A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors.

2501 Background: PRI-724 is a first-in-class modulator of Wnt signaling that inhibits the CREB binding protein and β-catenin interaction. In pre-clinical models, PRI-724 (active metabolite C82) increases p300/β-catenin binding and promotes stem cell differentiation thereby eliminating tumor initiating cells and increasing sensitivity to cytotoxic or targeted drugs. Methods: PRI-724 was given as a continuous infusion X 7 days q 2 wks. There was an initial accelerated dose escalation with one pt per dose level and a plan to revert to a 3+3 escalation after 640 mg/m2 unless a dose limiting toxicity (DLT) or 2 moderate toxicities occurred earlier. Eligibility criteria: adequate bone marrow function, AST/ALT <5XULN, total bilirubin<1.5 mg/dL. Survivin/BIRC5 expression was measured by immunomagnetic RT-PCR on circulating tumor cells (CTC). Results: 18 pts treated; median age: 53 years (38-71); 12 (67%) males; median number of prior therapies: 3 (1-5). There was one DLT of grade 3 hyperbilirubinemia. Grade 3 AEs were limited to hyperbilirubinemia in 2 pts, one of which did not meet DLT criteria. Grade 2 AEs were: diarrhea (2pts; 11%), bilirubin elevation (2 pts; 11%), hypophosphatemia (2pts; 11%), nausea (1pt; 6%), fatigue (1pt; 6%), anorexia (1pt; 6%), thrombocytopenia (1 pt; 6%) and alkaline phosphatase elevation (1pt; 6%). There was no MTD at the doses tested. The recommended phase 2 dose was 905 mg/m2 based on the incidence of AEs at 1280 mg/m2 and the plateau in pK parameters. The median Cmax and AUC 0-t for C-82 at 905 mg/m2/day were 887 ng/mL and 262787 h*ng/mL. Median elimination T ½ was 7.35 h. 3 pts with colon cancer had stable disease for 8, 10 and 12 weeks. Survivin expression in CTCs decreased in 72% of pts on C1D8 and 61% on C2D8. There was an inverse relationship between C82 plasma concentration and survivin expression on C1D8 (Spearman correlation coefficient r = -0.72; p=0.001). Conclusions: PRI-724 had an acceptable toxicity profile. Downregulation of survivin expression in CTCs may serve as a pharmacodynamic marker of drug-on-target effect. Studies combining PRI-724 with chemotherapy are ongoing. Clinical trial information: NCT01302405. [Table: see text]