title: Phase 1/2 study of everolimus in advanced hepatocellular carcinoma.
abstract: 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%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA. azhu@partners.org
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Abrams
authors.forename: Rebecca
authors.initials: R
authors.lastname: Miksad
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Blaszkowsky
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.forename: Deborah
authors.initials: D
authors.lastname: Schrag
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Jors
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Borger
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D000068338:Everolimus; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D020123:Sirolimus