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

Lookup NU author(s): Dr Nicola Cresti, Dr Yvette Drew

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2020, The Author(s). 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. Clinical trial registration: www.ClinicalTrials.gov code: NCT01618136.


Publication metadata

Author(s): Plummer R, Dua D, Cresti N, Drew Y, Stephens P, Foegh M, Knudsen S, Sachdev P, Mistry BM, Dixit V, McGonigle S, Hall N, Matijevic M, McGrath S, Sarker D

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2020

Volume: 123

Pages: 525-533

Print publication date: 18/08/2020

Online publication date: 11/06/2020

Acceptance date: 14/05/2020

Date deposited: 26/06/2020

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41416-020-0916-5

DOI: 10.1038/s41416-020-0916-5


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