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).
  
  
  OBJECTIVE
  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).
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors.forename: H-S
authors.initials: HS
authors.lastname: Shiah
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chen
authors.forename: C-Y
authors.initials: CY
authors.lastname: Dai
authors.forename: C-F
authors.initials: CF
authors.lastname: Hsiao
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Lin
authors.forename: W-C
authors.initials: WC
authors.lastname: Su
authors.forename: J-Y
authors.initials: JY
authors.lastname: Chang
authors.forename: J
authors.initials: J
authors.lastname: Whang-Peng
authors.forename: P-W
authors.initials: PW
authors.lastname: Lin
authors.forename: J-D
authors.initials: JD
authors.lastname: Huang
authors.forename: L-T
authors.initials: LT
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000821:virology; D004279:DNA, Viral / Q000097:blood; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005260:Female; D006509:Hepatitis B / Q000188:drug therapy / Q000821:virology; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D008103:Liver Cirrhosis / Q000821:virology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000821:virology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D055815:Young Adult
chemical_list: D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus