Targeted Therapy of Advanced Gallbladder Cancer and Cholangiocarcinoma with Aggressive Biology: Eliciting Early Response Signals from Phase 1 trials

// Ishwaria M. Subbiah 1 , Vivek Subbiah 1 , Apostolia M. Tsimberidou 1 , Aung Naing 1 , Ahmed O. Kaseb 2 , Milind Javle 2 , Siqing Fu 1 , David S. Hong 1 , Sarina Piha-Paul 1 , Jennifer J. Wheler 1 , Kenneth R. Hess 3 , Filip Janku 1 , Gerald S. Falchook 1 , Robert A Wolff 1,2 , and Razelle Kurzrock 1,4 1 Department of Investigational Cancer Therapeutics, 2 Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, 3 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 4 Moores Cancer Center, University of California, San Diego, California. Correspondence: Ishwaria M. Subbiah, email: // Keywords : gallbladder carcinoma, cholangiocarcinoma, phase I, targeted therapy, locoregional therapy Received : January 20, 2013, Accepted : January 26, 2013, Published : January 27, 2013 Abstract Purpose: 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.