A phase Ib dose-escalation study of PRI-724, a CBP/beta-catenin modulator, plus gemcitabine (GEM) in patients with advanced pancreatic adenocarcinoma (APC) as second-line therapy after FOLFIRINOX or FOLFOX.

e15721Background: PRI-724 is a first-in-class small molecule antagonist that inhibits the interaction between β-catenin and its transcriptional coactivator CBP (CREB-binding protein). Preclinical studies of PRI-724 in pancreatic cancer suggest this agent can promote differentiation of chemotherapy-insensitive cancer stem cells and tumor-initiating cells, inhibit stroma formation, and decrease metastatic potential. Methods: Pts with APC, ECOG PS 0-2, measurable disease by RECIST, and progression following 1st-line rx with FOLFIRINOX or FOLFOX were enrolled at 5 centers. A 3+3 dose cohort escalation design was used with standard GEM (1000 mg/m2 on d1, 8, 15 of 28 d cycle) plus escalating doses of PRI-724 administered as a continuous infusion x7 days every other week. DLTs were defined as gr 4 or prolonged gr 3 AEs during cycle 1. Tumor assessments were performed q2 cycles. PK and pharmacodynamic sampling for evaluation of potential biomarkers of PRI-724 activity was performed at multiple time points. Result...