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 journalArticlepeer-review

    31 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 languageEnglish
    Pages (from-to)1001-1007
    Number of pages7
    JournalInvestigational New Drugs
    Volume31
    Issue number4
    DOIs
    Publication statusPublished - 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

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