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 (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.

• Authors: 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
• Journal: Investigational new drugs (Invest New Drugs) Vol. 31 Issue 4 Pg. 1001-7 (Aug 2013) ISSN: 1573-0646 [Electronic] United States
• PMID: 23329066 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• N-(3-aminopropyl)-N-(1-(5-benzyl-3-methyl-4-oxo-(1,2)thiazolo(5,4-d)pyrimidin-6-yl)-2-methylpropyl)-4-methylbenzamide
• Pyrimidinones
• Kinesins

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Benzamides (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Demography
• Female
• Humans
• Kinesins (antagonists & inhibitors, metabolism)
• Male
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy, pathology)
• Neoplasm Staging
• Pyrimidinones (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Spindle Apparatus (drug effects, metabolism)
• Treatment Outcome
• Urinary Bladder Neoplasms (drug therapy, pathology)
• Urothelium (pathology)