A phase I dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma.

Abstract

4097 Background: Rapamycin combined with bevacizumab can inhibit tumor growth and downstream targets of the mTOR pathway in hepatocellular cancer xenografts. Methods: We performed a phase I study to determine the MTD and clinical activity of rapamycin with bevacizumab in patients with unresectable hepatocellular carcinoma. Patients with prior treatment, ECOG 0-2 and Child-Pugh A or B were included. Intravenous bevacizumab was given at 5 mg/kg every 2 weeks with daily oral dose-escalated rapamycin (levels 1 to 5: 1 to 5mg, respectively). An expanded cohort of 6 was recruited at MTD. Each cycle was 28 days. Rapamycin PK was determined at steady-state on day 8 of the first cycle. Pharmacodynamic analysis using DCE-CT to assess antiangiogenic effects were performed at baseline and on day 8. Results: Eighteen patients (M/F: 13/5; median age: 63; Child-Pugh A/B: 15/3; prior chemotherapy: 6) were treated. DLTs in the first cycle were grade 3 mucositis in 1 patient and grade 3 thrombocytopenia in another patient at dose level 5. Thus the MTD of rapamycin was 4mg with bevacizumab 5 mg/kg. Other common treatment-related toxicities included fatigue (50%), hyperlipidemia (50%), anorexia (50%) and diarrhea (39%). Rapamycin PK exhibited dose linearity for Cmax and AUC0-inf from dose levels 1-5. Trough levels increased 3-fold between dose levels 2 and 3-5. Rapamycin clearance was highest at dose level 1 but similar between dose levels 2 to 5. Blood flow reduction correlated linearly with AUC0-inf (r = 0.63, p = 0.039), and Cmax (r = 0.79, p = 0.004), and reduction in permeability correlated with Cmax (r = 0.72, p = 0.013) of rapamycin. One patient achieved complete response (5.6%), 9 stable disease (50%), 6 progressive disease (33.3%) and 2 dropped out of study before evaluation. Median OS was 17.5 months (Childs-Pugh A) and 3.1 months (Childs-Pugh B) (p = 0.0005). Median PFS was 6.6 months. Conclusions: The MTD for rapamycin was 4 mg daily when administered with bevacizumab 5 mg/kg fortnightly. Clinical activity was also seen at lower doses of rapamycin. No significant financial relationships to disclose.