Research Papers:

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

Ishwaria Subbiah, Vivek Subbiah _, Apostolia M Tsimberidou, Aung Naing, Ahmed Kaseb, Javle Milind, Siqing Fu, David S Hong, Sarina Piha-Paul, Jenifer Wheler, Kenneth Hess, Filip Janku, Gerald Falchook, Robert A Wolff and Razelle Kurzrock

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Oncotarget. 2013; 4:153-162. https://doi.org/10.18632/oncotarget.832

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Ishwaria M. Subbiah1, Vivek Subbiah1, Apostolia M. Tsimberidou1, Aung Naing1, Ahmed O. Kaseb2, Milind Javle2, Siqing Fu1, David S. Hong1, Sarina Piha-Paul1, Jennifer J. Wheler1, Kenneth R. Hess3, Filip Janku1, Gerald S. Falchook1, Robert A Wolff1,2, and Razelle Kurzrock1,4

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.


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


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.

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