Phase I trial of sorafenib following liver transplantation in patients with high-risk hepatocellular carcinoma.

Abstract

401 Background: Liver transplantation (LT) offers excellent long-term survival for hepatocellular carcinoma (HCC) patients who are within established criteria. For those outside such criteria, or with high risk pathologic features in the explant, HCC recurrence rates after LT are high. No treatment has been shown to decrease risk of recurrence post-LT. We conducted a multicenter phase I trial of sorafenib in LT patients with high-risk HCC. Methods: Subjects had pathologically proven high-risk HCC defined as outside Milan (pre- or post-transplant), poorly differentiated tumors, or tumors with vascular invasion. We used a standard 3+3 phase I design, beginning drug between 4 and 16 weeks after LT, with planned duration of treatment of 24 weeks. Cohort dosages were: 1) 200 mg per day, 2) 200 mg twice a day, 3) 200 mg/400 mg per day 4) 400 mg BID. Correlative studies included circulating endothelial cells (CECs) and plasma biomarkers collected prior to treatment, at 1 month, and at recurrence in a subset of subjects, and tumor expression of p-Erk, p-Akt, and c-Met in tissue microarrays. Results: We enrolled 14 patients. Median age was 63 years, and 93% were men. 71% had underlying HCV and 21% had HBV. Maximum tolerated dose (MTD) was 200 mg BID; only 43% of patients received >80% of planned dose. Grade 3-4 toxicities seen in >10% of subjects included: leukopenia (29%), LFT abnormalities (21%), hypertension (14%), hand-foot syndrome (14%) and diarrhea (14%). Over a median follow-up of 953 days, 1 patient died and 4 recurred, with a median recurrence-free survival of 716 days for the 4 patients who recurred. Mean CEC number at baseline was 21 cells/4 ml for those who recurred, and 80 cells/4 ml for those who did not (p=0.10). Mean sVEGFR2 levels decreased after 1 month on sorafenib (p=0.09), but did not correlate with recurrence. There was a trend for tumor c-Met expression with increased risk of recurrence. Conclusions: Post-transplant sorafenib is feasible and tolerable at 200 mg PO BID. Recurrence-free survival appears longer than expected but needs further validation in a larger study. Clinical trial information: NCT00997022.