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.

Gastrointestinal (Noncolorectal) Cancer
Session Type and Session Title: 
Oral Abstract Session, Gastrointestinal (Noncolorectal) Cancer
Abstract Number: 
J Clin Oncol 31, 2013 (suppl; abstr 4007)
Elizabeth Poplin, Harpreet Wasan, Lindsey Rolfe, Mitch Raponi, Tone Ikdahl, Ihor Bondarenko, Irina Davidenko, Volodymyr Bondar, August Garin, Stefan Hubert Boeck, Volker Heinemann, Claudio Bassi, T. R. Jeffry Evans, Cynthia Voong, Paramjit Kaur, Jeffrey D. Isaacson, Andrew R. Allen; The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ; Imperial College Healthcare NHS Trust, London, United Kingdom; Clovis Oncology, Inc., Boulder, CO; Clovis Oncology, Inc., San Francisco, CA; Department of Oncology, Oslo University Hospital, Oslo, Norway; Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine; Krasnodar City Oncology Center, Krasnodar, Russia; Donetsk Regional Anti-Tumor Centre, Donetsk, Ukraine; N. N. Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, Russia; Department of Hematology and Oncology, Klinikum Grosshadern and Comprehensive Cancer Center, LMU Munich, Munich, Germany; Department of Medical Oncology, Klinikum Grosshadern, University of Munich, Munich, Germany; Surgical Department, University of Verona, Verona, Italy; Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom

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Abstract Disclosures


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.