Abstract LB-246: A Phase I and first time in human study of the centromere associated protein E (CENP-E) inhibitor GSK923295A in patients with advanced solid tumors

Abstract

Abstract Background: CENP-E plays a critical role in maintaining and silencing mitotic checkpoint signaling. CENP-E mRNA is overexpressed in a variety of human tumors relative to adjacent normal tissue, suggesting that it may have an important role in tumor cell proliferation. GSK923295A is a potent and selective small molecule inhibitor of CENP-E with broad preclinical activity against solid and hematologic cancer cells in vitro and in murine tumor xenograft models. The purpose of this Phase I study is to determine the maximally tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics of GSK923295A in patients with advanced solid tumors. Methods: Adult patients with refractory advanced solid tumors are administered GSK923295A by a 1-hour intravenous infusion on days 1, 8, and 15 of 28-day treatment cycles. Doses are escalated in cohorts of 2 patients using an accelerated titration scheme. Transition to a standard (40% or 33%) dose escalation scheme is planned if 2 grade 2 toxicities or 1 DLT are observed in the first treatment cycle. Blood samples are collected on days 1 and 15 over 48 hours to determine the plasma PK of GSK923295A. Pre- and post-treatment FDG-PET and tumor biopsies are performed in selected patients. Results: Eight patients [4 males, 4 females; median age 54.5 years; cancers of pancreas (2), lung (2), stomach (1), colon (1), parotid gland (1), and liver (1)] have been treated at 10, 20, 40, and 80 mg/m2 (median of 1.5 and total of 15 cycles completed). One DLT (AST elevation) has been reported at 80 mg/m2. We have expanded this dose level to 3 patients. At the 4 dose levels studied thus far, PK appears dose proportional with low intrapatient variability, modest interpatient variability, and no apparent accumulation or time-dependent PK. Conclusions: One DLT has been observed at the 80 mg/m2 dose level. Evaluation of GSK923295A continues at a dose level of 80 mg/m2. Dose Level (mg/m2)NDayCmax* (ng/mL)AUC(0-¥)* (ng.h/mL)Clearance* (L/h/m2)Half-life* (h)1021279-377413-61516.3-24.22.72-3.7610215228-409377-76613.1-26.55.22-6.772021546-767992-156012.8-20.19.02-9.7020215499-889927-189010.6-21.68.11-8.9640211300-25302130-71305.61-18.84.50-13.6402151690-24202290-72705.50-17.55.64-20.580212090-25005210-655012.2-15.412.4-13.0*Denotes range from 2 patients.