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.

Abstract

TPS144 Background: Gemcitabine (Gem) is standard of care therapy for mPDAC, however many patients do not benefit. Gem requires a transporter protein, hENT1, to enter cells. Reduced tumor hENT1 expression predicts poor outcome after Gem therapy (Farrell). CO-1.01 is a Gem-elaidic acid conjugate which is able to enter cells independently of transporters. This clinical study tests the hypothesis that CO-1.01 is more effective than Gem at prolonging survival in patients with mPDAC and low tumor expression of hENT1 (NCT01124786). Methods: Patients with mPDAC, with no prior palliative chemotherapy are eligible. A screening biopsy of metastatic tumor tissue from every patient, assessed by a central pathology laboratory as adequate for future immunohistochemical measurement of hENT1, is required before randomization and then banked. 54/250 patients have been randomized 1:1 to Gem or CO-1.01. The primary endpoint is overall survival in the prospectively defined hENT1 low subgroup (see below). A fully validated hENT1 IHC assay (class I device) has been developed and a scoring system (modified H score) is being developed in parallel to the randomized study. The H-score cut-off that predicts poor clinical outcome with Gem is being derived from independent, large randomized controlled studies of Gem vs comparator for adjuvant treatment of PDAC. This cut-off will be applied, blinded and prospectively, to the screening metastasis biopsies to identify the patients in the primary endpoint population (hENT1 low subgroup). Additional exploratory analyses include pharmacogenetic analysis of Gem metabolizing enzymes, and pharmacogenomic analyses of tumor tissues. To our knowledge, this is the first randomized study in mPDAC that mandates metastatic tumor tissue collection to allow prospective testing of an efficacy hypothesis in a molecularly-defined subset of patients. The design of the study will enable robust investigation of the relationship between hENT1 tumor expression and clinical outcomes. Farrell J. Gastroenterology 2009:136;187