First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor.

British Journal of Cancer
Ruth PlummerDebashis Sarker

Abstract

This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor. E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50-800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines. Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n = 4, 800 mg; anaphylaxis, n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50-800-mg oral dosing. The res...Continue Reading

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Citations

Feb 12, 2021·Expert Opinion on Therapeutic Patents·Chirag C Mehta, Hardik G Bhatt
Aug 10, 2021·ACS Omega·Ahmed E FazaryAly F Mohamed
Sep 15, 2021·Cancer Discovery·Marie J ParsonsLukas E Dow
Sep 17, 2021·Blood Advances·Christina-Nefeli KontandreopoulouNora-Athina Viniou

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Methods Mentioned

BETA
xenograft
enzyme-linked
Assay
biopsies

Clinical Trials Mentioned

NCT01618136
NCT03878849
NCT03562832

Software Mentioned

Phoenix WinNonlin

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