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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

Research output: Contribution to journalArticlepeer-review

Ruth Plummer, Divyanshu Dua, Nicola Cresti, Yvette Drew, Peter Stephens, Marie Foegh, Steen Knudsen, Pallavi Sachdev, Bipin M. Mistry, Vaishali Dixit, Sharon McGonigle, Nancy Hall, Mark Matijevic, Shannon McGrath, Debashis Sarker

Original languageEnglish
Pages (from-to)525-533
Number of pages9
JournalBritish Journal of Cancer
Volume123
Issue number4
Early online date11 Jun 2020
DOIs
Accepted/In press1 Jan 2020
E-pub ahead of print11 Jun 2020
Published18 Aug 2020

King's Authors

Abstract

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.

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