taselisib in PIK3CA-mutant solid tumors.
