On November 5, 2019 eFFECTOR Therapeutics, Inc., a leader in the development of selective translation regulators (STRs) for the treatment of cancer, reported the dosing of the first subject in the phase 1/2 study of zotatifin (eFT226) being developed for advanced solid tumor malignancies (Press release, eFFECTOR Therapeutics, NOV 5, 2019, View Source [SID1234553137]). Zotatifin is a novel, potent and selective small molecule inhibitor of eukaryotic initiation factor 4A (eIF4A).
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The study will enroll patients with activating mutations, amplifications or fusions in HER2, ERBB3, FGFR1, or FGFR2 receptor tyrosine kinases, or any KRAS mutation subtype. It will also include pancreatic adenocarcinoma with no molecular typing since the large majority of those patients harbor a KRAS mutation.
"There is an immediate need for more effective treatment options in patients with advanced cancers unable to respond to alternative therapies," said Steve Worland, Ph.D., president and chief executive officer of eFFECTOR. "Tumors treated with agents targeting specific RTKs frequently become resistant, and there are no available therapies targeting multiple KRAS mutation subtypes. The antitumor response observed in preclinical studies demonstrates the potential for zotatifin in the treatment of solid tumors with genetic modifications associated with aggressive disease, including RTK alterations such as FGFR1/2 and HER2 and KRAS, and provides direction for patient selection in our clinical trial."
In the open label, dose escalation and cohort expansion study, subjects will be assigned sequentially to increasing zotatifin doses until the maximum tolerated dose is reached. Zotatifin will be administered as a monotherapy in weekly intravenous infusions in subjects with advanced solid tumor malignancies. Treatment and study subject evaluations will be performed in 21-day cycles.
The primary endpoints of the study include safety and tolerability of zotatifin as monotherapy. Secondary endpoints include antitumor activity and survival, as well as pharmacokinetics of the drug. Exploratory endpoints include pharmacodynamics of zotatifin.
Scientists from eFFECTOR recently presented preclinical data at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) – also known as the Triple Meeting. The data demonstrated that solid tumor cell lines driven by alterations in FGFR1, FGFR2 and HER2 treated with zotatifin showed decreased MAPK and AKT signaling, potent inhibition of cell proliferation and apoptosis and strong in vivo anti-tumor activity, indicating potential for zotatifin to treat FGFR1/2 or HER2-driven cancers.
About Zotatifin (eFT226)
Zotatifin (eFT226) is a potent and selective inhibitor of eukaryotic translation initiation factor 4A (eIF4A). eIF4A is located downstream from key oncogenic mutations and their common resistance mechanisms. Zotatifin inhibits the translation of mRNA encoding several important oncogenes and survival factors, including several RTKS, KRAS, Cyclin D, MCL1 and BCL-2 resulting in potent in vivo efficacy in multiple tumor models dependent on these factors, including colorectal cancer, non-small cell lung cancer, breast cancer, hepatocellular carcinoma and B cell lymphomas. Since Zotatifin inhibits the translation of mRNA encoding KRAS and RTK, it is not limited to any mutation subtypes. The drug is currently being evaluated in a Phase 1/2 clinical trial in patients with solid tumors.