Phase I evaluation of sorafenib (SOR) and bevacizumab (BEV) as first-line therapy in hepatocellular cancer (HCC): North Central Cancer Treatment Group trial N0745.

Abstract

4116 Background: HCC tumors are highly vascular and over express VEGF. The monoclonal antibody BEV and the oral multi-kinase inhibitor SOR inhibit VEGF-induced angiogenesis and the associated Ras/Raf/MEK/ERK signaling pathway. It is hypothesized that SOR will complement the mode of action of BEV by more fully blocking VEGF signaling. Methods: Eligibility included measurable locally advanced or metastatic HCC not amenable for surgery or liver transplant (BCLC-C), Child Pugh A or B7, esophageal varices if treated ≥ 6 mos, and acceptable blood chemistries. Patients with mixed cholangiocarcinoma/HCC were ineligible. Treatment doses/schedule appears in the table. The phase I starting dose level (0) was: BEV 1.25 mg/kg d1 and 15 plus SOR 400 mg BID d1-28. Results: 17 patients aged 18-79 (mean 62.4 yrs) were enrolled; 14 were male. A majority of patients presented with ascites (71%). Baseline characteristics included cirrhosis (41% of patients), prior RT (12%), prior chemoembolization (6%), and vascular invasion (20%). Cycle 1 dose limiting toxicities (DLTs) by dose level were: Dose 0 (2 pts with DLTs) – Gr 3 hand/foot skin reaction, fatigue, hypertension; Dose -1 (3 pts) – Gr 3 alanine/aspartate aminotransferase inc, dehydration, hypophosphatemia, creatinine inc, hypoglycemia, nausea vomiting, and Gr 4 hyponatremia; Dose -2 and -2a had 0 DLTs. Conclusions: With an acceptable toxicity profile, dose level -2a (SOR 200 mg BID d1-28, plus BEV 2.5 mg/kg d1 and 15) is currently used in the on-going phase II trial in this population. Supported by NCI Grant ca25224 & Bayer Pharmaceuticals and Bayer’s REACH Program. Dose levels evaluated. Dose 0 Dose -1 Dose -2 Dose -2a S (d1-28) 400 mg BID 400 mg BIDa 200 mg BID 200 mg BID BEV (d1 and 15) 1.25 mg/kg 1.25 mg/kg 1.25 mg/kg 2.5 mg/kg N 3 6 5 3 Had DLT 2 3 0 0 a Days 1-5 of each 7 days, only.