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.

A Highly Selective MNK Inhibitor Rescues Deficits Associated with Fragile X Syndrome in Mice

“…Phase I clinical data indicate that eFT508 is well tolerated in patients with advanced solid tumors [73]. Moreover, eFT508 has shown sufficient inhibition of eIF4E phosphorylation systemically in patients after oral administration [73]. Our experiments illustrate the potency and efficacy of eFT508 administration in a model of FXS.…”

“…To the best of our knowledge, it is the only MNK inhibitor currently in clinical trials. Phase I clinical data indicate that eFT508 is well tolerated in patients with advanced solid tumors [73]. Moreover, eFT508 has shown sufficient inhibition of eIF4E phosphorylation systemically in patients after oral administration [73].…”

Pharmacodynamic evaluation of AUM001/tinodasertib, an oral inhibitor of mitogen-activated protein kinase (MAPK)-interacting protein kinase 1, 2 (MNK1/2) in preclinical models and tissues from a Phase 1 clinical study

“…Blocking cap-dependent mRNA translation selective and potent inhibitors of MNK has proven to provide clinical benefits for cancer patients with eFT508 being granted orphan drug status by FDA for further development in diffuse large B-cell lymphoma [19] and having shown favorable clinical results in the Ph2 trial in NSCLC in combination with pembrolizumab [20]. There is strong evidence that MNK inhibition blocks multiple oncogenic proliferation pathways, reduces pro-inflammatory and pro-tumorigenic cytokines, while increasing antitumor immunity [22][23][24].…”

“…The latter led to only 46% inhibition of p-eIF4E in A549 tumors at approximately at T max at 200 mg/kg at steady state[24], compared to 70% inhibition with 12.5 mg for ETC-206 after a single dose(Fig 3C).To draw a conclusion on the doses of ETC-206 required for PD inhibition in different murine tissues more weight was given to tumor and skin effects rather than PBMC effects, as the processing time was much faster and hence less variability was observed. The mouse PBMC extraction protocol is lengthy and involves several steps without added phosphatase inhibitor and has previously been demonstrated to show relatively higher variability compared to other murine tissues, while providing much better results in humans ,800 µg•h/L and a C max of 540 µg/L after a single dose[19] with t 1/2 of 12 h. In the clinic, eFT508 was initially dosed as 450 mg of oral solution once daily, with dosing later changed to a twice daily 200 mg capsule formulation that has improved the AUC at steady state (increase from 5.4 to 10.9 h•µg/mL). At steady state (on Day 15), eFT508 reported a mean 74% inhibition of p-eIF4E in PBMCs for up to 10 h but all other doses tested from 50 mg to 600 mg only lead to mean inhibition of 50-55%[19].…”

MNK1 and MNK2 expression in the human dorsal root and trigeminal ganglion

“…We conclude that dual MNK1 and MNK2 inhibitors should be developed for testing as a novel treatment for pain based on expression of both genes in nearly all human nociceptors. Dual MNK inhibitors have progressed through phase II clinical trials for oncology and are well tolerated except for dose-limiting CNS-mediated side effects (Falchook et al, 2017; El-Khoueiry et al, 2020). This clinical data suggests that dual MNK inhibitors for pain can be progressed to clinical testing with appropriate optimization to increase the safety window for these inhibitors.…”