title: Targeted therapy of advanced gallbladder cancer and cholangiocarcinoma with aggressive biology: eliciting early response signals from phase 1 trials.
abstract: OBJECTIVE
  Patients with advanced cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few therapeutic options for relapsed disease. methods: Given the overall poor prognosis in this population and the availability of novel targeted therapies, we systematically analyzed the characteristics and outcomes for GC and CC patients treated on phase I trials with an emphasis on targeted agents and locoregional therapies.
  
  
  RESULTS
  Of 40 treated patients (GC=6; CC=34; median age, 60 years), 8 (20%) had stable disease (SD) > 6 months, 3 (8%) partial response (PR), on protocols with hepatic arterial drug infusion and anti-angiogenic, anti-HER-2/neu or novel MAPK/ERK kinase (MEK) inhibitors. Median progression-free survival (PFS) on phase I trials was 2.0 months (95% CI 1.7, 2.8) versus 3.0 months (95% CI 2.4, 5.0), 3.0 months (95% CI 2.3, 4.6), and 3.0 months (95% CI 2.4, 3.9) for their first-, second-, and last-line FDA-approved therapy. In univariate analysis, >3 metastatic sites, elevated alanine aminotransferase (ALT) (>56IU/L), serum creatinine (>1.6mg/dL), and CA19-9 (>35U/mL) were associated with a shorter PFS. Mutational analysis revealed mutation in the KRAS oncogene in 2 of 11 patients (18%). The SD >6 months/PR rate of 28% was seen with hepatic arterial infusion of oxaliplatin, and inhibitors of angiogenesis, HER-2/neu or MEK.
  
  
  CONCLUSIONS
  The PFS in phase I trials was similar to that of the first, second, and last-line therapy (P=0.95, 0.98, 0.76, respectively) with FDA-approved agents given in the advanced setting, emphasizing a role for targeted agents in a clinical trials setting as potentially valuable therapeutic options for these patients.
authors: Department of Investigational Cancer Therapeutics. isubbiah@mdanderson.org
authors: Ishwaria M
authors: IM
authors: Subbiah
authors: Vivek
authors: V
authors: Subbiah
authors: Apostolia M
authors: AM
authors: Tsimberidou
authors: Aung
authors: A
authors: Naing
authors: Ahmed O
authors: AO
authors: Kaseb
authors: Milind
authors: M
authors: Javle
authors: Siqing
authors: S
authors: Fu
authors: David S
authors: DS
authors: Hong
authors: Sarina
authors: S
authors: Piha-Paul
authors: Jennifer J
authors: JJ
authors: Wheler
authors: Kenneth R
authors: KR
authors: Hess
authors: Filip
authors: F
authors: Janku
authors: Gerald S
authors: GS
authors: Falchook
authors: Robert A
authors: RA
authors: Wolff
authors: Razelle
authors: R
authors: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001164:Arteriovenous Fistula / Q000139:chemically induced; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects* / Q000473:pathology; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin
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