First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor
| Autor: | Nicola Cresti, Marie Foegh, Mark Matijevic, Divyanshu Dua, Peter Stephens, Yvette Drew, Pallavi Sachdev, Sharon McGonigle, Ruth Plummer, Debashis Sarker, Nancy Hall, Steen Knudsen, Vaishali Dixit, Shannon McGrath, Bipin Mistry |
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| Rok vydání: | 2019 |
| Předmět: |
Oncology
Adult Male Cancer Research medicine.medical_specialty Maximum Tolerated Dose Cancer therapy Colorectal cancer Cell Survival Administration Oral Poly(ADP-ribose) Polymerase Inhibitors Drug Administration Schedule Article 03 medical and health sciences 0302 clinical medicine Internal medicine Cell Line Tumor Neoplasms medicine Biomarkers Tumor Humans Dosing Adverse effect Survival analysis 030304 developmental biology Aged Cell Proliferation Quinazolinones Cancer 0303 health sciences Dose-Response Relationship Drug business.industry Middle Aged medicine.disease Isoquinolines Survival Analysis Clinical trial Gene Expression Regulation Neoplastic Treatment Outcome Tolerability 030220 oncology & carcinogenesis Toxicity Biomarker (medicine) Female business Azo Compounds |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 |
| Popis: | BackgroundThis 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.MethodsE7449 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.ResultsForty-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.ConclusionThe results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP.Clinical trial registrationwww.ClinicalTrials.gov code: NCT01618136. |
| Databáze: | OpenAIRE |
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