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

H. S. Shiah, Chiung Yu Chen, Chia Yen Dai, Chin Fu Hsiao, Yih Jyh Lin, Wu Chou Su, Jang Yang Chang, J. Whang-Peng, P. W. Lin, Jin Ding Huang, Li Tzong Chen

Research output: Contribution to journalArticle

42 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)62-73
Number of pages12
JournalAlimentary Pharmacology and Therapeutics
Volume37
Issue number1
DOIs
Publication statusPublished - Jan 2013

Fingerprint

Hepatocellular Carcinoma
Appointments and Schedules
Randomized Controlled Trials
Hepatitis B Surface Antigens
Alanine Transaminase
Hepatitis B virus
Maximum Tolerated Dose
Sirolimus
Serum
Everolimus
DNA
Incidence
Thrombocytopenia
Hepatitis
Pharmacokinetics
Safety
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)
  • Pharmacology (medical)

Cite this

Randomised clinical trial : Comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma. / Shiah, H. S.; Chen, Chiung Yu; Dai, Chia Yen; Hsiao, Chin Fu; Lin, Yih Jyh; Su, Wu Chou; Chang, Jang Yang; Whang-Peng, J.; Lin, P. W.; Huang, Jin Ding; Chen, Li Tzong.

In: Alimentary Pharmacology and Therapeutics, Vol. 37, No. 1, 01.2013, p. 62-73.

Research output: Contribution to journalArticle

Shiah, H. S. ; Chen, Chiung Yu ; Dai, Chia Yen ; Hsiao, Chin Fu ; Lin, Yih Jyh ; Su, Wu Chou ; Chang, Jang Yang ; Whang-Peng, J. ; Lin, P. W. ; Huang, Jin Ding ; Chen, Li Tzong. / Randomised clinical trial : Comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma. In: Alimentary Pharmacology and Therapeutics. 2013 ; Vol. 37, No. 1. pp. 62-73.
@article{6954e764b52040099adbc91a15d43ae7,
title = "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).",
author = "Shiah, {H. S.} and Chen, {Chiung Yu} and Dai, {Chia Yen} and Hsiao, {Chin Fu} and Lin, {Yih Jyh} and Su, {Wu Chou} and Chang, {Jang Yang} and J. Whang-Peng and Lin, {P. W.} and Huang, {Jin Ding} and Chen, {Li Tzong}",
year = "2013",
month = "1",
doi = "10.1111/apt.12132",
language = "English",
volume = "37",
pages = "62--73",
journal = "Alimentary Pharmacology and Therapeutics",
issn = "0269-2813",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Randomised clinical trial

T2 - Comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma

AU - Shiah, H. S.

AU - Chen, Chiung Yu

AU - Dai, Chia Yen

AU - Hsiao, Chin Fu

AU - Lin, Yih Jyh

AU - Su, Wu Chou

AU - Chang, Jang Yang

AU - Whang-Peng, J.

AU - Lin, P. W.

AU - Huang, Jin Ding

AU - Chen, Li Tzong

PY - 2013/1

Y1 - 2013/1

N2 - 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).

AB - 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).

UR - http://www.scopus.com/inward/record.url?scp=84870609803&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870609803&partnerID=8YFLogxK

U2 - 10.1111/apt.12132

DO - 10.1111/apt.12132

M3 - Article

C2 - 23134470

AN - SCOPUS:84870609803

VL - 37

SP - 62

EP - 73

JO - Alimentary Pharmacology and Therapeutics

JF - Alimentary Pharmacology and Therapeutics

SN - 0269-2813

IS - 1

ER -