Background: The P13K/Akt/mTOR signaling axis plays a central role in cell growth and survival in a variety of cancers. MLN0128 is an oral TORC1/2 inhibitor. Bevacizumab is a monoclonal antibody targeting VEGF with activity in some cancers, including glioblastoma (GBM). Methods: This ongoing Cancer Therapeutic Evaluation Program (CTEP)-sponsored phase I trial uses a 3+3 dose escalation design to determine the maximum tolerated dose (MTD/recommended phase 2 dose (RP2D) of MLN0128 when administered daily with bevacizumab (10 mg/kg every 2 weeks) and includes a dose expansion at the MTD/RP2D for recurrent GBM (n=10) and recurrent endometrial/ovarian cancer (n=30) patients (pts). Eligibility includes histologically confirmed recurrent GBM or other advanced solid tumors, >18 years old, KPS> 60, adequate bone marrow and organ function. The starting dose of MLN0128 was 3 mg daily. Results: Thirty-six pts have enrolled (12 in dose escalation and 24 in dose expansion). The median age and KPS were 56 (range: 25-74) and 80 (range 70-100), and 25 were women. Histologic diagnosis included GBM (n=16), ovarian (n=14) and endometrial (n=6) cancer. Three MLN0128 dose levels were evaluated including 3,4 and 5 mg daily. Only 1 dose limiting toxicity (DLT) occurred (grade 3 fatigue at the 5 mg dose level). There were 31 additional related grade 3 events and 1 grade 4 event. Most common toxicities were rash, hypercholesterolemia, gastrointestinal symptoms, lymphopenia and fatigue. Median number of completed cycles was 2 (range, 1-17). Sixteen pts came off for disease progression, 8 withdrew, 2 patient/physician’s decision, 3 toxicity, 1 other; 6 remain on treatment. Best response to treatment among GBM pts was complete response (n=1), partial response (PR, n=3), stable disease (SD, n=6). Three ovarian cancer pts achieved PR and 8 SD, while 2 endometrial cancer pts achieved SD. Conclusions: The RP2D of daily MLN0128 is 5mg when combined with bevacizumab. The dose expansion phase continues to enroll. Clinical trial information: NCT02142803