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A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors.
J Clin Oncol 31, 2013 (suppl; abstr 2501)
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
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.
|Dose mg/m2/day||No. of pts||No. of evaluable
for dose escalation
Abstracts by A. B. El-Khoueiry:
A phase I trial of cixutumumab (C) (IMC-A12) and sorafenib (S) for treatment of advanced hepatocellular carcinoma (HCC).
Multicenter phase I trial of sorafenib (S) in high-risk hepatocellular carcinoma (HCC) patients after liver transplantation (LT).
Potential factors influencing initial sorafenib dose selection in hepatocellular carcinoma (HCC): U.S. regional analysis of GIDEON.
Educational Book Articles by A. B. El-Khoueiry:
Presentations by A. B. El-Khoueiry:
SWOG 0941: A phase II study of sorafenib and erlotinib in patients (pts) with advanced gallbladder cancer or cholangiocarcinoma.Session: Gastrointestinal (Noncolorectal) Cancer (General Poster Session)
Second interim analysis of GIDEON (Global Investigation of Therapeutic Decisions in Unresectable HCC and of Its Treatment with Sorafenib): Sorafenib dosing and safety in U.S. patients.Session: General Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract (General Poster Session)
A phase I study of two different schedules of nab-paclitaxel (nab-P) with ascending doses of vandetanib (V) with expansion in patients (Pts) with pancreatic cancer (PC).Session: Gastrointestinal (Noncolorectal) Cancer (General Poster Session)