A multicenter, randomized, controlled study of CO-1.01 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and low tumor expression of human equilibrative nucleoside transporter-1 (hENT1) determined by metastasis biopsy.

Purpose Gemcitabine requires transporter proteins to cross cell membranes. Low expression of human equilibrative nucleoside transporter-1 (hENT1) may result in gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). CO-101, a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1. We conducted a randomized controlled trial to determine whether CO-101 improved survival versus gemcitabine in patients with metastatic PDAC (mPDAC) with low hENT1. The study also tested the hypothesis that gemcitabine is more active in patients with mPDAC tumors with high versus low hENT1 expression. Patients and Methods Patients were randomly assigned to CO-101 or gemcitabine, after providing a metastasis sample for blinded hENT1 assessment. An immunohistochemistry test measuring tumor hENT1 was developed. To dichotomize the population, an hENT1 cutoff value was defined using primary PDAC samples from an adjuvant trial, and a high/low cutoff was applied. The primary end point was overall survival (OS) in the low hENT1 subgroup. Results Of 367 patients enrolled, hENT1 status was measured in 358 patients (97.5%). Two hundred thirty-two (64.8%) of 358 patients were hENT1 low. There was no difference in OS between treatments in the low hENT1 subgroup or overall, with hazard ratios (HRs) of 0.994 (95% CI, 0.746 to 1.326) and 1.072 (95% CI, 0.856 to 1.344), respectively. The toxicity profiles in both arms were similar. Within the gemcitabine arm, there was no difference in survival between the high and low hENT1 subgroups (HR, 1.147; 95% CI, 0.809 to 1.626). Conclusion CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1. Metastasis hENT1 expression did not predict gemcitabine outcome.

Download Full-text

Human Equilibrative Nucleoside Transporter 1 Expression in Endoscopic Ultrasonography-Guided Fine-Needle Aspiration Biopsy Samples Is a Strong Predictor of Clinical Response and Survival in the Patients With Pancreatic Ductal Adenocarcinoma Undergoing Gemcitabine-Based Chemoradiotherapy

Pancreas ◽

10.1097/mpa.0000000000000597 ◽

2016 ◽

Vol 45 (5) ◽

pp. 761-771 ◽

Cited By ~ 18

Author(s):

Reiko Yamada ◽

Shugo Mizuno ◽

Katsunori Uchida ◽

Misao Yoneda ◽

Kazuki Kanayama ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Clinical Response ◽

Fine Needle Aspiration ◽

Fine Needle Aspiration Biopsy ◽

Strong Predictor ◽

Needle Aspiration ◽

Ductal Adenocarcinoma ◽

Nucleoside Transporter ◽

Fine Needle ◽

Equilibrative Nucleoside Transporter

Download Full-text

Modeling interactions between Human Equilibrative Nucleoside Transporter-1 and other factors involved in the response to gemcitabine treatment to predict clinical outcomes in pancreatic ductal adenocarcinoma patients

Journal of Translational Medicine ◽

10.1186/s12967-014-0248-4 ◽

2014 ◽

Vol 12 (1) ◽

Cited By ~ 9

Author(s):

Francesca Tavano ◽

Andrea Fontana ◽

Fabio Pellegrini ◽

Francesca Paola Burbaci ◽

Francesca Rappa ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Clinical Outcomes ◽

Ductal Adenocarcinoma ◽

Nucleoside Transporter ◽

Equilibrative Nucleoside Transporter ◽

Modeling Interactions ◽

Gemcitabine Treatment

Download Full-text

A predictive analysis of the SP120 and 10D7G2 antibodies for human equilibrative nucleoside transporter 1 (hENT1) in pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine

The Journal of Pathology Clinical Research ◽

10.1002/cjp2.75 ◽

2017 ◽

Vol 3 (3) ◽

pp. 179-190 ◽

Cited By ~ 7

Author(s):

Steve E Kalloger ◽

Maziar Riazy ◽

Basile Tessier-Cloutier ◽

Joanna M Karasinska ◽

Dongxia Gao ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Predictive Analysis ◽

Nucleoside Transporter ◽

Equilibrative Nucleoside Transporter

Download Full-text

Randomized multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and a prospective evaluation of the of the association between tumor hENT1 expression and clinical outcome with gemcitabine treatment.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.4007 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 4007-4007

Author(s):

Elizabeth Poplin ◽

Harpreet Wasan ◽

Lindsey Rolfe ◽

Mitch Raponi ◽

Tone Ikdahl ◽

...

Keyword(s):

Overall Survival ◽

Controlled Trial ◽

Ductal Adenocarcinoma ◽

Nucleoside Transporter ◽

Adjuvant Trial ◽

Equilibrative Nucleoside Transporter ◽

Randomized Controlled ◽

Hazard Ratios ◽

Gemcitabine Treatment ◽

Clinical Trial Information

4007 Background: Gemcitabine requires membrane transporter proteins to cross the cell membrane. Low expression of the human equilibrative nucleoside transporter-1 (hENT1) may play a role in gemcitabine resistance in PDAC. CO-101 (also known as CP-4126), a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1 and to circumvent transporter-mediated resistance. We conducted a randomized, controlled trial (LEAP) in patients with mPDAC to determine whether CO-101 improved survival vs gemcitabine in patients with low hENT1 tumors. The study also prospectively tested the hypothesis that gemcitabine is more active in patients with hENT1 high than hENT1 low tumors in metastatic disease. Methods: Patients were randomized to CO-101 or gemcitabine. An immunohistochemistry test measuring tumor hENT1 expression was developed in parallel with the recruitment phase of LEAP. To dichotomize the population, a hENT1 cut-off was defined using primary PDAC tumor samples from an adjuvant trial. LEAP participants provided a metastasis sample during screening for blinded hENT1 assessment, and the cut-off was applied to these samples. The primary endpoint of the study was overall survival in the low hENT1 subgroup. Results: 367 patients were enrolled, with metastasis hENT1 status available for 358/367 (97.5%). 232/357 (65%) were hENT1 low. There was no difference in overall survival between CO-101 and gemcitabine in the hENT1 low subgroup, or overall, with hazard ratios of 0.994 [95% CI 0.746, 1.326] and 1.072 [95% CI 0.856, 1.344] respectively. Within the gemcitabine arm, there was no difference in survival between the hENT1 high and low subgroups (HR 1.147 95% CI 0.809, 1.626). The observed side effect profile was typical of gemcitabine and was similar in both treatment arms, in the hENT1 low subgroups and overall. Conclusions: CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1 expression. Metastasis hENT1 expression did not predict gemcitabine treatment outcome in patients with mPDAC. Clinical trial information: NCT01124786.

Download Full-text