Abstract
3012 Background: CENP-E plays a key role in maintaining and silencing mitotic checkpoint signaling. CENP-E is overexpressed in many tumors relative to surrounding normal tissue. Inhibition of CENP-E protein results in cell cycle arrest in mitosis. GSK923295 is a selective inhibitor of CENP-E with potent and broad spectrum antitumor activity against solid tumors and hematologic malignancies in vitro. We present the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of this first-in-class CENP-E inhibitor, GSK923295, in patients (pts) with advanced solid tumors. Methods: Adult pts with relapsed or refractory advanced solid tumors received GSK923295 by 1-hour IV infusion on days 1, 8, and 15 of a 28-day cycle. Pts continued therapy until disease progression or toxicity. Doses were escalated using a modified accelerated titration schema. Results: 38 of 39 pts enrolled were evaluable. Doses were escalated from 10 to 250 mg/m2. DLTs included grade 3 AST elevation (n=1/7 at 80 mg/m2), grade 3 hypoxia (n=1/7 at 140 mg/m2), and 3 DLTs at 250 mg/m2 (grade 3 fatigue (n=2) and grade 3 hypokalemia (n=1)). Thus, MTD was determined to be 190 mg/m2. Fatigue was the most common adverse event (AE) (n=21/37), mostly grade 1 (n=16/21), but appeared dose related. Other grade 3 and 4 AEs occurring after cycle 1 were (n=1 each): grade 3 vomiting (105 mg/m2), grade 4 hyponatremia (140 mg/m2), grade 4 AST (140 mg/m2), grade 4 ALT (140 mg/m2), grade 3 total bilirubin (250 mg/m2). Preliminary PK data show that GSK923295 exposure appears dose proportional with low (15%) intrasubject- and moderate (41%) intersubject-variability in body-size normalized systemic clearance. One pt with urothelial carcinoma experienced a partial response (RECIST) after 6 months (mo) of GSK923295 at 250 mg/m2, lasting ≥ 3 mo. Six pts had stable disease lasting ≥ 3 mo across a wide range of doses (20 mg/m2 6 mo, n=1 [liver]; 80 mg/m2 3 mo, n=3 [colon/rectum, pancreas]; 140 mg/m2 5 mo, n=1 [prostate]; 190 mg/m2 4 mo, n=1 [ovary]). Conclusions: The MTD of GSK923295 is 190 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle. Fatigue was the most common AE and was dose limiting. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.