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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)525-533
Number of pages9
JournalBritish Journal of Cancer
Volume123
Issue number4
Early online date11 Jun 2020
DOIs
Publication statusPublished - 18 Aug 2020

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