A phase 1 dose escalation study of eFT508, an inhibitor of mitogen-activated protein kinase-interacting serine/threonine kinase-1 (MNK-1) and MNK-2 in patients with advanced solid tumors.

Abstract

2579 Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of multiple solid tumors. eFT508, a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, and thereby selectively regulates translation of a small set of mRNAs. In addition to direct antitumor activity, eFT508 triggers an anti- tumor immune response and enhances responses to checkpoint inhibitors in preclinical models. Methods: Using a 3+3 dose escalation schema, cohorts of solid tumor patients (pts) were treated with eFT508 administered orally once daily at doses ranging from 50 mg to 600 mg. Results: 28 pts were treated, and the most common tumor types were colorectal cancer (8), prostate cancer (3), and soft tissue sarcoma (3). Median number of prior therapies was 4. The most common observed adverse events (AEs) included nausea (47%), vomiting (47%), dyspepsia (23%), fatigue (20%), and constipation (20%). Two pts treated at 600 mg experienced Gr 3 related AEs, including one pt with Gr3 nausea and vomiting (met criteria for dose limiting toxicity) and one pt with reversible Gr3 AST/ALT elevation. 6 pts achieved stable disease with duration ranging from 82 to 196 days. Pharmacokinetic analysis revealed that eFT508 is bioavailable and rapidly absorbed, with median Tmax of 2 hours and a mean T1/2 of 12 hours. Minimal accumulation was observed between Days 1 and 14/15, with mean accumulation factor of 1.2-fold. Analysis of eIF4E phosphorylation in peripheral blood cells suggested that doses ≥ 300 mg achieved engagement sufficient for maximal efficacy as predicted by preclinical models. Conclusions: Preliminary results suggest that eFT508 is well tolerated, and dose escalation continues with a cohort of pts providing pretreatment and on treatment biopsies for evaluation of target engagement and immunomodulatory effects. After determination of the recommended phase 2 dose, further evaluation will include monotherapy cohorts in specific tumor types as well as cohorts to evaluate efficacy and tolerability in combination with checkpoint inhibitors. Clinical trial information: NCT02605083.