Phase I and pharmacokinetic study of oral thalidomide in patients with advanced hepatocellular carcinoma.

PURPOSE: To evaluate the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics of thalidomide in patients with advanced hepatocellular carcinoma (HCC).

METHODS

Patients with advanced HCC who were not feasible for definitive local therapy were eligible. Patients were enrolled in a cohort of three to receive thalidomide twice daily for 1 week to determine the MTD. Intra-patient dose escalation was permitted. Pharmacokinetic studies were performed at the first dose level and repeated at the second dose level of each patient.

RESULTS

Fifteen patients were accrued at four dose levels with the starting dose range 100-400 mg/day. Two patients at 400 mg/day experienced DLT (grade 3 angioedema and dyspnea, respectively). The MTD of twice-daily schedule was determined as 300 mg/day. The mean steady-state maximal blood concentration and mean steady-state area under the curve had a trend toward positive correlation, but non-linear proportionate, to the daily dose of thalidomide. Pharmacokinetic parameters are comparable for patients of Child-Pugh's A and B. Apparent mild, transient drug-induced transaminitis was early onset, self-limited, which occurred in 30.7% of patients. Serum hepatitis B or C viral titers was largely not affected.

CONCLUSION

The absorption and elimination of thalidomide are not significantly different in HCC patients with compensated or decompensated hepatic dysfunction.