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Phase 1/2 study of everolimus in advanced hepatocellular carcinoma
Author(s) -
Zhu Andrew X.,
Abrams Thomas A.,
Miksad Rebecca,
Blaszkowsky Lawrence S.,
Meyerhardt Jeffrey A.,
Zheng Hui,
Muzikansky Alona,
Clark Jeffrey W.,
Kwak Eunice L.,
Schrag Deborah,
Jors Kathryn R.,
Fuchs Charles S.,
Iafrate A. John,
Borger Darrell R.,
Ryan David P.
Publication year - 2011
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.26165
Subject(s) - everolimus , medicine , rash , gastroenterology , adverse effect , alanine transaminase , hepatocellular carcinoma , aspartate transaminase , sorafenib , proteinuria , urology , kidney , biochemistry , chemistry , alkaline phosphatase , enzyme
BACKGROUND: The phosphoinositide 3‐kinase/Akt/mammalian target of rapamycin pathway plays a critical role in the pathogenesis of hepatocellular carcinoma (HCC). We performed a single‐arm, phase 1/2 study of everolimus in patients with advanced HCC. METHODS: Patients with histologically confirmed measurable advanced HCC, 0‐2 prior regimens, and adequate hematologic, hepatic, and renal functions received everolimus at 5 mg/day or 10 mg/day orally (6 weeks/cycle). The primary end points were determination of a safe dosage of everolimus (phase 1) and progression‐free survival (PFS) at 24 weeks (phase 2). RESULTS: Twenty‐eight patients were enrolled and evaluable for efficacy and toxicity. No dose‐limiting toxicities were observed at the 5 mg/day (n = 3) or 10 mg/day (n = 6) dosage level in phase 1. Twenty‐five patients received everolimus at 10 mg/day. Grade 3‐4 adverse events included lymphopenia (n = 3), aspartate transaminase (n = 3), hyponatremia (n = 2), and 1 patient each with anemia, alanine transaminase, hyperglycemia, proteinuria, rash, and hypoxia. One patient (4%) had partial response (95% confidence interval [CI], 0.9%‐19.6%). The median PFS and overall survival were 3.8 months (95% CI, 2.1‐4.6) and 8.4 months (95% CI, 3.9‐21.1), respectively. The estimated PFS rate at 24 weeks was 28.6% (95% CI, 7.9%‐49.3%). CONCLUSION: Everolimus was well tolerated in patients with advanced HCC, and 10 mg/day was defined as the phase 2 dosage. Although the study did not proceed to the second stage of phase 2, preliminary antitumor activity was observed with everolimus in patients with advanced HCC, most of whom had prior systemic treatment. Cancer 2011. © 2011 American Cancer Society.