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

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/m(2). 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/m(2). 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/m(2) 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/m(2) 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.

• Authors: 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
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 69 Issue 3 Pg. 733-41 (Mar 2012) ISSN: 1432-0843 [Electronic] Germany
• PMID: 22020315 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimitotic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• Chromosomal Proteins, Non-Histone
• GSK923295
• centromere protein E
• Sarcosine

Topics

• Adult
• Aged
• Antimitotic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Bridged Bicyclo Compounds, Heterocyclic (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Chromosomal Proteins, Non-Histone (antagonists & inhibitors)
• Cohort Studies
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Resistance, Neoplasm
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Sarcosine (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Treatment Outcome
• Young Adult