Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours

S. Kaye; S. Aamdal; R. Jones; G. Freyer; E. Pujade-Lauraine; E. G. E. de Vries; J. Barriuso; S. Sandhu; D. S-W Tan; V. Hartog; B. Kuenen; R. Ruijter; G. B. Kristensen; M. Nyakas; S. Barrett; W. Burke; M. Stuart; U. Emeribe; E. Boven; D. Pietersma

doi:10.1038/bjc.2012.158

Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours

S. Kaye^*, S. Aamdal, R. Jones, G. Freyer, E. Pujade-Lauraine, E. G. E. de Vries, J. Barriuso, S. Sandhu, D. S-W Tan, V. Hartog, B. Kuenen, R. Ruijter, G. B. Kristensen, M. Nyakas, S. Barrett, W. Burke, M. Stuart, U. Emeribe, E. Boven, D. Pietersma

^*Corresponding author voor dit werk

Faculteit Medische Wetenschappen/UMCG

Onderzoeksoutput › Academic › peer review

31 Citaten (Scopus)

209 Downloads (Pure)

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BACKGROUND: As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel.

METHODS: Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mgm(-2) q3w, paclitaxel 80mgm(-2) every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175mgm(-2) q3w. The primary endpoint was safety/tolerability.

RESULTS: A total of 116 patients received saracatinib 125 (N - 20), 175 (N - 44), 225 (N - 40), 250 (N - 9), or 300mg (N - 3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade >= 3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; >= 225 mg, 33%), and grade >= 3 neutropenia occurred more commonly at doses >= 225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w.

CONCLUSION: Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials.

Originele taal-2	English
Pagina's (van-tot)	1728-1734
Aantal pagina's	7
Tijdschrift	British Jounal of Cancer
Volume	106
Nummer van het tijdschrift	11
DOI's	https://doi.org/10.1038/bjc.2012.158
Status	Published - 22-mei-2012

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10.1038/bjc.2012.158Licentie: CC BY-NC-SA

Phase I study of saracatinib (AZD0530) in combinationFinal publisher's version, 342 KBLicentie: CC BY-NC-SA

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Kaye, S., Aamdal, S., Jones, R., Freyer, G., Pujade-Lauraine, E., de Vries, E. G. E., Barriuso, J., Sandhu, S., Tan, D. S.-W., Hartog, V., Kuenen, B., Ruijter, R., Kristensen, G. B., Nyakas, M., Barrett, S., Burke, W., Stuart, M., Emeribe, U., Boven, E., & Pietersma, D. (2012). Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours. British Jounal of Cancer, 106(11), 1728-1734. https://doi.org/10.1038/bjc.2012.158

@article{a66343f4b2984bb6a7b12b73c6bc679c,

title = "Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours",

abstract = "BACKGROUND: As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel.METHODS: Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mgm(-2) q3w, paclitaxel 80mgm(-2) every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175mgm(-2) q3w. The primary endpoint was safety/tolerability.RESULTS: A total of 116 patients received saracatinib 125 (N - 20), 175 (N - 44), 225 (N - 40), 250 (N - 9), or 300mg (N - 3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade >= 3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; >= 225 mg, 33%), and grade >= 3 neutropenia occurred more commonly at doses >= 225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w.CONCLUSION: Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials.British Journal of Cancer (2012) 106, 1728-1734. doi:10.1038/bjc.2012.158 www.bjcancer.com Published online 24 April 2012 (C) 2012 Cancer Research UK",

keywords = "carboplatin, combination chemotherapy, paclitaxel, saracatinib, Src, OVARIAN-CANCER CELLS, TYROSINE KINASE, CISPLATIN RESISTANCE, SRC, INHIBITION, PHARMACOKINETICS, EXPRESSION, CARCINOMA, APOPTOSIS, VIVO",

author = "S. Kaye and S. Aamdal and R. Jones and G. Freyer and E. Pujade-Lauraine and {de Vries}, {E. G. E.} and J. Barriuso and S. Sandhu and Tan, {D. S-W} and V. Hartog and B. Kuenen and R. Ruijter and Kristensen, {G. B.} and M. Nyakas and S. Barrett and W. Burke and M. Stuart and U. Emeribe and E. Boven and D. Pietersma",

year = "2012",

month = may,

day = "22",

doi = "10.1038/bjc.2012.158",

language = "English",

volume = "106",

pages = "1728--1734",

journal = "British Jounal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "11",

