Jeffrey R Infante1, E Claire Dees1, Anthony J Olszanski1, Shyeilla V Dhuria1, Suman Sen1, Scott Cameron1, Roger B Cohen2. 1. Jeffrey R. Infante, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; E. Claire Dees, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Antony J. Olszanski, Fox Chase Cancer Center; Roger B. Cohen, Perelman School of Medicine, Philadelphia, PA; Shyeilla V. Dhuria and Suman Sen, Novartis Pharmaceuticals Corp, East Hanover, NJ; and Scott Cameron, Novartis Institutes for Biomedical Research, Cambridge, MA. 2. Jeffrey R. Infante, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; E. Claire Dees, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Antony J. Olszanski, Fox Chase Cancer Center; Roger B. Cohen, Perelman School of Medicine, Philadelphia, PA; Shyeilla V. Dhuria and Suman Sen, Novartis Pharmaceuticals Corp, East Hanover, NJ; and Scott Cameron, Novartis Institutes for Biomedical Research, Cambridge, MA. roger.cohen@uphs.upenn.edu.
Abstract
PURPOSE: LCL161 antagonizes the function of inhibitor of apoptosis proteins (IAPs), thereby promoting cancer cell death. This first-in-human dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of LCL161 in patients with advanced solid tumors. A second part of the study assessed the relative bioavailability of a tablet versus solution formulation. PATIENTS AND METHODS: LCL161 was administered orally, once weekly, on a 21-day cycle to adult patients with advanced solid tumors by using an adaptive Bayesian logistic regression model with overdose control-guided dose escalation. RESULTS: Fifty-three patients received at least one dose of LCL161 (dose range, 10 to 3,000 mg). LCL161 was well tolerated at doses up to 1,800 mg. Cytokine release syndrome (CRS) was the only dose-limiting toxicity (in three [6%] of 53 patients) and was the most common grades 3 to 4 event (in five [9%] of 53 patients). Vomiting, nausea, asthenia/fatigue, and anorexia were common but not severe. Although the MTD was not formally determined, an 1,800-mg dose was selected in compliance with the protocol for additional study, given the dose-limiting CRS at higher doses and pharmacodynamic activity at lower doses. LCL161 was rapidly absorbed, and exposure was generally increased with dose. The tablet formulation of LCL161 was better tolerated than the solution; tablet and solution formulations had similar exposures, and the solution was discontinued. No patient had an objective response. LCL161 induced degradation of cellular IAP1 protein in the blood, skin, and tumor and increased circulating cytokine levels. CONCLUSION: The 1,800-mg dose of LCL161, administered as a single agent once weekly, in tablet formulation is the recommended dose for additional study. This combined dose and formulation was well tolerated and had significant pharmacodynamic activity, which warrants additional investigation.
PURPOSE:LCL161 antagonizes the function of inhibitor of apoptosis proteins (IAPs), thereby promoting cancer cell death. This first-in-human dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of LCL161 in patients with advanced solid tumors. A second part of the study assessed the relative bioavailability of a tablet versus solution formulation. PATIENTS AND METHODS: LCL161 was administered orally, once weekly, on a 21-day cycle to adult patients with advanced solid tumors by using an adaptive Bayesian logistic regression model with overdose control-guided dose escalation. RESULTS: Fifty-three patients received at least one dose of LCL161 (dose range, 10 to 3,000 mg). LCL161 was well tolerated at doses up to 1,800 mg. Cytokine release syndrome (CRS) was the only dose-limiting toxicity (in three [6%] of 53 patients) and was the most common grades 3 to 4 event (in five [9%] of 53 patients). Vomiting, nausea, asthenia/fatigue, and anorexia were common but not severe. Although the MTD was not formally determined, an 1,800-mg dose was selected in compliance with the protocol for additional study, given the dose-limiting CRS at higher doses and pharmacodynamic activity at lower doses. LCL161 was rapidly absorbed, and exposure was generally increased with dose. The tablet formulation of LCL161 was better tolerated than the solution; tablet and solution formulations had similar exposures, and the solution was discontinued. No patient had an objective response. LCL161 induced degradation of cellular IAP1 protein in the blood, skin, and tumor and increased circulating cytokine levels. CONCLUSION: The 1,800-mg dose of LCL161, administered as a single agent once weekly, in tablet formulation is the recommended dose for additional study. This combined dose and formulation was well tolerated and had significant pharmacodynamic activity, which warrants additional investigation.
Authors: Roy Xiao; Clint T Allen; Linda Tran; Priya Patel; So-Jin Park; Zhong Chen; Carter Van Waes; Nicole C Schmitt Journal: Oncoimmunology Date: 2018-08-01 Impact factor: 8.110
Authors: Roy Xiao; Yi An; Wenda Ye; Adeeb Derakhshan; Hui Cheng; Xinping Yang; Clint Allen; Zhong Chen; Nicole C Schmitt; Carter Van Waes Journal: Clin Cancer Res Date: 2019-07-02 Impact factor: 12.531
Authors: Marta Chesi; Noweeda N Mirza; Victoria M Garbitt; Meaghen E Sharik; Amylou C Dueck; Yan W Asmann; Ilseyar Akhmetzyanova; Heidi E Kosiorek; Arianna Calcinotto; Daniel L Riggs; Niamh Keane; Gregory J Ahmann; Kevin M Morrison; Rafael Fonseca; Martha Q Lacy; David Dingli; Shaji K Kumar; Sikander Ailawadhi; Angela Dispenzieri; Francis Buadi; Morie A Gertz; Craig B Reeder; Yi Lin; Asher A Chanan-Khan; A Keith Stewart; David Fooksman; P Leif Bergsagel Journal: Nat Med Date: 2016-11-14 Impact factor: 53.440