First-in-human phase I study of immunomodulatory E7046, an antagonist of PGE

BACKGROUND

E7046 is a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4) for prostaglandin E2, an immunosuppressive mediator of the tumor immune microenvironment. This first-in-human phase 1 study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD) and recommended phase 2 dose of E7046.

METHODS

This first-in-human study enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates. E7046 was administered orally once-daily in sequential escalating dose cohorts (125, 250, 500, and 750 mg) with ≥6 patients per cohort. Tumor assessments were performed every 6 weeks. Paired tumor biopsies and blood samples, before and on treatment, were collected for pharmacokinetic and pharmacodynamic characterization of the treatment.

RESULTS

No dose-limiting toxicities were observed, and the MTD was not reached. E7046 had an elimination half-life (t

CONCLUSIONS

In this first-in-human study, E7046 administered orally once daily demonstrated manageable tolerability, immunomodulatory effects, and a best response of stable disease (≥18 weeks) in several heavily pretreated patients with advanced malignancies. The 250 and 500 mg doses are proposed for further development in the combination setting.

TRIAL REGISTRATION NUMBER

NCT02540291.

Informations de copyright

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: DSH has received research grant funding from AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, and Takeda; DSH received travel, accommodations, and expenses from LOXO and MiRNA; DSH held a consulting or advisory role for the following: Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer (advisory boards and Speakers’ Bureaux), Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, and Trieza Therapeutics. DSH discloses the following other ownership interests: Molecular Match (Advisor), OncoResponse (founder), and Presagia (Advisor). AN has received research funding from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, BMS, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, and the Immune Deficiency Foundation (spouse); AN has served on an advisory board for CytomX Therapeutics and Novartis; AN has received travel and accommodation expenses paid for by ARMO BioSciences. GIS has received research funding from EL, Merck KGaA/EMD-Serono, Merck, and Sierra Oncology. GIS has served on advisory boards for Pfizer, EL, G1 Therapeutics, Roche, Merck KGaA/EMD-Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Almac, Ipsen, Bayer, Angiex, and Daiichi Sankyo. The Dana-Farber Cancer Institute has received funding from Pfizer and Array BioPharma for the conduct of investigator-initiated clinical trials of palbociclib led by GIS. GIS holds Patent 9872874, entitled, “Dosage regimen for sapacitabine and seliciclib,” and also has a pending patent related to his work on CDK4/6 inhibition entitled, ‘‘Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition.’’ FMB has no conflicts of interest to disclose. AP is a consultant/advisory board member for Puretech, Driver, Foundation Medicine, and Eisai; AP has institutional research funding from Array, Plexxikon, Guardant, BMS, MacroGenics, Genentech, Novartis, OncoMed, and Tolero; AP has received travel support from Eisai. AM has received honoraria and consulting fees from Eisai. XB is an employee of H3 Biomedicine, a subsidiary of Eisai. LR, TAB, MR, SD, PS, LX, IT, ViB-P, and CEO are employees of Eisai or Eisai Ltd. ML, ÖA, and AYS were employees of Eisai at the time the study was conducted.