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


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.
City of Hope Medical Center, 1500 East Duarte Road, Durate, CA, 91010, USA. vchung@coh.org
Vincent
V
Chung
Elisabeth I
EI
Heath
William R
WR
Schelman
Brendan M
BM
Johnson
Lyndon C
LC
Kirby
Kerlin M
KM
Lynch
Jeffrey D
JD
Botbyl
Thomas A
TA
Lampkin
Kyle D
KD
Holen
D000328:Adult; D000368:Aged; D050256:Antimitotic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012521:Sarcosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
D050256:Antimitotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002868:Chromosomal Proteins, Non-Histone; C571460:GSK923295; C068688:centromere protein E; D012521:Sarcosine