3097 Background: BV is a potent inhibitor of vascular endothelial growth factor (VEGF) with broad clinical activity. E is an mTOR (mammalian target of rapamycin) inhibitor in development for cancer and solid organ transplant therapy. VEGF and mTOR inhibitors have anti-tumor and anti-angiogenesis effects alone and in combination in preclinical models. As a combination anti-angiogenesis therapy, we evaluated BV + E in a phase I, pharmacokinetic (PK), biomarker study. Methods: BV was dosed at 10mg/kg IV q14d. E was dosed at 5mg PO QD, escalating to 10mg QD. Cycle length was 28 days. DLT was defined as any grade 4 heme or grade 3/4 non-heme event in Cycle 1 related to treatment. Pts had advanced solid tumors, adequate organ function, and no increased risks for class-related toxicities. Serial blood samples were collected for PK studies of E. Dermal wound angiogenesis assays were performed pre and on treatment for phospho VEGFR2, AKT, mTOR, and S6K. Results: 14 pts have been enrolled (8 F, 6 M), 12 evaluable for toxicity, 14 for efficacy. Median age is 58y (range 29–73). At dose level 1 (BV 10mg/E 5mg) there were no DLT’s in 5 pts. At dose level 2 (BV 10mg/E 10mg), no DLT’s were noted in the initial 3 pts and the cohort was expanded to 9 pts. Side effects were primarily grade 1–2: pain (10/14), mucositis (9/14), anorexia (8/14), rash (7/14), bleeding (7/14), hyperlipidemia (6/14), fatigue (6/14), and HTN (4/14). 1 pt had a myocardial infarction at day 72 and one pt developed nephrotic syndrome at day 70. 7/14 pts had stable disease as best response (70–278d). Conclusions: BV + E is generally well-tolerated. Preliminary clinical activity and class-related side effects were noted. The recommended phase II dose is BV 10mg/kg IV q14d and E 10mg PO QD. [Table: see text]
Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors
