82310-102

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

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

3030

Citation: 
J Clin Oncol 29: 2011 (suppl; abstr 3030)
Author(s): 
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

Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract: 

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.