Multicenter phase I trial of sorafenib (S) in high-risk hepatocellular carcinoma (HCC) patients after liver transplantation (LT).

Abstract

285 Background: LT offers excellent long-term survival for HCC patients within the Milan criteria. For those outside Milan, recurrence rates are higher. No known treatments have been shown to decrease risk of recurrence post-transplant. Methods: Subjects had pathologically proven HCC that was outside Milan (pre- or post-transplant), was poorly differentiated, or had vascular invasion. We used a standard 3+3 design, beginning drug between 4 and 16 weeks after LT, with planned duration of treatment of 24 weeks. Cohort dosages were: 1) 200 mg q day, 2) 200 mg BID, 3) 200 mg/400 mg q day. Correlative studies included circulating endothelial cells (CECs-Veridex) and plasma biomarkers (VEGF, sVEGFR1, sVEGFR2, IL-6 and HGF) collected prior to treatment, at 1 month, and at recurrence. Results: We enrolled 14 patients; 93% were men. Median age was 63; 71% had underlying HCV, 21% HBV, and 21% ETOH. 57% were outside Milan on preoperative imaging. On explant, 29% had poorly-differentiated tumors, and 36% had vascular invasion. MTD was 200 mg BID; only 43% of patients received >80% of planned dose. DLTs included liver function abnormalities (1), transplant rejection leading to death (1), and grade 3 hypertension (1). 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 836 days, 1 patient died and 4 recurred (median time to recurrence=716 days). Two recurrences were in subjects with limited exposure to S. Median CEC number at baseline was 16 cells/4 ml for those who recurred, and 42 cells/4 ml for those who did not (p=0.10). Median sVEGFR2 levels decreased after 1 month on S (p=0.09), but did not predict recurrence. Conclusions: To our knowledge, this is the first multicenter phase I trial of S completed in the post-transplant setting for high-risk HCC. MTD of S was 200 mg PO BID. Post-transplant S was feasible. Exploratory biomarker data suggest that low CECs at baseline were potentially associated with a higher recurrence rate. Time to recurrence was promising compared with historic controls, but needs to be further explored and validated in a larger study. Clinical trial information: NCT00997022.