}

Kaye, S, Aamdal, S, Jones, R, Freyer, G, Pujade-Lauraine, E, de Vries, EGE, Barriuso, J, Sandhu, S, Tan, DS-W, Hartog, V, Kuenen, B, Ruijter, R, Kristensen, GB, Nyakas, M, Barrett, S, Burke, W, Stuart, M, Emeribe, U, Boven, E & Pietersma, D 2012, 'Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours', British Jounal of Cancer, vol. 106, nr. 11, blz. 1728-1734. https://doi.org/10.1038/bjc.2012.158

TY - JOUR

T1 - Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours

AU - Kaye, S.

AU - Aamdal, S.

AU - Jones, R.

AU - Freyer, G.

AU - Pujade-Lauraine, E.

AU - de Vries, E. G. E.

AU - Barriuso, J.

AU - Sandhu, S.

AU - Tan, D. S-W

AU - Hartog, V.

AU - Kuenen, B.

AU - Ruijter, R.

AU - Kristensen, G. B.

AU - Nyakas, M.

AU - Barrett, S.

AU - Burke, W.

AU - Stuart, M.

AU - Emeribe, U.

AU - Boven, E.

AU - Pietersma, D.

PY - 2012/5/22

Y1 - 2012/5/22

N2 - BACKGROUND: As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel.METHODS: Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mgm(-2) q3w, paclitaxel 80mgm(-2) every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175mgm(-2) q3w. The primary endpoint was safety/tolerability.RESULTS: A total of 116 patients received saracatinib 125 (N - 20), 175 (N - 44), 225 (N - 40), 250 (N - 9), or 300mg (N - 3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade >= 3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; >= 225 mg, 33%), and grade >= 3 neutropenia occurred more commonly at doses >= 225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w.CONCLUSION: Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials.British Journal of Cancer (2012) 106, 1728-1734. doi:10.1038/bjc.2012.158 www.bjcancer.com Published online 24 April 2012 (C) 2012 Cancer Research UK

AB - BACKGROUND: As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel.METHODS: Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mgm(-2) q3w, paclitaxel 80mgm(-2) every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175mgm(-2) q3w. The primary endpoint was safety/tolerability.RESULTS: A total of 116 patients received saracatinib 125 (N - 20), 175 (N - 44), 225 (N - 40), 250 (N - 9), or 300mg (N - 3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade >= 3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; >= 225 mg, 33%), and grade >= 3 neutropenia occurred more commonly at doses >= 225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w.CONCLUSION: Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials.British Journal of Cancer (2012) 106, 1728-1734. doi:10.1038/bjc.2012.158 www.bjcancer.com Published online 24 April 2012 (C) 2012 Cancer Research UK

KW - carboplatin

KW - combination chemotherapy

KW - paclitaxel

KW - saracatinib

KW - Src

KW - OVARIAN-CANCER CELLS

KW - TYROSINE KINASE

KW - CISPLATIN RESISTANCE

KW - SRC

KW - INHIBITION

KW - PHARMACOKINETICS

KW - EXPRESSION

KW - CARCINOMA

KW - APOPTOSIS

KW - VIVO

U2 - 10.1038/bjc.2012.158

DO - 10.1038/bjc.2012.158

M3 - Article

C2 - 22531637

SN - 0007-0920

VL - 106

SP - 1728

EP - 1734

JO - British Jounal of Cancer

JF - British Jounal of Cancer

IS - 11

ER -

Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours

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