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

Victoria K Woodcock, Sally Clive, Richard H Wilson, Vicky M Coyle, Michael R L Stratford, Lisa K Folkes, Richard Eastell, Claire Barton, Paul Jones, Shamim Kazmi-Stokes, Helen Turner, Sarah Halford, Adrian L Harris, Mark R Middleton

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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.
Original languageEnglish
Pages (from-to)770-776
Number of pages7
JournalBritish Journal of Cancer
Volume118
Early online date13 Feb 2018
DOIs
Publication statusPublished - 20 Mar 2018

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Maximum Tolerated Dose
Neoplasms
Bone Remodeling
Alopecia
Anorexia
Nausea
Area Under Curve
Fatigue
Pharmacokinetics
Neoplasm Metastasis
Safety

Cite this

Woodcock, V. K., Clive, S., Wilson, R. H., Coyle, V. M., Stratford, M. R. L., Folkes, L. K., ... Middleton, M. R. (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, 770-776. https://doi.org/10.1038/bjc.2017.484
Woodcock, Victoria K ; Clive, Sally ; Wilson, Richard H ; Coyle, Vicky M ; Stratford, Michael R L ; Folkes, Lisa K ; Eastell, Richard ; Barton, Claire ; Jones, Paul ; Kazmi-Stokes, Shamim ; Turner, Helen ; Halford, Sarah ; Harris, Adrian L ; Middleton, Mark R . / A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424. In: British Journal of Cancer. 2018 ; Vol. 118. pp. 770-776.
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title = "A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424",
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.",
author = "Woodcock, {Victoria K} and Sally Clive and Wilson, {Richard H} and Coyle, {Vicky M} and Stratford, {Michael R L} and Folkes, {Lisa K} and Richard Eastell and Claire Barton and Paul Jones and Shamim Kazmi-Stokes and Helen Turner and Sarah Halford and Harris, {Adrian L} and Middleton, {Mark R}",
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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 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, vol. 118, pp. 770-776. https://doi.org/10.1038/bjc.2017.484

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424. / Woodcock, Victoria K; Clive, Sally; Wilson, Richard H; Coyle, Vicky M; Stratford, Michael R L; Folkes, Lisa K; Eastell, Richard; Barton, Claire; Jones, Paul; Kazmi-Stokes, Shamim; Turner, Helen; Halford, Sarah; Harris, Adrian L; Middleton, Mark R .

In: British Journal of Cancer, Vol. 118, 20.03.2018, p. 770-776.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

AU - Woodcock, Victoria K

AU - Clive, Sally

AU - Wilson, Richard H

AU - Coyle, Vicky M

AU - Stratford, Michael R L

AU - Folkes, Lisa K

AU - Eastell, Richard

AU - Barton, Claire

AU - Jones, Paul

AU - Kazmi-Stokes, Shamim

AU - Turner, Helen

AU - Halford, Sarah

AU - Harris, Adrian L

AU - Middleton, Mark R

PY - 2018/3/20

Y1 - 2018/3/20

N2 - 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.

AB - 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.

U2 - 10.1038/bjc.2017.484

DO - 10.1038/bjc.2017.484

M3 - Article

VL - 118

SP - 770

EP - 776

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

ER -