This phase I dose-escalation study investigated the maximum tolerated dose (MTD),
safety, pharmacokinetics, pharmacodynamics (PDs), and preliminary antitumor activity
of BGT226, a potent, oral dual phosphatidylinositol-3-kinase (PI3K)/mammalian target
of rapamycin inhibitor.
Fifty-seven patients with advanced solid tumors received BGT226 2.5-125 mg/day three
times weekly (TIW). Dose escalation was guided by an adaptive Bayesian logistic regression
model with overdose control. Assessments included response per RECIST, [18F]-fluorodeoxyglucose
uptake, and phosphorylated-S6 in skin and paired tumor samples.
Three patients (125 mg cohort) had dose-limiting toxic effects (grade 3 nausea/vomiting,
diarrhea). BGT226-related adverse events included nausea (68%), diarrhea (61%), vomiting
(49%), and fatigue (19%). BGT226 demonstrated rapid absorption, variable systemic
exposure, and a median half-life of 6-9 h. Seventeen patients (30%) had stable disease
(SD) as best response. Nine patients had SD for ≥16 weeks. Thirty patients (53%) achieved
stable metabolic disease as assessed by [18F]-fluorodeoxyglucose-positron emission
tomography; however, no correlation between metabolic response and tumor shrinkage
according to computed tomography was observed. PD changes suggested PI3K pathway inhibition
but were inconsistent.
The MTD of BGT226 was 125 mg/day TIW, and the clinically recommended dose was 100
mg/day TIW. Limited preliminary antitumor activity and inconsistent target inhibition
were observed, potentially due to low systemic exposure.