December 3, 2013

Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma

J Hepatol. 2013 Dec;59(6):1271-7. doi: 10.1016/j.jhep.2013.07.029. Epub 2013 Aug 6.

Finn RS, Poon RT, Yau T, Klümpen HJ, Chen LT, Kang YK, Kim TY, Gomez-Martin C, Rodriguez-Lope C, Kunz T, Paquet T, Brandt U, Sellami D, Bruix J.

University of California Los Angeles, Los Angeles, CA, United States. Electronic address:


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 28days 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 4.5months and 7.4months, respectively, and 1.8months and 11.7months, 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.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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

PMID: 23928403 [PubMed - in process]


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