E7386

P1/2, N=89, Completed, Eisai Inc. | Active, not recruiting --> Completed

P1/2, N=301, Recruiting, Eisai Inc. | Phase classification: P1 --> P1/2 | N=181 --> 301 | Trial completion date: Mar 2027 --> Nov 2026 | Trial primary completion date: Mar 2027 --> Nov 2026

P1/2, N=89, Active, not recruiting, Eisai Inc. | Trial completion date: Sep 2025 --> Nov 2024 | Trial primary completion date: Sep 2025 --> Nov 2024

P1/2, N=89, Active, not recruiting, Eisai Inc. | Recruiting --> Active, not recruiting | N=156 --> 89

P1, N=60, Active, not recruiting, Eisai Inc. | Recruiting --> Active, not recruiting | Trial completion date: May 2024 --> Mar 2026 | Trial primary completion date: May 2024 --> Mar 2026

P1, N=181, Recruiting, Eisai Inc. | Trial completion date: Oct 2024 --> Mar 2027 | Trial primary completion date: Oct 2024 --> Mar 2027

P1, N=70, Active, not recruiting, Eisai Co., Ltd. | Recruiting --> Active, not recruiting

P1, N=181, Recruiting, Eisai Inc. | Phase classification: P1b --> P1

These exploratory tumor biomarker analyses suggest that E7386 in combination with lenvatinib may affect the tumor microenvironment in HCC pts through effects on Wnt signaling, angiogenesis, hypoxic response, and glycolysis pathways. This concept is the basis for treatment with this combination. However, given the small sample size, further investigation is needed to confirm these effects on the tumor microenvironment.

P1/2, N=156, Recruiting, Eisai Inc. | Phase classification: P1b/2 --> P1/2

P1, N=0, Withdrawn, Eisai Limited | N=12 --> 0 | Trial completion date: Nov 2023 --> May 2023 | Suspended --> Withdrawn | Trial primary completion date: Nov 2023 --> May 2023

E7386 100 mg BID plus lenvatinib (8/12 mg QD per bodyweight) was deemed the recommended phase 2 dose in HCC, was tolerable and manageable with antiemetics, and showed promising activity, including in patients pretreated with lenvatinib.

Inhibition of β-catenin-CBP activity through the use of the orally active small molecule, E7386, reduced the expression of CCT5 and mTORC1 activity in vitro, and inhibited p-EMT-associated markers and tumor development in a murine model of OSCC. Our study highlights the use of multi-resolution network analyses of scRNAseq data to identify targetable signals for therapeutic benefit, thus defining an underappreciated association between β-catenin/CBP and mTORC1 signaling in head and neck cancer plasticity.

P1b, N=181, Recruiting, Eisai Inc. | Trial completion date: Jan 2025 --> Oct 2024 | Trial primary completion date: Jan 2025 --> Oct 2024

P1, N=70, Recruiting, Eisai Co., Ltd. | Active, not recruiting --> Recruiting | N=50 --> 70 | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

P1b, N=181, Recruiting, Eisai Inc. | Trial primary completion date: Jun 2024 --> Jan 2025

E7386 100 mg BID, in combination with lenvatinib (8 or 12 mg based on bodyweight) QD, was determined as the recommended phase 2 dose, and was deemed tolerable and manageable with antiemetic administration. The combination showed promising activity in patients with HCC, including those pretreated with lenvatinib. Clinical trial information: NCT04008797.

In addition, atezolizumab + bevacizumab combination therapy is approved for unresectable hepatocellular carcinoma. E7386 + LEN combination shows antitumor activity in the mouse KLN 205 lung tumor model when there is prior ICI-based (CTLA-4 + PD-1 or AFL + PD-1) combination treatment. Further, E7386 + LEN shows enhanced antitumor activity with prior AFL + PD-1; possibly due to activation of Wnt-signaling pathway during prior treatments.

Clinical studies of E7386 in combination with LEN and with pembrolizumab are in progress. E7386 suppressed the Wnt signal that was activated with LEN in tumor endothelial cells and E7386 + LEN, and the triple combination also decreased the immunosuppressive myeloid cells that were increased with LEN, and LEN + anti-PD-1 Ab. These activities of E7386 on the tumor microenvironment could provide unique mechanisms of antitumor activity for this triple combination in preclinical tumor models.

P1b/2, N=156, Recruiting, Eisai Inc. | N=108 --> 156 | Trial completion date: May 2025 --> Sep 2025 | Trial primary completion date: May 2025 --> Sep 2025

P1b/2, N=108, Recruiting, Eisai Inc. | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: Nov 2023 --> May 2025

P1b, N=181, Recruiting, Eisai Inc. | Trial completion date: Jun 2024 --> Jan 2025

E7386 120 mg BID was tolerated and determined as the recommended dose for the expansion part. Based on additional analyses of the dose-escalation part of this study, further investigation of safety, preliminary efficacy, PK, and biomarker analyses of E7386 is ongoing using 2 dose levels (100 and 120 mg BID) in the expansion part. Clinical trial information: NCT03833700.

Cmax 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.

P1b, N=181, Recruiting, Eisai Inc. | N=61 --> 181 | Trial completion date: Mar 2022 --> Jun 2024 | Trial primary completion date: Mar 2022 --> Jun 2024

NF-κB pathway inhibitors acted synergistically with E7386 to block proliferation and induce cell cycle arrest in E7386-resistant spheroids. These findings suggest a possibility that a combination of E7386 and NF-κB inhibition may effectively block the proliferation of a subset of colon cancer cells.

P1b/2, N=108, Recruiting, Eisai Inc. | Not yet recruiting --> Recruiting

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., Newtown, PA, USA.

Furthermore, E7386 showed synergistic antitumor activity against MMTV-Wnt1 tumor in combination with anti-PD-1 antibody. In conclusion, E7386 demonstrates clear antitumor activity via modulation of the Wnt/β-catenin signal pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody.

Importantly, E7386 inhibition-associated transcriptional signatures tracked with tumor grade and poor human HNSCC patient survival. In conclusion, inhibiting β-catenin/CBP activity with E7386 represents a novel approach aimed at targeting epigenetically driven changes in the chromatin structure in HNSCC.

Current anti-EGFR therapy relies on the use of cetuximab, a monoclonal antibody against EGFR, although it has had only a limited response in patients...Additionally, treatment with either ICG-001 or E7386, which are both small molecule inhibitors of β-catenin/CBP signaling, leads to increased transcriptional expression of fucosyltransferases FUT2 and FUT3, with a concomitant increase in EGFR N-glycan antennary fucosylation...Data are available via ProteomeXchange with identifier PXD017060. We propose that β-catenin/CBP signaling promotes EGFR oncogenic activity in OSCC by inhibiting its N-glycan antennary fucosylation through transcriptional repression of FUT2 and FUT3.