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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 o.d. at doses ranging from 5 mg to 150 mg, and seven received 40 mg b.d. 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/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 ± SD t1/2 was 8.4 ± 2.8 hours. Clear evidence of Src target inhibition was seen at doses ≥ 20 mg/day. No responses were observed and seven patients (17.1%) achieved stable disease lasting 6 weeks or more. Conclusion: 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.