Clinical Research Papers:

Exploring response signals and targets in aggressive unresectable hepatocellular carcinoma: an analysis of targeted therapy phase 1 trials

Ishwaria M. Subbiah _, Gerald S. Falchook, Ahmed O. Kaseb, Kenneth R. Hess, Apostolia M. Tsimberidou, Siqing Fu, Vivek Subbiah, David S. Hong, Aung Naing, Sarina A. Piha-Paul, Owais Akmal, Filip Janku and Razelle Kurzrock

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Oncotarget. 2015; 6:28453-28462. https://doi.org/10.18632/oncotarget.4601

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Ishwaria M. Subbiah1, Gerald S. Falchook2, Ahmed O. Kaseb3, Kenneth R. Hess4, Apostolia M. Tsimberidou2, Siqing Fu2, Vivek Subbiah2, David S. Hong2, Aung Naing2, Sarina A. Piha-Paul2, Owais Akmal3, Filip Janku2 and Razelle Kurzrock5

1 Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA

2 Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA

3 Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

4 Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA

5 Moores Cancer Center, University of California San Diego, San Diego, CA, USA

Correspondence to:

Ishwaria M. Subbiah, email:

Keywords: targeted agents, novel therapeutics, management, systemic therapy, clinical trials

Received: June 01, 2015 Accepted: June 11, 2015 Published: June 23, 2015


PURPOSE: 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.

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