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, José Angel Arranz, John Chester, Simon Chowdhury, Arkadiusz Z. Dudek, Volker Müller-Mattheis, Marc Oliver Grimm, Jürgen E. Gschwend, Christian Wülfing, Peter Albers, Jianguo Li, Anna Osmukhina, Jeffrey Skolnik, Gary Hudes

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Summary: 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 (Cmax) 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 ≤2 of the first 20 evaluable patients achieved an objective tumor response. Cmax 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 ≥8 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 ≥3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean Cmax 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 languageEnglish (US)
Pages (from-to)1001-1007
Number of pages7
JournalInvestigational New Drugs
Volume31
Issue number4
DOIs
StatePublished - Aug 2013

Fingerprint

Kinesin
Spindle Apparatus
Safety
Neoplasms
Neutropenia
N-(3-aminopropyl)-N-(1-(5-benzyl-3-methyl-4-oxo-(1,2)thiazolo(5,4-d)pyrimidin-6-yl)-2-methylpropyl)-4-methylbenzamide
Leukopenia
Constipation
Fatigue
Disease Progression
Therapeutics
Pharmacokinetics

Keywords

  • AZD4877
  • Bladder cancer
  • Eg5
  • Mitotic kinesin inhibitor
  • Objective tumor response
  • Phase II
  • Transitional cell carcinoma
  • Urothelial cancer

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer. / Jones, Robert; Vuky, Jacqueline; Elliott, Tony; Mead, Graham; Arranz, José Angel; Chester, John; Chowdhury, Simon; Dudek, Arkadiusz Z.; Müller-Mattheis, Volker; Grimm, Marc Oliver; Gschwend, Jürgen E.; Wülfing, Christian; Albers, Peter; Li, Jianguo; Osmukhina, Anna; Skolnik, Jeffrey; Hudes, Gary.

In: Investigational New Drugs, Vol. 31, No. 4, 08.2013, p. 1001-1007.

Research output: Contribution to journalArticle

Jones, R, Vuky, J, Elliott, T, Mead, G, Arranz, JA, Chester, J, Chowdhury, S, Dudek, AZ, Müller-Mattheis, V, Grimm, MO, Gschwend, JE, Wülfing, 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
Jones, Robert ; Vuky, Jacqueline ; Elliott, Tony ; Mead, Graham ; Arranz, José Angel ; Chester, John ; Chowdhury, Simon ; Dudek, Arkadiusz Z. ; Müller-Mattheis, Volker ; Grimm, Marc Oliver ; Gschwend, Jürgen E. ; Wülfing, Christian ; Albers, Peter ; Li, Jianguo ; Osmukhina, Anna ; Skolnik, Jeffrey ; Hudes, Gary. / Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer. In: Investigational New Drugs. 2013 ; Vol. 31, No. 4. pp. 1001-1007.
@article{dcbca402d9a64943a898503aee1d8935,
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 = "Summary: 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 (Cmax) 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 ≤2 of the first 20 evaluable patients achieved an objective tumor response. Cmax 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 ≥8 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 ≥3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean Cmax 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 = "AZD4877, Bladder cancer, Eg5, Mitotic kinesin inhibitor, Objective tumor response, Phase II, Transitional cell carcinoma, Urothelial cancer",
author = "Robert Jones and Jacqueline Vuky and Tony Elliott and Graham Mead and Arranz, {Jos{\'e} Angel} and John Chester and Simon Chowdhury and Dudek, {Arkadiusz Z.} and Volker M{\"u}ller-Mattheis and Grimm, {Marc Oliver} and Gschwend, {J{\"u}rgen E.} and Christian W{\"u}lfing and Peter Albers and Jianguo Li and Anna Osmukhina and Jeffrey Skolnik and Gary Hudes",
year = "2013",
month = "8",
doi = "10.1007/s10637-013-9926-y",
language = "English (US)",
volume = "31",
pages = "1001--1007",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "4",

}

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 - Arranz, José Angel

AU - Chester, John

AU - Chowdhury, Simon

AU - Dudek, Arkadiusz Z.

AU - Müller-Mattheis, Volker

AU - Grimm, Marc Oliver

AU - Gschwend, Jürgen E.

AU - Wülfing, Christian

AU - Albers, Peter

AU - Li, Jianguo

AU - Osmukhina, Anna

AU - Skolnik, Jeffrey

AU - Hudes, Gary

PY - 2013/8

Y1 - 2013/8

N2 - Summary: 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 (Cmax) 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 ≤2 of the first 20 evaluable patients achieved an objective tumor response. Cmax 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 ≥8 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 ≥3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean Cmax 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 - Summary: 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 (Cmax) 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 ≤2 of the first 20 evaluable patients achieved an objective tumor response. Cmax 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 ≥8 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 ≥3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean Cmax 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 - AZD4877

KW - Bladder cancer

KW - Eg5

KW - Mitotic kinesin inhibitor

KW - Objective tumor response

KW - Phase II

KW - Transitional cell carcinoma

KW - Urothelial cancer

UR - http://www.scopus.com/inward/record.url?scp=84880924613&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880924613&partnerID=8YFLogxK

U2 - 10.1007/s10637-013-9926-y

DO - 10.1007/s10637-013-9926-y

M3 - Article

C2 - 23329066

AN - SCOPUS:84880924613

VL - 31

SP - 1001

EP - 1007

JO - Investigational New Drugs

JF - Investigational New Drugs

SN - 0167-6997

IS - 4

ER -