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.
OBJECTIVE
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.


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).


CONCLUSIONS
CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1. Metastasis hENT1 expression did not predict gemcitabine outcome.
Elizabeth Poplin, Cancer Institute of New Jersey, New Brunswick, NJ; Mitch Raponi, Elaina Mann, Cynthia Voong, and Andrew Allen, Clovis Oncology, San Francisco, CA; Hejin Hahn and Vince Picozzi, Virginia Mason Medical Center, Seattle, WA; Adam Dicker, Radiation Therapy Oncology Group, Philadelphia, PA; Jeff Isaacson, Clovis Oncology, Boulder, CO; Harpreet Wasan, Hammersmith Hospital, London; Lindsey Rolfe and Paramjit Kaur, Clovis Oncology UK, Cambridge; T.R. Jeffrey Evans, University of Glasgow, Glasgow, United Kingdom; Tone Ikdahl, Oslo Universitetssykehus, Oslo, Norway; Ihor Bondarenko, Dnipropetrovsk State Medical Academy, Dnipropetrovsk; Volodymyr Bondar, Donetsk Regional Antitumor Center, Donetsk, Ukraine; Irina Davidenko, Clinical Oncology Center 1, Krasnodar; August Garin, Blokhin Russian Cancer Research Center, Moscow, Russia; Stefan Boeck, Steffen Ormanns, and Volker Heinemann, Ludwig-Maximilians-University of Munich, Munich, Germany; Claudio Bassi, Ospedale Policlinico G.B. Rossi, Verona, Italy; and Roland Andersson, Lund University, Lund, Sweden.
Elizabeth
E
Poplin
Harpreet
H
Wasan
Lindsey
L
Rolfe
Mitch
M
Raponi
Tone
T
Ikdahl
Ihor
I
Bondarenko
Irina
I
Davidenko
Volodymyr
V
Bondar
August
A
Garin
Stefan
S
Boeck
Steffen
S
Ormanns
Volker
V
Heinemann
Claudio
C
Bassi
T R Jeffrey
TR
Evans
Roland
R
Andersson
Hejin
H
Hahn
Vince
V
Picozzi
Adam
A
Dicker
Elaina
E
Mann
Cynthia
C
Voong
Paramjit
P
Kaur
Jeff
J
Isaacson
Andrew
A
Allen
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; C538828:CP 4126; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine