Randomized, multicenter, phase ii study of co-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: Including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity

Elizabeth Poplin, Harpreet Wasan, Lindsey Rolfe, Mitch Raponi, Tone Ikdahl, Ihor Bondarenko, Irina Davidenko, Volodymyr Bondar, August Garin, Stefan Boeck, Steffen Ormanns, Volker Heinemann, Claudio Bassi, T. R.Jeffrey Evans, Roland Andersson, Hejin Hahn, Vince Picozzi, Adam Dicker, Elaina Mann, Cynthia VoongParamjit Kaur, Jeff Isaacson, Andrew Allen

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4453-4461
Number of pages9
JournalJournal of Clinical Oncology
Volume31
Issue number35
DOIs
StatePublished - Dec 10 2013

Fingerprint

gemcitabine
Adenocarcinoma
Survival
CP 4126
human SLC29A1 protein

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Randomized, multicenter, phase ii study of co-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma : Including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. / Poplin, Elizabeth; Wasan, Harpreet; Rolfe, Lindsey; Raponi, Mitch; Ikdahl, Tone; Bondarenko, Ihor; Davidenko, Irina; Bondar, Volodymyr; Garin, August; Boeck, Stefan; Ormanns, Steffen; Heinemann, Volker; Bassi, Claudio; Evans, T. R.Jeffrey; Andersson, Roland; Hahn, Hejin; Picozzi, Vince; Dicker, Adam; Mann, Elaina; Voong, Cynthia; Kaur, Paramjit; Isaacson, Jeff; Allen, Andrew.

In: Journal of Clinical Oncology, Vol. 31, No. 35, 10.12.2013, p. 4453-4461.

Research output: Contribution to journalArticle

Poplin, E, Wasan, H, Rolfe, L, Raponi, M, Ikdahl, T, Bondarenko, I, Davidenko, I, Bondar, V, Garin, A, Boeck, S, Ormanns, S, Heinemann, V, Bassi, C, Evans, TRJ, Andersson, R, Hahn, H, Picozzi, V, Dicker, A, Mann, E, Voong, C, Kaur, P, Isaacson, J & Allen, A 2013, 'Randomized, multicenter, phase ii study of co-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: Including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity', Journal of Clinical Oncology, vol. 31, no. 35, pp. 4453-4461. https://doi.org/10.1200/JCO.2013.51.0826
Poplin, Elizabeth ; Wasan, Harpreet ; Rolfe, Lindsey ; Raponi, Mitch ; Ikdahl, Tone ; Bondarenko, Ihor ; Davidenko, Irina ; Bondar, Volodymyr ; Garin, August ; Boeck, Stefan ; Ormanns, Steffen ; Heinemann, Volker ; Bassi, Claudio ; Evans, T. R.Jeffrey ; Andersson, Roland ; Hahn, Hejin ; Picozzi, Vince ; Dicker, Adam ; Mann, Elaina ; Voong, Cynthia ; Kaur, Paramjit ; Isaacson, Jeff ; Allen, Andrew. / Randomized, multicenter, phase ii study of co-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma : Including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. In: Journal of Clinical Oncology. 2013 ; Vol. 31, No. 35. pp. 4453-4461.
@article{7a747468b2274afeace0c7212dc6b27e,
title = "Randomized, multicenter, phase ii study of co-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: Including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity",
abstract = "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.",
author = "Elizabeth Poplin and Harpreet Wasan and Lindsey Rolfe and Mitch Raponi and Tone Ikdahl and Ihor Bondarenko and Irina Davidenko and Volodymyr Bondar and August Garin and Stefan Boeck and Steffen Ormanns and Volker Heinemann and Claudio Bassi and Evans, {T. R.Jeffrey} and Roland Andersson and Hejin Hahn and Vince Picozzi and Adam Dicker and Elaina Mann and Cynthia Voong and Paramjit Kaur and Jeff Isaacson and Andrew Allen",
year = "2013",
month = "12",
day = "10",
doi = "10.1200/JCO.2013.51.0826",
language = "English (US)",
volume = "31",
pages = "4453--4461",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "35",

}

TY - JOUR

T1 - Randomized, multicenter, phase ii study of co-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma

T2 - Including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity

AU - Poplin, Elizabeth

AU - Wasan, Harpreet

AU - Rolfe, Lindsey

AU - Raponi, Mitch

AU - Ikdahl, Tone

AU - Bondarenko, Ihor

AU - Davidenko, Irina

AU - Bondar, Volodymyr

AU - Garin, August

AU - Boeck, Stefan

AU - Ormanns, Steffen

AU - Heinemann, Volker

AU - Bassi, Claudio

AU - Evans, T. R.Jeffrey

AU - Andersson, Roland

AU - Hahn, Hejin

AU - Picozzi, Vince

AU - Dicker, Adam

AU - Mann, Elaina

AU - Voong, Cynthia

AU - Kaur, Paramjit

AU - Isaacson, Jeff

AU - Allen, Andrew

PY - 2013/12/10

Y1 - 2013/12/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84894297251&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84894297251&partnerID=8YFLogxK

U2 - 10.1200/JCO.2013.51.0826

DO - 10.1200/JCO.2013.51.0826

M3 - Article

C2 - 24220555

AN - SCOPUS:84894297251

VL - 31

SP - 4453

EP - 4461

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 35

ER -