Abstract CT523: An open-label, multicenter, phase 1b/2 Study of E7386 (Wnt/β-catenin pathway inhibitor) + pembrolizumab in patients with pretreated advanced solid tumors
Authors: Yoshino Takayuki , Ikeda Masafumi , Finn Richard S. , Evans Thomas R. Jeffry , Weng Lidong , Saito Kenichi , Mody Kalgi , Tamai Toshiyuki , Paoletti Costanza , Iwasa Satoru 
Published: June 2022

Abstract
Background: Development of primary or secondary resistance to anticancer treatments has been a critical challenge since implementation of immune checkpoint inhibitor (ICI) treatments across multiple cancer subtypes. Preclinical studies have indicated that a mechanism of resistance to ICIs, including PD-1/PD-L1 inhibitors, is activation of the Wnt/β-catenin signaling pathway. E7386 is a novel compound that has been shown to modulate this pathway in vivo, by inhibiting the interactions between CREB-binding protein and β-catenin. Preclinical models have also shown that E7386 may be able to eliminate drug-resistant cancer stem cells and resensitize resistant tumors to conventional treatment or therapy with an ICI, such as the PD-1 inhibitor pembrolizumab. There are no expected overlapping clearance, metabolic pathways, nor any known overlapping toxicities between E7386 and pembrolizumab monotherapies. Therefore, this combination may provide a novel anticancer treatment in patients with ICI-resistant tumors. This study aims to determine tolerability and efficacy of E7386 in combination with pembrolizumab in previously treated patients with selected solid tumors.
Methods: This open-label, multicenter, phase 1b/2 study (NCT05091346) will assess E7386 + pembrolizumab in patients with certain pretreated advanced solid tumors. Patients with melanoma, colorectal cancer (CRC), or hepatocellular carcinoma (HCC) are eligible. Patients should be ≥ 18 years of age with measurable lesions as assessed by an investigator by RECIST v1.1. In the phase 1b dose escalation, patients (n=6 per dose level; up to n=18 in total) are treated with E7386 orally + pembrolizumab 200 mg IV Q3W (fixed dose). If the initial starting dose of E7386 100 mg BID is considered tolerable (≤1 patient with a dose-limiting toxicity), E7386 may be escalated to 120 mg BID; if not tolerable, E7386 may be reduced to 80 mg BID. Primary objectives for phase 1b are to assess safety and tolerability, as well as to determine the recommended phase 2 dose (RP2D), of E7386 + pembrolizumab. Upon determination of the RP2D, additional patients will be enrolled (approximately 30 patients in each tumor cohort) at this dose to assess safety, tolerability, and efficacy. The primary objective of phase 2 is to assess objective response rate according to RECIST v1.1. Secondary objectives for phases 1b and 2 include efficacy assessments (duration of response, disease control rate, clinical benefit rate) in each tumor cohort, and pharmacokinetics of E7386 when administered in combination with pembrolizumab. Exploratory objectives include assessment of biomarkers, PFS, and OS. Tumors will be assessed by an investigator based on RECIST v1.1, every 6 weeks, and all adverse events (as graded by CTCAE v5.0) will be monitored and recorded. As of January 6, 2022, 2 patients have been enrolled in phase 1b.
Citation Format: Takayuki Yoshino, Masafumi Ikeda, Richard S. Finn, Thomas R. Jeffry Evans, Lidong Weng, Kenichi Saito, Kalgi Mody, Toshiyuki Tamai, Costanza Paoletti, Satoru Iwasa. An open-label, multicenter, phase 1b/2 Study of E7386 (Wnt/β-catenin pathway inhibitor) + pembrolizumab in patients with pretreated advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT523.