Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer

Robert Jones; Jacqueline Vuky; Tony Elliott; Graham Mead; Jose Angel Arranz; John Chester; Simon Chowdhury; Arkadiusz Z. Dudek; Volker Mueller-Mattheis; Marc-Oliver Grimm; Juergen E. Gschwend; Christian Wuelfing; Peter Albers; Jianguo Li; Anna Osmukhina; Jeffrey Skolnik; Gary Hudes

doi:10.1007/s10637-013-9926-y

Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer

Robert Jones^*, Jacqueline Vuky, Tony Elliott, Graham Mead, Jose Angel Arranz, John Chester, Simon Chowdhury, Arkadiusz Z. Dudek, Volker Mueller-Mattheis, Marc-Oliver Grimm, Juergen E. Gschwend, Christian Wuelfing, Peter Albers, Jianguo Li, Anna Osmukhina, Jeffrey Skolnik, Gary Hudes

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

34 Citations (Scopus)

Abstract

Background AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (C-max) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609). Patients and methods AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if a parts per thousand currency sign2 of the first 20 evaluable patients achieved an objective tumor response. C-max was assessed on days 1 and 8 of cycle 1. Results None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for a parts per thousand yen8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade a parts per thousand yen3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean C-max of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively. Conclusions AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.

Original language	English
Pages (from-to)	1001-1007
Number of pages	7
Journal	Investigational New Drugs
Volume	31
Issue number	4
DOIs	https://doi.org/10.1007/s10637-013-9926-y
Publication status	Published - Aug 2013

Keywords

Urothelial cancer
AZD4877
Phase II
Objective tumor response
Bladder cancer
Transitional cell carcinoma
Eg5
Mitotic kinesin inhibitor
PLATINUM-CONTAINING REGIMEN
BLADDER-CANCER
CELL CARCINOMA
TRIAL
ISPINESIB
SB-715992
EG5
KSP
CHEMOTHERAPY
METHOTREXATE

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s10637-013-9926-y

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Jones, R., Vuky, J., Elliott, T., Mead, G., Angel Arranz, J., Chester, J., Chowdhury, S., Dudek, A. Z., Mueller-Mattheis, V., Grimm, M.-O., Gschwend, J. E., Wuelfing, C., Albers, P., Li, J., Osmukhina, A., Skolnik, J., & Hudes, G. (2013). Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer. Investigational New Drugs, 31(4), 1001-1007. https://doi.org/10.1007/s10637-013-9926-y

@article{3fe2f668e7aa4c74826a2349fbcb7b18,

title = "Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer",

abstract = "Background AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (C-max) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609). Patients and methods AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if a parts per thousand currency sign2 of the first 20 evaluable patients achieved an objective tumor response. C-max was assessed on days 1 and 8 of cycle 1. Results None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for a parts per thousand yen8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade a parts per thousand yen3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean C-max of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively. Conclusions AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.",

keywords = "Urothelial cancer, AZD4877, Phase II, Objective tumor response, Bladder cancer, Transitional cell carcinoma, Eg5, Mitotic kinesin inhibitor, PLATINUM-CONTAINING REGIMEN, BLADDER-CANCER, CELL CARCINOMA, TRIAL, ISPINESIB, SB-715992, EG5, KSP, CHEMOTHERAPY, METHOTREXATE",

author = "Robert Jones and Jacqueline Vuky and Tony Elliott and Graham Mead and {Angel Arranz}, Jose and John Chester and Simon Chowdhury and Dudek, {Arkadiusz Z.} and Volker Mueller-Mattheis and Marc-Oliver Grimm and Gschwend, {Juergen E.} and Christian Wuelfing and Peter Albers and Jianguo Li and Anna Osmukhina and Jeffrey Skolnik and Gary Hudes",

year = "2013",

month = aug,

doi = "10.1007/s10637-013-9926-y",

language = "English",

volume = "31",

pages = "1001--1007",

journal = "Investigational New Drugs",

issn = "0167-6997",

publisher = "Kluwer Academic Publishers",

number = "4",

}

Jones, R, Vuky, J, Elliott, T, Mead, G, Angel Arranz, J, Chester, J, Chowdhury, S, Dudek, AZ, Mueller-Mattheis, V, Grimm, M-O, Gschwend, JE, Wuelfing, C, Albers, P, Li, J, Osmukhina, A, Skolnik, J & Hudes, G 2013, 'Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer', Investigational New Drugs, vol. 31, no. 4, pp. 1001-1007. https://doi.org/10.1007/s10637-013-9926-y

TY - JOUR

T1 - Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer

AU - Jones, Robert

AU - Vuky, Jacqueline

AU - Elliott, Tony

AU - Mead, Graham

AU - Angel Arranz, Jose

AU - Chester, John

AU - Chowdhury, Simon

AU - Dudek, Arkadiusz Z.

AU - Mueller-Mattheis, Volker

AU - Grimm, Marc-Oliver

AU - Gschwend, Juergen E.

AU - Wuelfing, Christian

AU - Albers, Peter

AU - Li, Jianguo

AU - Osmukhina, Anna

AU - Skolnik, Jeffrey

AU - Hudes, Gary

PY - 2013/8

Y1 - 2013/8

N2 - Background AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (C-max) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609). Patients and methods AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if a parts per thousand currency sign2 of the first 20 evaluable patients achieved an objective tumor response. C-max was assessed on days 1 and 8 of cycle 1. Results None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for a parts per thousand yen8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade a parts per thousand yen3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean C-max of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively. Conclusions AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.

AB - Background AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (C-max) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609). Patients and methods AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if a parts per thousand currency sign2 of the first 20 evaluable patients achieved an objective tumor response. C-max was assessed on days 1 and 8 of cycle 1. Results None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for a parts per thousand yen8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade a parts per thousand yen3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean C-max of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively. Conclusions AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.

KW - Urothelial cancer

KW - AZD4877

KW - Phase II

KW - Objective tumor response

KW - Bladder cancer

KW - Transitional cell carcinoma

KW - Eg5

KW - Mitotic kinesin inhibitor

KW - PLATINUM-CONTAINING REGIMEN

KW - BLADDER-CANCER

KW - CELL CARCINOMA

KW - TRIAL

KW - ISPINESIB

KW - SB-715992

KW - EG5

KW - KSP

KW - CHEMOTHERAPY

KW - METHOTREXATE

U2 - 10.1007/s10637-013-9926-y

DO - 10.1007/s10637-013-9926-y

M3 - Article

SN - 0167-6997

VL - 31

SP - 1001

EP - 1007

JO - Investigational New Drugs

JF - Investigational New Drugs

IS - 4

ER -

Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer

Abstract

Keywords

UN SDGs

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