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Ref Type Journal Article
PMID (29438361)
Authors Woodcock VK, Clive S, Wilson RH, Coyle VM, Stratford MRL, Folkes LK, Eastell R, Barton C, Jones P, Kazmi-Stokes S, Turner H, Halford S, Harris AL, Middleton MR
Title A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424.
Journal Vol Issue Date Pages Journal Short Title
British journal of cancer 118 6 2018 03 20 770-776 Br J Cancer
URL
Abstract Text 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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
AZD0424 AZD0424 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD0424 AZD-0424|AZD 0424 BCR-ABL Inhibitor 31 SRC Inhibitor 31 AZD0424 is a tyrosine kinase inhibitor of Abl and Src kinases, which may result in apoptosis and tumor growth inhibition (PMID: 25662515, PMID: 17704648, PMID: 29438361).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References