Final results of 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.

Abstract

e15721 Background: 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. Results: A total of 20 pts were enrolled across 3 dose cohorts (PRI-724 at 320, 640 and 905 mg/m2/d). Median age = 60 years (range 51-73). Evaluable pts completed a median of 2 cycles (range, 1 to 7). There were 7 gr 3/4 AEs attributed to study rx (1 abdom pain, 3 neutropenia, 1 anemia, 1 fatigue, and 1 alk phos elevation), none meeting DLT definition. MTD was not reached. Best response by RECIST was stable disease in 8 pts (40%), inc 2 minor responses. 5 of 8 pts (62.5%) with elevated baseline CA19-9 levels showed a marker decline of > 30%. Median PFS = 2.0 months [range, 0.7 to 7.7]. While most pts demonstrated a decline in serum S100P levels at the end of cycle 1 (median decline 49.95%), neither this nor any other serum PD marker evaluated (S100A4, MMP-7, survivin) showed clear correlation with clinical outcomes. Conclusions: To our knowledge, this study is the first to evaluate a unique strategy of modulating Wnt signaling in APC. WhilePRI-724 combined with GEM is safe and demonstrates modest clinical activity, further work is required to identify useful predictive and PD markers for this novel therapeutic approach. Clinical trial information: NCT01764477.