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Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma.

Abstract：

BACKGROUND:Deregulation of mammalian target of rapamycin (mTOR) signalling is common in human hepatocellular carcinoma (HCC). AIM:To determine the maximum tolerated dose (MTD) of the oral mTOR inhibitor everolimus in advanced HCC patients. METHODS:Patients with locally advanced or metastatic HCC (Child-Pugh class A or B) were enrolled in an open-label phase 1 study and randomly assigned to daily (2.5-10 mg) or weekly (20-70 mg) everolimus in a standard 3 + 3 dose-escalation design. MTD was based on the rate of dose-limiting toxicities (DLTs). Secondary endpoints included safety, pharmacokinetics and tumour response. In a post hoc analysis, serum hepatitis B virus (HBV) DNA levels were quantified. RESULTS:Thirty-nine patients were enrolled. DLTs occurred in five of 21 patients in the daily and two of 19 patients in the weekly cohort. Daily and weekly MTDs were 7.5 mg and 70 mg respectively. Grade 3/4 adverse events with a ≥10% incidence were thrombocytopenia, hypophosphataemia and alanine transaminase (ALT) elevation. In four hepatitis B surface antigen (HBsAg)-seropositive patients, grade 3/4 ALT elevations were accompanied by significant (>1 log) increases in serum HBV levels. The incidence of hepatitis flare (defined as ALT increase >100 IU/mL from baseline) in HBsAg-seropositive patients with and without detectable serum HBV DNA before treatment was 46.2% and 7.1% respectively (P < 0.01, Fisher exact test). Disease control rates in the daily and weekly cohorts were 71.4% and 44.4% respectively. CONCLUSIONS:The recommended everolimus dosing schedule for future hepatocellular carcinoma studies is 7.5 mg daily. Prophylactic anti-viral therapy should be mandatory for HBsAg-seropositive patients (ClinicalTrials.gov NCT00390195).

journal_name

Aliment Pharmacol Ther

journal_title

Alimentary pharmacology & therapeutics

authors

Shiah HS,Chen CY,Dai CY,Hsiao CF,Lin YJ,Su WC,Chang JY,Whang-Peng J,Lin PW,Huang JD,Chen LT

doi

10.1111/apt.12132

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

62-73

issue

eissn

0269-2813

issn

1365-2036

journal_volume

pub_type

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Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma.