A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

Woodcock, V. K. et al. (2018) A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424. British Journal of Cancer, 118(6), pp. 770-776. (doi: 10.1038/bjc.2017.484) (PMID:29438361) (PMCID:PMC5877436)

Abstract

Background: Src is involved in cancer invasion and metastasis. AZD0424, an oral inhibitor of Src and ABL1, has shown evidence of anti-tumour activity in pre-clinical studies. Methods: A phase Ia, dose escalation study was performed to assess the safety of continuous oral dosing with AZD0424 in advanced solid tumours. Secondary objectives included investigation of AZD0424 pharmacokinetics, effect on Src activity using markers of bone turnover, and anti-tumour activity. Results: 41 patients were treated; 34 received AZD0424 once-daily at doses ranging from 5 mg to 150 mg, and 7 received 40 mg bi-daily 41.5% of patients experienced at least one AZD0424-related adverse event that was Grade 3–5 in severity, with patients treated at doses above 60 mg per day experiencing multiple treatment-related toxicities. The most commonly observed AZD0424-related adverse events were nausea, fatigue, anorexia and alopecia. Cmax and AUC increased linearly with dose and the mean±standard deviation t1/2 was 8.4±2.8 h. Clear evidence of Src target inhibition was seen at doses ⩾20 mg per day. No responses were observed and 7 patients (17.1%) achieved stable disease lasting 6 weeks or more. Conclusions: AZD0424 displayed no evidence of efficacy as monotherapy despite a clear pharmacodynamic effect. Further evaluation of AZD0424 monotherapy in patients with solid tumours is not recommended.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Wilson, Professor Richard
• Authors: Woodcock, V. K., Clive, S., Wilson, R. H., Coyle, V. M., Stratford, M. R. L., Folkes, L. K., Eastell, R., Barton, C., Jones, P., Kazmi-Stokes, S., Turner, H., Halford, S., Harris, A. L., and Middleton, M. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: British Journal of Cancer
• Publisher: Springer Nature on behalf of Cancer Research UK
• ISSN: 0007-0920
• ISSN (Online): 1532-1827
• Published Online: 13 February 2018
• Copyright Holders: r The Author(s) named above
• First Published: First published in British Journal of Cancer 118(6):770-776
• Publisher Policy: Reproduced under a Creative Commons licence