Background & aims: Sorafenib is the only therapy shown to improve overall survival in advanced hepatocellular carcinoma (HCC). Combination therapy targeting multiple signaling pathways may improve outcomes. This phase I study was designed to determine the maximum tolerated dose (MTD) of everolimus given with sorafenib 400mg twice daily in patients with advanced HCC of Child-Pugh class A liver function who were naive to systemic therapy.
Methods: Everolimus was initiated at 2.5mg once daily and increased per a Bayesian sequential dose-escalation scheme based on the dose-limiting toxicities experienced within the first 28 days of treatment. Adverse events were assessed continuously. Efficacy was evaluated using the best overall response rate per RECIST.
Results: Thirty patients were enrolled; 25 were evaluable for MTD determination. One out of 12 patients treated with everolimus 2.5mg once daily and 6 out of 13 patients treated with everolimus 5.0mg once daily experienced a dose-limiting toxicity, most commonly thrombocytopenia (n=5). All patients experienced 1 adverse event, most commonly diarrhea (66.7%), hand-foot skin reaction (66.7%), and thrombocytopenia (50.0%). Best overall response was stable disease (62.5% and 42.9% in the 2.5-mg and 5.0-mg cohorts, respectively). Median time to progression and overall survival in the 2.5-mg cohort were 4.5 months and 7.4 months, respectively, and 1.8 months and 11.7 months, respectively, in the 5.0-mg cohort.
Conclusions: In patients with advanced HCC, the everolimus MTD in combination with standard-dose sorafenib was 2.5mg once daily. The inability to achieve a biologically effective everolimus concentration at the MTD precluded phase II study of this combination.
Keywords: AE; AST; BCLC; BID; Barcelona Clinic Liver Cancer; C(max); C(min); CI; DCR; DLT; Dose-finding; ECOG; Eastern Cooperative Oncology Group; Everolimus; HBV; HCC; Hepatocellular carcinoma; MTD; Mammalian target of rapamycin; OS; PDGFR; QD; RCC; RDI; RECIST; Response Evaluation Criteria in Solid Tumors; SD; SHAR; Sorafenib; Sorafenib HCC Assessment Randomized Protocol; TTP; ULN; VEGFR; adverse event; aspartate aminotransferase; confidence interval; disease control rate; dose-limiting toxicity; hepatitis B virus; hepatocellular carcinoma; mTOR; mammalian target of rapamycin; maximum blood concentration; maximum tolerated dose; minimum blood concentration; once daily; overall survival; platelet-derived growth factor receptor; relative dose intensity; renal cell carcinoma; standard deviation; time to progression; twice daily; upper limit of normal; vascular endothelial growth factor receptor.
Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.