On August 4, 2021 eFFECTOR Therapeutics, Inc. (eFFECTOR), a leader in the development of selective translation regulation inhibitors (STRIs) for the treatment of cancer, reported the initiation of dosing in the Phase 2a expansion portion of an ongoing Phase 1/2 trial of zotatifin (eFT226) in solid tumors (Press release, eFFECTOR Therapeutics, AUG 4, 2021, View Source [SID1234585736]). This followed conclusion of the Phase 1 dose escalation portion of the trial and selection of a recommended Phase 2 dose (RP2D). eFFECTOR expects to initiate multiple indication-specific expansion cohorts in ER+ breast cancer and KRAS-mutant non-small cell lung cancer (NSCLC). Zotatifin will be evaluated both as a single agent and in combination with targeted therapies in each indication.

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"Following successful conclusion of dose escalation and selection of the RP2D, we are expanding our zotatifin program with the initiation of several Phase 2a expansion cohorts in cancers with substantial unmet need, including ER+ breast cancer and KRAS-mutant NSCLC," said Steve Worland, Ph.D., president and CEO of eFFECTOR. "Zotatifin has been generally well-tolerated in our clinical trials to date and showed very compelling preclinical activity, including in combination with palbociclib for breast cancer and in combination with sotorasib for KRAS-mutant NSCLC, two indications that we plan to evaluate in expansion cohorts."

The Phase 2a expansion cohorts will evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of zotatifin in subjects with biomarker-positive solid tumor malignancies, including ER+ breast cancer and KRAS-mutant NSCLC. Each of the Phase 2a monotherapy and combination expansion cohorts will utilize a Simon’s Two Stage design, in which seven patients will be enrolled in the first stage of the trial and assessed for activity prior to advancing to the second stage of the trial. Zotatifin will be administered as a 1-hour intravenous (IV) infusion at the selected RP2D of 0.07 mg/kg on Day 1 and Day 8 of a 21-day cycle. eFFECTOR expects to present additional data from the Phase 1 dose escalation portion of the trial, as well as preliminary response data from Phase 2a expansion cohorts, at a medical conference in 2022.

The primary objective of this study is to assess the safety, tolerability and activity of zotatifin as a monotherapy treatment and in combination with targeted agents in biomarker-specific patient populations. If positive activity is observed in a Phase 2a expansion cohort, the company plans to evaluate zotatifin, potentially as a combination in a randomized trial against a relevant comparator control group, or potentially in a single-arm monotherapy trial following demonstration of an appropriate overall response rate (ORR) in the Phase 2a expansion cohort.

About Zotatifin (eFT226)

Zotatifin is a potent and sequence-selective inhibitor of eukaryotic translation initiation factor 4A (eIF4A) mediated translation. eIF4A is responsible for unwinding complex structures in the non-coding 5’ untranslated region of messenger RNA. Zotatifin is designed to block this process, thereby inhibiting the translation of mRNAs encoding several important oncogenes and survival factors, including receptor tyrosine kinases (RTKs), KRAS, Cyclin D, CDK4/6 and MYC. In vivo studies have shown potent tumor regression in multiple tumor models dependent on these factors, including non-small cell lung cancer (NSCLC) and breast cancer. Since zotatifin inhibits the translation of mRNA by acting in the non-coding region of mRNAs, it is not limited to specific KRAS activating mutation subtypes such as KRAS G12C or KRAS G12D. Zotatifin is currently being evaluated as an intravenous (IV) infusion in a Phase 2a clinical trial that will include patients with breast cancer and KRAS-mutant NSCLC and in a Phase 1b clinical trial in patients with mild to moderate COVID-19 infections pursuant to grant sponsorship by the Defense Advanced Research Projects Agency (DARPA).