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

e15270 Background: PRI-724 is a first-in-class cAMP-response element-binding protein (CBP)/β-catenin modulator that induces stem cell differentiation. In pre-clinical models, PRI-724 increases p300/β-catenin binding and promotes differentiation, eliminating tumor initiating cells and increasing sensitivity to cytotoxic drugs. Methods: Patients with APC who progressed following first-line therapy with FFX or FX were enrolled. A 3+3 dose escalation design was applied, with GEM (1000 mg/m2 of d1,8,15, 28 d cycle), and PRI-724 administered as a continuous infusion X 7 d every other week. The starting dose was decided at 320 mg/m2/d based on a prior Phase 1a PRI-724 monotherapy study. DLT is defined based on study treatment related AEs. PK and PD sampling for potential biomarkers of PRI-724 activity was performed. Results: The dose-escalation phase was completed with 10 patients in 3 cohorts (320, 640 and 905 mg/m2). Median age was 61 yrs(range 51-70). Nine of 10 pts (90 %) were evaluable for tolerability; 1 pt discontinued early for PD without DLT. Evaluable patients completed a median of 3 cycles (range 1 to 7). The maximum dose was determined to be 905 mg/m2/day, consistent with the Phase 1a study, with no observed DLTs and no MTD established. Of 153 reported AEs with 9 evaluable pts, five gr 3/4 AEs (1 abd pain, 3 neutropenia, and 1alk phos elev) were judged possibly related to study treatment. No related fatal events observed. Median PFS was 2.7 mo. [range 0.97 to 7.2]. Four had a decrease in CA19-9 at the end of Cycle2, with a median decrease of 43% [range 21-76%].Best response by RECIST: 6 SD (including 2 minor responses), 3 PD. Assessments of candidate biomarkers (MMP7 and Claudin 18) are ongoing. Conclusions: In this phase Ib study,PRI-724 administered in combination with GEM demonstrates acceptable toxicity in patients with APC after progression on FFX or FX, with some evidence of clinical activity. Biomarker studies in progress. This dose escalation study determined 905mg/m2/d was generally well tolerated with no MTD reached. A dose expansion cohort of additional 9 patients is enrolling. Clinical trial information: NCT01764477.