ATNT-18A PHASE I STUDY OF MLN0128 AND BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA AND OTHER SOLID TUMORS

Abstract

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 inhibitor of TORC1/2 complexes. Bevacizumab is a monoclonal antibody targeting VEGF with activity in some cancers. METHODS: We are conducting NCI 9552, a Cancer Therapeutic Evaluation Program (CTEP)-sponsored phase I trial of MLN0128 and bevacizumab. Eligibility criteria include histologically confirmed recurrent glioblastoma (GBM) and advanced solid tumors, >18 years old, KPS> 60, adequate bone marrow reserve and organ function. The study has 2 stages; dose escalation using a 3 + 3 design to estimate MTD/RP2D defined as the highest dose at which <2/6 patients experience dose-limiting toxicity (DLT); followed by dose expansion at MTD to include 10 patients with recurrent GBM and up to 30 with endometrial and ovarian cancer. During escalation, patients received increasing doses of oral MLN0128 beginning at 3 mg daily in combination with standard dose bevacizumab at 10mg/kg intravenously every 2 weeks in 28-day cycles. RESULTS: Thirteen patients consented for stage 1; one withdrew consent before starting study treatment. There were 7 men and 5 women. Median age and KPS were 56 years and 90. Eight patients had a diagnosis of GBM and 4, ovarian cancer. Three dose levels were evaluated, including MLN0128 at 3, 4 and 5 mg daily. At 5 mg dose level, 1/6 pts experienced a DLT of grade 3 fatigue. Two additional grade 3 events included reversible hypercholesterolemia and hypophosphatemia. Other toxicities were < grade 2. Of 8 GBM patients, 2 remain on treatment (1 complete response), 6 progressed; (median number of cycles, 3(range, 1-12). Of 4 ovarian cancer patients, 2 had partial responses,1 stable disease,1 progression. CONCLUSION: MLN0128 at 5mg oral daily in combination with bevacizumab at 10mg/kg intravenously every 2 weeks is the RP2D and well-tolerated. The dose expansion portion of the study is now enrolling.