Background: 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.
Methods: 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.
Results: 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.
Conclusion: The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This work was supported by Eisai Inc., Woodcliff Lake, NJ, USA.
Editorial assistance was provided by Tarah M. Connolly, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, which was funded by Eisai Inc., Woodcliff Lake, NJ, USA.
The University of Newcastle and King’s College London receive support from Cancer
Research UK and Department of Health (England) as Experimental Cancer Medicine
Centres. Financial support for the study was also provided by the National Institute
for Health Research (NIHR) Biomedical Research Centre (BRC) award to Guy’s & St
Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s
College Hospital NHS Foundation Trust (and NIHR Clinical Research Facility).published version, accepted version (6 month embargo), submitted versio
