zotatifin (eFT226)

P2, N=130, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Aug 2029 --> Aug 2030 | Trial primary completion date: Aug 2026 --> Aug 2027

P2, N=19, Active, not recruiting, Stanford University | Recruiting --> Active, not recruiting | N=150 --> 19

P2, N=130, Recruiting, Dana-Farber Cancer Institute | N=60 --> 130 | Trial completion date: May 2026 --> Aug 2029 | Trial primary completion date: May 2024 --> Aug 2026

Surprisingly, Zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened interferon response resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for Zotatifin, and provide a rationale for new combination regimens comprising Zotatifin and chemotherapy or immunotherapy as treatments for TNBC.

P1b, N=36, Completed, Effector Therapeutics | Active, not recruiting --> Completed

P1/2, N=30, Recruiting, Effector Therapeutics | N=228 --> 30 | Trial completion date: Sep 2023 --> Mar 2025 | Trial primary completion date: Jul 2023 --> Dec 2024

In dose expansion cohorts of heavily pre-treated metastatic breast cancer pts, eIF4A inhibitor zotatifin showed evidence of anti-tumor activity in combination with fulvestrant and abemaciclib and had a favorable safety profile consisting of primarily grade 1/2 adverse events. Clinical trial information: NCT04092673.

P2, N=150, Recruiting, Stanford University | Not yet recruiting --> Recruiting

P2, N=150, Not yet recruiting, Stanford University | N=100 --> 150

However, the primary mechanism of PKA effects on MYC in our cell models was translation and could be blocked with the eIF4A inhibitor zotatifin. This compound dramatically reduced c-MYC expression and inhibited FLC cell line growth in vitro. Thus, targeting PKA effects on translation is a potential treatment strategy for FLC and other PKA-driven cancers.

P2, N=100, Not yet recruiting, Stanford University | N=264 --> 100

Background: Up to 40% of diffuse large B-cell lymphoma (DLBCL) patients do not achieve a cure in response to standard immunochemotherapy R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)...To further explore the role of the CD98hc counteracting mechanism, we established a doxycycline-inducible (TET-on) CD98hc-overexpressing DLBCL cell line (SU-DHL10), and we consistently found that overexpression of CD98hc was responsible for decreased sensitivity to zotatifin treatment (48h, 72h) by ATP-dependent viability assay... We define for the first time CD98hc as a new putative driver of rocaglate resistance in B-cell lymphoma. Paradoxically, CD98hc is upregulated as part of an overall cellular translational response to rocaglate exposure, but it provides insights and new potential targets for further drug combinations. This study lays the foundation for new treatment strategies to optimize the use of zotatifin to overcome rocaglate resistance in lymphoma patients.

eIF4A inhibitor zotatifin achieves pharmacologically relevant exposures with on-target AEs that are manageable at the MTD, with evidence of target knockdown from on-treatment biopsies. Part 2 indication-specific expansions (including in ER+ FGFR-amplified MBC as single agent, ER+ MBC in combination with fulvestrant and abemaciclib, and KRAS NSCLC in combination with sotorasib) are on-going.

P1/2, N=198, Recruiting, Effector Therapeutics | N=45 --> 198 | Trial primary completion date: Dec 2022 --> Jul 2023

P1/2, N=45, Recruiting, Effector Therapeutics | Trial completion date: Dec 2021 --> Jul 2023 | Trial primary completion date: Oct 2021 --> Dec 2022

This dependency identifies the potential for rational combination strategies aimed at vertical inhibition of the PI3K/AKT/eIF4F pathway. Combination of zotatifin with PI3K or AKT inhibitors was beneficial across RTK-driven cancer models by blocking RTK-driven resistance mechanisms demonstrating the clinical potential of these combination strategies.

P1/2, N=45, Recruiting, Effector Therapeutics | Trial primary completion date: Apr 2021 --> Oct 2021

AKT activation leads to the degradation of PDCD4 which can alter eIF4F complex formation. The association of eFT226 activity with PTEN/PI3K/mTOR pathway regulation of mRNA translation provides a means to identify patient subsets during clinical development.

The association of eFT226 activity in RTK tumor models with mTOR pathway activation provides a means to further enrich for sensitive patient subsets during clinical development. Clinical trials with eFT226 in patients with solid tumor malignancies have initiated.