title: Exploring response signals and targets in aggressive unresectable hepatocellular carcinoma: an analysis of targeted therapy phase 1 trials.
abstract: OBJECTIVE
  Patients with advanced hepatocellular carcinoma (HCC) have limited effective therapeutic options. Given the rapid advanced in drug development and emergence of novel agents, we analyzed the characteristics and outcomes of HCC patients treated on early phase trials with an emphasis on targeted therapies.
  
  
  METHODS
  We reviewed the records of consecutive HCC patients evaluated in the Phase I Clinical Trials Program at MD Anderson from March 2004.
  
  
  RESULTS
  Thirty-nine patients were not treated due to poor performance status (n = 22, 56%) and decision to pursue alternate therapies (n = 10, 27%). Of 61 treated patients (median age, 60 years; median prior therapies, 3), eight patients (13%) attained stable disease lasting ≥6 months; four (7%) had a partial response, mainly with anti-angiogenic or multikinase inhibitors. Median Phase I progression-free survival (PFS) was 2.6 months versus 4.4 months (p 0.019) and 4.1 months (p 0.27) for their first-, and second-line FDA-approved therapy. Molecular analysis showed frequent PTEN loss (10/19 patients, 53%) and P53 mutation (4/4 patients tested). On multivariate analysis, independent factors predicting shorter survival were white ethnicity/race (p 0.031), cirrhosis (p 0.016), and serum sodium (p 0.0013).
  
  
  CONCLUSIONS
  In our heavily-pretreated HCC patients, the phase I PFS was comparable to that of 2nd-line therapy, highlighting a potential role for clinical trials after progression on first-line therapy. The response rate (SD>6 months/PR) of 20% was observed with early signals of activity in regimens combining inhibitors of angiogenesis, multiple kinases and mTOR with preliminary molecular analysis revealing prevalence of PTEN loss.
authors.affiliation: Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ishwaria M
authors.initials: IM
authors.lastname: Subbiah
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ahmed O
authors.initials: AO
authors.lastname: Kaseb
authors.affiliation: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Owais
authors.initials: O
authors.lastname: Akmal
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002648:Child; D017321:Clinical Trials, Phase I as Topic; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D015999:Multivariate Analysis; D009154:Mutation; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D011379:Prognosis; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor
keywords: clinical trials; management; novel therapeutics; systemic therapy; targeted agents