Phase 1/2 study of everolimus in advanced hepatocellular carcinoma

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 mea...

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Published in:Cancer 2011-11, Vol.117 (22), p.5094-5102
Main Authors: 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.
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
anemia
angiogenesis
Antineoplastic Agents - adverse effects
Antineoplastic Agents - therapeutic use
Biological and medical sciences
Cancer
Carcinoma, Hepatocellular - drug therapy
clinical trial
Everolimus
Female
Gastroenterology. Liver. Pancreas. Abdomen
hepatocellular carcinoma
Humans
Hypoxia
Liver Neoplasms - drug therapy
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Male
Medical sciences
Middle Aged
mTOR inhibitors
renal function
Side effects
Sirolimus - analogs & derivatives
Sirolimus - therapeutic use
survival
Toxicity
Tumors
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Summary: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. Everolimus was well tolerated in patients with advanced hepatocellular carcinoma, and 10 mg/day was defined as the phase 2 dosage. Preliminary antitumor activity was observed with everolimus in patients with advanced hepatocellular carcinoma, most of whom had prior systemic treatment.
ISSN:0008-543X
1097-0142
1097-0142
DOI:10.1002/cncr.26165