A phase I dose-escalation, pharmacokinetic (PK), and pharmacodynamic (PD) evaluation of intravenous LY2090314 a GSK3 inhibitor administered in combination with pemetrexed and carboplatin.

Developmental Therapeutics - Experimental Therapeutics
Session Type and Session Title: 
Poster Discussion Session, Developmental Therapeutics - Experimental Therapeutics
Abstract Number: 


J Clin Oncol 29: 2011 (suppl; abstr 3030)
L. H. Brail, J. E. Gray, H. Burris, G. R. Simon, J. Cooksey, S. F. Jones, D. Farrington, T. Lam, K. Jackson, K. Chow, J. T. Brandt, J. R. Infante; Eli Lilly & Co., Indianapolis, IN; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Sarah Cannon Research Institute, Nashville, TN; Medical University of South Carolina, Charleston, SC; Moffitt Cancer Center, Tampa, FL; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; i3 Statprobe, Maidenhead, United Kingdom; The Sarah Cannon Cancer Center, Nashville, TN

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Abstract Disclosures


Background: LY2090314 (LY) is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) which plays an important role in many pathways, including initiation of protein synthesis, cell proliferation, cell differentiation, and apoptosis. Pre-clinically LY stabilizes β-catenin and enhances the efficacy of platinum based regimens. With limited predicted efficacy as monotherapy, this first in human study was conducted in combination with pemetrexed + carboplatin (PC). Methods: In advanced solid tumor patients (pts), LY was dosed intravenously as a lead-in 7 days prior to the first administration of the triplet combination with PC (500 mg/m2 and AUC 5 or 6, respectively). PBMCs were collected to determine effects on β-catenin. The objectives of this first in human study were to investigate the safety, PK, and PD of LY in pts with advanced solid tumors in combination with PC. Results: Thus far, 40 pts were treated with LY at 10 mg (n=10), 20 mg (n=5), 40 mg (n=11), 60 mg (n=5), 80 mg (n=5), and 120 mg (n=4). The maximum tolerated dose (MTD) is LY 40 mg in combination with PC (500 mg/m2 and AUC 6). DLTs were visual disturbance, back pain, and chest pain at 120 mg and chest pain at 80 mg. At these doses above the MTD, this transient non-cardiac chest pain was frequently reported after a single dose of LY. Zantac prior to infusion seemed to help but did not eliminate this adverse effect. Other frequently (≥ 10%) reported toxicities attributed to LY were nausea (18.9%), fatigue (16.2%), and vomiting (13.5%). Preliminary PK analysis results show that exposure increased as dose increased over the dose range studied with a short terminal elimination half-life calculated in the majority of patients. Exposures at the MTD resulted in a significant, transient up regulation of β-catenin in PBMCs. 16 pts received ≥ 4 cycles of therapy and 7 patients received ≥ 6 cycles of therapy. Conclusions: LY at 40 mg can be safely combined with PC. At these exposures, β-catenin is up-regulated and the adverse event profile is acceptable. The large number of pretreated patients that experienced stable disease suggests continued evaluation of LY in NSCLC may be warranted.