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.
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.
| Original language | English |
|---|---|
| Pages (from-to) | 770-776 |
| Number of pages | 7 |
| Journal | British Journal of Cancer |
| Volume | 118 |
| Early online date | 13 Feb 2018 |
| DOIs | |
| Publication status | Published - 20 Mar 2018 |
Access to Document
- A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424
Copyright 2018 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.