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01.03.2012 | Original Article | Ausgabe 3/2012

Cancer Chemotherapy and Pharmacology 3/2012

First-time-in-human study of GSK923295, a novel antimitotic inhibitor of centromere-associated protein E (CENP-E), in patients with refractory cancer

Zeitschrift:
Cancer Chemotherapy and Pharmacology > Ausgabe 3/2012
Autoren:
Vincent Chung, Elisabeth I. Heath, William R. Schelman, Brendan M. Johnson, Lyndon C. Kirby, Kerlin M. Lynch, Jeffrey D. Botbyl, Thomas A. Lampkin, Kyle D. Holen
Wichtige Hinweise
Presented, in part, at the American Association of Cancer Research 2008 International Conference, European Organization for Research and Treatment of Cancer-National Cancer Institute-Association of Cancer Research 2008 symposium, and the American Society of Clinical Oncology 2010 meeting.

Abstract

Purpose

GSK923295 is an inhibitor of CENP-E, a key cellular protein important in the alignment of chromosomes during mitosis. This was a Phase I, open-label, first-time-in-human, dose-escalation study, to determine the maximum-tolerated dose (MTD), safety, and pharmacokinetics of GSK923295.

Patients and methods

Adult patients with previously treated solid tumors were enrolled in successive cohorts at GSK923295 doses ranging from 10 to 250 mg/m2. GSK923295 was administered by a 1-h intravenous infusion, once weekly for three consecutive weeks, with treatment cycles repeated every 4 weeks.

Results

A total of 39 patients were enrolled. The MTD for GSK923295 was determined to be 190 mg/m2. Observed dose-limiting toxicities (all grade 3) were as follows: fatigue (n = 2, 5%), increased AST (n = 1, 2.5%), hypokalemia (n = 1, 2.5%), and hypoxia (n = 1, 2.5%). Across all doses, fatigue was the most commonly reported drug-related adverse event (n = 13; 33%). Gastrointestinal toxicities of diarrhea (n = 12, 31%), nausea (n = 8, 21%), and vomiting (n = 7, 18%) were generally mild. Frequency of neutropenia was low (13%). There were two reports of neuropathy and no reports of mucositis or alopecia. GSK923295 exhibited dose-proportional pharmacokinetics from 10 to 250 mg/m2 and did not accumulate upon weekly administration. The mean terminal elimination half-life of GSK923295 was 9–11 h. One patient with urothelial carcinoma experienced a durable partial response at the 250 mg/m2 dose level.

Conclusions

The novel CENP-E inhibitor, GSK923295, had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.

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