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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 eve
rolimus given with sorafenib 400 mg 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 2.5 mg 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 2.5 mg once daily and 6 out of 13 patients treated with everolimus 5.0 mg once daily experienced a dose-limiting toxicity, most commonly thrombocytopenia (n = 5). All patients experienced 猢? 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 2.5 mg once daily. The inability to achieve a biologically effective everolimus concentration at the MTD precluded phase II study of this combination.
