Phase I dose escalation study of dual PI3K/mTOR inhibition by Sapanisertib and Serabelisib in combination with paclitaxel in patients with advanced solid tumors.

Background: Phase I trial to determine the safety and efficacy of paclitaxel, sapanisertib, and serabelisib. Patients and methods : Patients with previously treated advanced solid tumors were eligible for this open label, cohort study of sapanisertib (TAK-228) and serabelisib (TAK-117) with weekly paclitaxel. A traditional 3 + 3 dose escalation design with 5 dosing cohorts was used. Patient reported outcomes were also evaluated. Results: 19 heavily pretreated patients were enrolled (10 ovarian, 3 breast, and 6 endometrial cancers). All patients received comprehensive genomic profiling prior to enrollment. RP2D is sapanisertib 3 or 4 mg, serabelisib 200 mg on days 2–4, 9–11, 16–18 and 23–25 with paclitaxel 80 mg/m2 on days 1, 8 and 15 every 28 days. All patients in Cohort 5 required dose reductions and one patient experienced a DLT. The most frequent grade 3 or 4 adverse events were decreased WBCs (20%), nonfebrile neutropenia (12%), anemia (9%), elevated liver enzymes (4%), and hyperglycemia (11%). 3 patients had a CR, 4 had a PR, and 4 patients had SD > six months. ORR was 47% and CBR was 73% in 15 evaluable patients. Including all 19 enrolled patients, the PFS was 11 months and OS is still ongoing at 17 months. Conclusions: The combination of sapanisertib, serabelisib, and paclitaxel was safe and generally well tolerated. Preliminary efficacy was remarkable in an area of unmet need, especially for patient with PI3K/AKT/mTOR pathway aberrations. Positive effects and sustained clinical benefit were even seen in patients that were refractory to platinum and had failed taxane, everolimus, or temsirolimus. Clinical Trial number : ClinicalTrials.gov , NCT03154294 • Sapanisertib, serabelisib and paclitaxel was a safe and well tolerated combination in heavily pretreated patients • Antitumor activity was observed, especially with endometrioid endometrial cancer and those with PI3K aberrations • In this heavily pretreated population with advanced solid tumors, the ORR = 47%, the CBR = 73%, PFS = 11 months, and OS = 17 months, and is ongoing • The study was awarded a plenary session at this year's Society of Gynecologic Oncology meeting in March 2022 [ABSTRACT FROM AUTHOR]