A phase I study of brivanib alaninate (BMS-582664), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in combination with full dose cetuximab (BC) in patients (pts) with advanced gastrointestinal malignancies (AGM) who failed prior therapy

4111 Background: Brivanib alaninate (B) is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling. Prior studies have validated both VEGF and EGF signaling pathways as targets in AGM. The MTD of B is 800 mg qd (ASCO #3051, 2006). Methods: An open-label phase I dose-escalation study of B in combination with cetuximab (C) was conducted in pts with AGM who failed prior therapy. B was given po Day 1 and qd from Day 8, starting at 320 mg. C was given IV Day 8 (400 mg/m2) then weekly (250 mg/m2). Dose escalation of B continued to 800 mg qd, when an expansion cohort for pts with colorectal cancer (CRC) was opened for additional safety and efficacy. Fresh tissue and blood sampling for biomarker and PK analysis was acquired. FDG-PET was obtained at baseline x 2, and Days 15 and 56. Tumor response (modified WHO) was evaluated q 8 weeks. Results: 60 pts (57 CRC, 2 esophageal, and 1 hepatocellular carcinoma) were treated with B 320, 600 or 800 mg qd in combination with C for a median 8.3 weeks (range 0.1–57.3+). A single DLT, bilateral pulmonary emboli, occurred at 320 mg. B+C was tolerable with few G3/4 AEs (fatigue 16%, transaminitis 12%, diarrhea 2%). PK was linear up to 800 mg. There was no apparent effect of C or B on each drug’s PK. FDG-PET results from 48 pts with 1–3 target lesions showed baseline reproducibility for SUVmax, SUVpeak and SUVmean, with intrasubject CV of 15%, 16% and 20%, respectively. There was a dose-dependent decline in plasma COL IV and sVEGFR2 levels at Day 36 compared with baseline (COL IV: 320 mg, 26%, 800 mg 41%; sVEGFR2: 320 mg, 1.5%, 800 mg 31%). Best responses in subsets of 34 evaluable CRC pts treated with B 800 mg + C are shown in the Table. Conclusions: B ≤800 mg qd + C was tolerable and had clinical activity in pts with advanced CRC. Pretreatment FDG-PET is a reproducible imaging modality. Prior therapy EGF inhibitor - - + + VEGF inhibitor - + - + Evaluable pts (total) 12 12 1 9 34 PR 4 1 0 0 5 (15%) SD 5 7 1 6 19 (56%) PD 3 4 0 3 10 (30%) PR + SD ≥ 6 mo 4 3 0 3 10 (30%) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb