BGT226

Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors

Background: This phase I dose-escalation study investigated the utmost tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics (PDs), and preliminary antitumor activity of BGT226, a powerful, dental dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin inhibitor.

Patients and techniques: Fifty-seven patients with advanced solid tumors received BGT226 2.5-125 mg/the third day occasions weekly (TIW). Dose escalation was led by an adaptive Bayesian logistic regression model with overdose control. Assessments incorporated response per RECIST, [18F]-fluorodeoxyglucose uptake, and phosphorylated-S6 in skin and paired tumor samples.

Results: Three patients (125 mg cohort) had dose-restricting toxic effects (grade 3 nausea/vomiting, diarrhea). BGT226-related adverse occasions incorporated nausea (68%), diarrhea (61%), vomiting (49%), and fatigue (19%). BGT226 shown rapid absorption, variable systemic exposure, along with a median half-existence of 6-9 h. 17 patients (30%) had stable disease (SD) as well as response. Nine patients had SD for =16 days. Thirty patients (53%) achieved stable metabolic disease as assessed by [18F]-fluorodeoxyglucose-positron emission tomography however, no correlation between metabolic response and tumor shrinkage based on computed tomography was observed. PD changes recommended PI3K path inhibition but were sporadic.

Conclusions: The MTD of BGT226 was 125 mg/day TIW, and also the clinically suggested dose was 100 mg/day TIW. Limited preliminary antitumor activity and sporadic target inhibition were observed, potentially because of low systemic exposure.