Phase I trial of sorafenib in hepatocellular carcinoma (HCC) patients after liver transplantation (LT).

Abstract

TPS172 Background: Liver transplantation offers long term survival for 75-80% of HCC patients within Milan and UCSF criteria. For those who fall outside, rates of recurrence are higher. There are no known treatments which decrease risk of recurrence post-transplant. Sorafenib is a multi-targeted tyrosine kinase inhibitor against VEGFR2-3, PDGFR and Raf, and is the only approved HCC drug in the US. We began a Phase I study of sorafenib in high-risk HCC patients after liver transplantation at our center. Methods: Eligible subjects had biopsy-proven HCC outside Milan criteria preoperatively or at explant, poorly differentiated tumors, or tumors with microvascular invasion. We began a phase I dose-escalation study, beginning drug between 4 and 12 weeks after liver transplantation, with a planned duration of treatment of 6 months. Cohort dosages are as follows: 1) 200 mg q day, 2) 200 mg BID, 3) 200 mg/400 mg, and 4) 400 mg BID. Correlative studies include circulating endothelial cells (CECs), sVEGFR1 and IL-6. These are being collected prior to treatment, at 1 month, and at recurrence as possible predictive and prognostic biomarkers. We have enrolled 7 patients out of a planned 24. Median age is 65, and all are men. Underlying etiologies include HCV (5), HBV (1) and ETOH (1). 5 patients (71%) were within Milan on imaging (1 tumor ≤5cm, 3 or fewer tumors each ≤3 cm, and no vascular invasion); 3 of these were upstaged when explants were examined. 6 (86%) were within UCSF criteria (1 lesion ≤6.5 cm, 2-3 lesions each ≤ 4.5 cm, with total tumor diameter ≤8 cm) on explant. 2 subjects had vascular invasion on explant, and 3 had high grade disease. We have completed the first cohort. Mean follow up is 355 days, and mean time on sorafenib is 148 days. The maximum tolerated dose to date is 200 mg/day. Most patients are within UCSF criteria, so we would expect relatively low recurrence rates, but it is still reassuring that we have had no recurrences thus far, and have seen no grade 4 or 5 toxicities. Our phase I study is being expanded to other sites to increase accrual, and a phase III study may be considered in patients with a higher risk of recurrence who fall outside the Milan and/or UCSF criteria.