Abstract 473P
Background
E7386, a novel oral anticancer agent, inhibits the binding of β-catenin to its transcriptional co-activator, CBP, thereby modulating Wnt/β-catenin signaling. The objectives of this phase I study were to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamic activity, and preliminary efficacy of E7386 in patients with advanced solid tumors including CRC.
Methods
E7386 was administered orally in escalating doses on a twice-daily (BID) continuous schedule in 28-day cycles. Adverse events (AEs) were graded using CTCAE v5.0. Tolerability was judged by dose-limiting toxicities (DLTs) during cycle 1. Samples for PK analyses were collected on days 1 and 8 of cycle 1 and on day 1 of cycle 2. Biomarker analyses were conducted using samples collected at defined time points. An expansion part (at the recommended dose) is planned to enroll patients with CRC and other selected tumor types.
Results
Twenty-eight patients (17 men, 11 women; median age, 59.5 years) were enrolled in E7386 dose cohorts ranging from 10 mg BID to 160 mg BID. Two DLTs (both grade 3 decreased appetite) were reported with E7386 160 mg BID—the recommended dose for expansion was E7386 100 mg BID. The most common treatment-related AEs (all grades) were nausea (78.6% of patients), vomiting (67.9%), and anemia, alanine aminotransferase increased, aspartate aminotransferase increased, and decreased appetite (10.7%, each). Nausea and vomiting were controlled with 5HT3 antagonists, except in the E7386 160 mg BID-cohort. One patient with small bowel adenocarcinoma with adenomatous polyposis coli (APC)-mutation had a partial response (PR) (tumor shrinkage: -69%; duration of response: 165 days). Preliminary PK analysis showed plasma exposure of E7386 generally increased with an increasing dose over the assessed dose range. Circulating tumor DNA analysis in plasma showed a decrease in variant allele frequency of APC after E7386 treatment in the patient with a PR.
Conclusions
E7386 was tolerated at doses up to 100 mg BID—the dose selected as the recommended dose for the expansion part. Further investigation of safety, preliminary efficacy, PK, and biomarker analyses of E7386 will be performed.
Clinical trial identification
NCT03833700.
Editorial acknowledgement
Medical writing support was provided by Oxford PharmaGenesis Inc., Newtown, PA, USA.
Legal entity responsible for the study
Eisai Co., Ltd., Woodcliff Lake, NJ, USA.
Funding
Eisai Co., Ltd.
Disclosure
A. Kawazoe: Financial Interests, Personal, Speaker’s Bureau: Ono; BMS; Taiho; Merck; Financial Interests, Institutional, Research Grant: Ono; Taiho; MSD. S. Iwasa: Financial Interests, Personal, Speaker’s Bureau: Ono; BMS; Financial Interests, Institutional, Research Grant: Eisai; Ono; BMS. K. Shitara: Financial Interests, Personal, Invited Speaker: AbbVie; Novartis; Novartis; Ono; Pfizer; Taiho; Takeda; Yakult Honsha; Financial Interests, Personal, Advisory Board: AbbVie; Amgen; Astellas; Boehringer Ingelheim; Bristol-Myers Squibb; Daiichi Sankyo; GlaxoSmithKline; Lilly; MSD; Financial Interests, Institutional, Research Grant: Astellas; Chugai; Daiichi Sankyo; Eisai; Lilly; Medi Science; MSD; Ono; Sumitomo Dainippon; Taiho. T. Koyama: Financial Interests, Personal, Speaker’s Bureau: Sysmex; Chugai; Financial Interests, Institutional, Principal Investigator: PACT. Y. Ueda: Financial Interests, Personal, Invited Speaker: Merck Biopharma Co.; Ono. S. Nagao: Financial Interests, Personal, Full or part-time Employment: Eisai Co., Ltd. T. Kimura: Financial Interests, Personal, Full or part-time Employment: Eisai Co., Ltd.. I. Suzuki: Financial Interests, Personal, Full or part-time Employment: Eisai Co., Ltd.. S. Dayal: Financial Interests, Personal, Full or part-time Employment: Eisai Ltd.. T. Tamai: Financial Interests, Personal, Full or part-time Employment: Eisai Co., Ltd.; Financial Interests, Personal, Stocks/Shares: Eisai Co., Ltd.. A. Nayudu: Financial Interests, Personal, Full or part-time Employment: Eisai Ltd.. N. Yamamoto: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Chugai; Cimic; Eisai; Otsuka; Takeda; Financial Interests, Personal, Invited Speaker: AstraZeneca; Chugai; Daiichi Sankyo; Eli Lilly; Ono; Pfizer; Sysmex; Financial Interests, Institutional, Principal Investigator: AbbVie; Astellas; Bayer; BMS; Boehringer Ingelheim; Chiome Bioscience; Chugai; Daiichi Sankyo; Eisai; Eli Lilly; GSK; Janssen Pharma; Kyowa-Hakko Kirin; Merck; MSD; Novartis; Ono; Otsuka; Pfizer; Sumitomo Dainippon; Taiho; Takeda.