401P - A phase Ib study of E7386, a CREB-binding protein (CBP)/β-catenin interaction inhibitor, in combination with lenvatinib in patients (pts) with advanced solid tumors

Background

E7386, a novel oral anticancer agent, inhibits β-catenin binding to its transcriptional co-activator, CBP, thus modulating Wnt/β-catenin signaling. The objectives of the dose-escalation part in this phase 1b study were to assess safety, tolerability, pharmacokinetics (PK), biomarkers, and preliminary efficacy of E7386 combined with lenvatinib in pts with advanced hepatocellular carcinoma or other solid tumors (ST). We present the results from the ST subpart.

Methods

In cycle 0, E7386 was administered orally in escalating doses once daily (QD) or twice daily (BID) for 5 or 6 days. From cycle 1 day 1, E7386 QD or BID, combined with lenvatinib 20 mg QD, were administered on a continuous schedule in 28-day cycles. Tolerability was evaluated with a 3+3+3 design. Adverse events (AEs) were graded using CTCAE v5.0. No prophylactic treatment was allowed during the dose-limiting toxicity (DLT) evaluation period. Tumor response was assessed by investigators using RECIST v1.1. PK and biomarker analyses were conducted using samples collected at defined time points.

Results

As of data cutoff (24 May 2022), 36 pts had been treated in the ST subpart with E7386 dose ranges from 10 to 160 mg QD and from 100 to 120 mg BID. Generalized edema (grade 3) and liver disorder (grade 4) were DLTs noted in 1 of 6 pts each in the 15 mg QD and 120 mg BID cohorts, respectively. The most common treatment-emergent AEs (TEAEs; ≥50% of pts) were nausea (72.2%), vomiting (58.3%), hypertension (58.3%), diarrhea (58.3%), and proteinuria (52.8%). The most common grade ≥3 TEAEs (≥10% of pts) were proteinuria (19.4%) and gamma-glutamyltransferase increased (11.1%). Serious TEAEs (≥5% of pts) were biliary tract infection (5.6%) and hepatic infection (5.6%). Among 34 pts who had ≥1 tumor assessment after study-drug administration, 6 partial responses (2 biliary tract carcinoma, 2 neuroendocrine tumor, 2 thymic cancer) were observed regardless of wnt related gene mutation. C_max and AUC for E7386 increased with increasing E7386 dose.

Conclusions

E7386 120 mg BID, in combination with lenvatinib 20 mg QD, was deemed tolerable and manageable with antiemetic administration and determined as the recommended dose for the expansion part.

Clinical trial identification

NCT04008797.

Editorial acknowledgement

Medical writing support was provided by Jeffrey Bratz, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, with funding by Eisai Inc., Nutley, NJ, USA.

Legal entity responsible for the study

Eisai Inc.

Funding

Eisai Inc., Nutley, NJ, USA.

Disclosure

S. Kondo: Financial Interests, Personal, Invited Speaker: Incyte, Chugai; Financial Interests, Personal, Expert Testimony: Takeda; Financial Interests, Institutional, Invited Speaker: Eisai, Asteras, Incyte, Eli Lilly, AstraZeneca, AbbVie. T. Koyama: Financial Interests, Personal, Invited Speaker: Chugai, Sysmex; Financial Interests, Personal, Research Grant: PACT Pharma, Lilly, Daiichi Sankyo, Novartis, Takeda. A. Kawazoe: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Lilly, Ono, Taiho, Bristol Myers Squibb, Merck Serono; Financial Interests, Institutional, Research Grant: Ono, MSD, Taiho, Bayer, Sumitomo Dainippon, AstraZeneca. S. Iwasa: Financial Interests, Institutional, Research Grant: Eisai. K. Yonemori: Financial Interests, Personal, Advisory Board: Novartis, Eisai, AstraZeneca, Chugai, Takeda, Genmab, OncXerna; Non-Financial Interests, Institutional, Principal Investigator: MSD, Daiichi Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle Genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, Haihe; Financial Interests, Personal, Other, Honorarium for lecture: Pfizer, Eisai, AstraZeneca, Eli Lilly, Takeda, Chugai, Fuji Film Pharma, MSD, Boehringer Ingelheim, Ono, Daiichi-Sankyo. K. Shitara: Financial Interests, Personal, Advisory Board: Lilly, Bristol Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Novartis, AbbVie, GlaxoSmithKline, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Guardant Health Japan Corp, Astellas Pharma Inc.; Financial Interests, Personal, Invited Speaker: Takeda Pharmaceutical Company Limited, Bristol Myers Squibb, Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Research Grant: Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Eisai, Amgen. Y. Nakamura: Financial Interests, Personal, Invited Speaker: Chugai, Merck Biopharma, Guardant Health AMEA; Financial Interests, Institutional, Funding: Taiho, Chugai, Guardant Health, Genomedia, Daiichi Sankyo, Roche Diagnostics; Financial Interests, Institutional, Invited Speaker: Seagen. N. Yamamoto: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Eli Lilly, Ono, Chugai, Sysmex, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eisai, Takeda, Otsuka, Boehringer Ingelheim, Cimic, Chugai; Financial Interests, Institutional, Invited Speaker, Principal Investigator in industry sponsored trial: Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Takeda, ONO, Janssen Pharma, MSD, Merck, GSK, Sumitomo Dainippon, Chiome Bioscience, Otsuka; Financial Interests, Institutional, Invited Speaker, Principal investigator in industry sponsored trial: Carna Biosciences, Genmab, Shionogi, TORAY. T. Sahara, N. Hayata, S. Yamamuro, T. Kimura, L. Dutta, T. Tamai: Financial Interests, Personal, Full or part-time Employment: Eisai. M. Ikeda: Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai, Eli Lilly Japan, Eisai, NIHON Servier, Novartis, Ono, Takeda, GlaxoSmithKline; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Eli Lilly Japan, Eisai, NIHON Servier, Novartis, Taiho, Yakult, Teijin Pharma, AbbVie, Abbott Japan, Fujifilm Toyama Chemical, Incyte Biosciences Japan, ASLAN, Chugai, NIHON Servier, Takeda; Financial Interests, Institutional, Invited Speaker: Bayer, Bristol Myers Squibb, Eisai, AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, Merck Serono, MSD, Ono, Yakult, Novartis, Takeda, J-Pharma, Pfizer, Chiome Bioscience, NIHON Servier, Delta-Fly Pharma, Syneos Health, Merus.N.V. All other authors have declared no conflicts of interest.