Results of a phase I study of bevacizumab (BV), everolimus (EV), and erlotinib (E) in patients with advanced solid tumors

Abstract

3548 Background: BV inhibits vascular endothelial growth factor (VEGF). EV is an mTOR (mammalian target of rapamycin) inhibitor. E inhibits epidermal growth factor receptor (EGFR) tyrosine kinase. VEGF, mTOR, and EGFR inhibitors have anti-tumor and anti-angiogenesis effects alone and in combination in preclinical models. As a combination targeted therapy, we evaluated BV + EV + E in a phase I, pharmacokinetic (PK), biomarker study. Methods: Cycle length was 28 days. Doses: BV 10mg/kg IV q14d. EV 5mg PO QD, escalating to 10mg QD. Once the recommended phase II dose (RPTD) of BV + EV was reached, E was added, starting at 75 mg PO QD. DLT was defined as any treatment-related grade 4 heme or grade 3/4 non-heme event in Cycle 1. Results: 34 pts have been enrolled (18 F, 16 M), 28 evaluable for DLT, 24 for efficacy. Median age is 58y (range 29–73). Dose level 1 (BV 10mg/EV 5mg) had no DLT’s. Dose level 2 (BV 10mg/EV 10mg) had no DLT’s and the cohort was expanded to 13 evaluable pts. E (75mg) was added to BV 10mg/ EV 10mg. 2/6 patients had DLT (grade 3 mucositis and grade 3 rash). The doses were adjusted to BV 5mg/EV 5mg/E 75mg. 3 patients had no DLT and this dose is the MTD and RPTD for the 3-drug combination. 20 more patients are being enrolled at the RPTD for biomarker studies. Other grade ¾ toxicity included: nephrotic syndrome, cardiac ischemia, ventricular thrombus, portacath thrombosis, and bowel perforation. 2 patients had PR: 1 renal and 1 osteosarcoma. 16/24 pts had SD (10–112+ weeks). 5/6 patients with colorectal cancer (CRC) previously progressing on BV had SD (16+ - 112 weeks). One CRC patient had 19% radiologic decrease. Conclusions: BV + EV + E preliminary clinical activity (notably in refractory CRC) and class-related side effects were seen. The MTD is BV 5mg/kg IV q14d + EV 5mg PO QD + E 75mg PO QD. Updated data will be presented. No significant financial relationships to disclose.