Abstract:
Background: Many patients with hepatocellular carcinoma (HCC) have liver impairment as a result of tumor burden and cirrhosis. Brivanib, which is administered orally as the prodrug brivanib alaninate, is a selective, dual inhibitor of fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases that is currently in phase III studies for HCC.
Methods: This phase I study compared the pharmacokinetic profile of brivanib in patients with HCC and varying levels of hepatic impairment with that of patients with advanced solid non-HCC malignancies and normal hepatic function. Patients were assigned to 1 of 4 study groups: Group A, HCC plus Child-Pugh (CP) A status (mild hepatic impairment); Group B, HCC plus CP B (moderate hepatic impairment); Group C, HCC plus CP C (severe hepatic impairment); and Group D, non-HCC malignancy and normal hepatic function. Plasma brivanib concentrations were determined on Days 1 and 28. Brivanib alaninate doses were 400 mg/day in Groups A, B, and D, and 200 mg/day in Group C.
Results: Of the 52 enrolled patients, 24 were assigned to 1 of the 4 groups (6 patients/group). After a single brivanib alaninate dose, the brivanib maximum observed plasma concentration and the area under the concentration-time curve from time zero extrapolated to infinity (AUCinf) in patients with HCC and mild or moderate hepatic impairment (Groups A and B) were comparable with those in patients with normal hepatic function (Group D). Brivanib AUCinf was approximately 50% higher in patients with HCC and severe hepatic impairment (Group C) compared with patients with normal hepatic function (Group D). Brivanib alaninate 400 mg/day was tolerated in Groups A, B, and D. Tolerability could not be assessed in Group C because of dose interruptions and discontinuations. Based on modified World Health Organization criteria, stable disease was achieved in 8 of 18 patients (44.4%) with HCC and 1 of 6 patients (17%) with non-HCC tumors.
Conclusions: Brivanib exposure in patients with HCC and mild or moderate hepatic impairment was similar to that in patients with non-HCC malignancies and normal hepatic function, suggesting that dose adjustment is not necessary in HCC patients with CP A and B status. Experience in patients with HCC and CP C status is insufficient to recommend brivanib use in this population.
