A Phase 1-2 Dose-Escalation and Cohort- Expansion Study of eFT508, a Selective, Orally Bioavailable Inhibitor of MNK1 and MNK2, in Patients with Hematological Malignancies

Introduction

Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of multiple hematological and 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. Significant anti-tumor activity has been observed in preclinical models of diffuse large B-cell lymphoma (DLBCL), particularly in tumor models that have a mutation in MyD88. In addition to direct antitumor activity, eFT508 triggers an anti- tumor immune response and enhances responses to checkpoint inhibitors in preclinical models.

The current study is a first-in-human dose escalation and cohort expansion trial of eFT508 in patients with advanced hematological malignancies

Methods

Using a 3+3 dose escalation schema, cohorts of 3-6 patients (pts) with performance status 0-1, adequate bone marrow, hepatic and renal function and advanced hematological tumors of mainly B cell origin were treated with eFT508 administered orally once daily at a starting dose of 300 mg. A study in pts with solid tumors had previously shown that a dose of 450 mg once daily was well tolerated and based on a pharmacodynamic assay was associated with a degree of target engagement sufficient for maximal efficacy in preclinical models. Efficacy evaluations were performed every 6 weeks.

Results

6 pts (4 male, 2 female, median age 65 years, range 32-79 years) were treated; 3 at 300 mg daily and 3 at 450 mg daily using an oral suspension of eFT508. 3 pts had DLBCL, 1 had Waldenström macroglobulinemia (WM), 1 had Hodgkin lymphoma (HL) and 1 had follicular lymphoma (FL). The mean number of prior therapies was 4 (range 2-7). Two patients had relapsed after autologous stem cell transplant.

The most common adverse events occurring in ≥ 2 pts irrespective of causality, were Grade 1 or 2 unless specified. These included fatigue (n=5), constipation (n=3), hypercalcemia (n=3 with 2 patients experiencing grade 3 toxicity), gastroesophageal reflux (n=2), nausea (n=2) and upper respiratory tract infection (n=2). One of the cases of grade 3 hypercalcemia, felt to be possibly drug related in a patient treated at 450 mg, resolved after a single infusion of zoledronate

In 6 pts evaluated for PK, eFT508 was bioavailable and rapidly absorbed, with a median T_max of 3 hours and a mean T_1/2 of 9.7 hours. Minimal accumulation was observed between Days 1 and 15 in 4 evaluable pts, with a mean accumulation factor of 1.3-fold determined for AUC_0-24. Target engagement is being assessed with a pharmacodynamic assay measuring P-eIF4E in peripheral blood cells. In addition, a set of circulating cytokines (including IL-6, IL-8, IL-10, CXCL10 and TNFα) are being measured throughout treatment as MNK1/2 have been shown to regulate cytokine production.

Preliminary signs of efficacy were observed with 3 of the 6 pts experiencing stable disease. These included a 32 year old patient with classical HL who had relapsed following multiple lines of chemotherapy, autologous transplant, brentuximab and immune checkpoint inhibition who was treated with 300 mg daily of eFT508. He experienced rapid resolution of B symptoms (fever and night sweats) and at a 6 week scan had a 30% reduction in measurable nodal disease. This nodal reduction was maintained at 12 weeks but a new bone lesion was observed

A pt with WM treated at the 450 mg dose level had a reduction in M protein of 22% and remains on treatment for 102 days

A pt with rituximab refractory FL treated at 300 mg remains on treatment with stable disease (6% reduction in tumor volume) for 156 days

Conclusions

Preliminary data suggest that eFT508 has acceptable safety and pharmacological activity at the tested dose levels. Dosing has now switched to a capsule formulation that will be used to determine a recommended phase 2 dose. Expansion cohorts for more formal evaluation of efficacy will follow. Updated results will be presented at the ASH meeting.