A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors
Background: Bimiralisib is a pan-PI3K/mTOR inhibitor that has shown antitumor activity in preclinical models. This study aimed to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), optimal dosing schedule, and adverse events (AEs) in patients with advanced solid tumors.
Patients and Methods: Patients were administered oral bimiralisib to establish the MTD for one continuous dosing schedule (once daily) and two intermittent schedules: Schedule A (Days 1 and 2 weekly) and Schedule B (Days 1 and 4 weekly). Treatment continued until disease progression or unacceptable AEs occurred.
Results: The MTD for the continuous dosing schedule was 80 mg, with grade 3 fatigue identified as the dose-limiting toxicity (DLT). No MTD was reached for the intermittent schedules, with only one DLT observed in Schedule B. PK analysis indicated that a 140 mg dose in Schedule A fell within the biologically active range and was selected for further study. The most common treatment-emergent AE in the continuous schedule was hyperglycemia (76.2%), while nausea was the most frequent AE in both intermittent schedules (56-62.5%). The most common treatment-emergent AE of grade 3 or higher was hyperglycemia (28.6% in the continuous schedule, 12.0% in Schedule A, and 12.5% in Schedule B). A partial response was observed in a patient with head and neck squamous cell carcinoma harboring a NOTCH1T1997M mutation.
Conclusions: Bimiralisib exhibited a manageable AE profile consistent with its compound class. The intermittent dosing schedules resulted in fewer grade 3 or higher AEs while maintaining favorable PK profiles. Schedule A is recommended for further development in biomarker-selected patient populations.