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A Phase I dose-escalation study of LCL161, an oral IAP inhibitor, in patients with advanced solid tumors

infante, Jeffrey R and Dees, E Claire and Olszanski, Anthony J and Dhuria, Shyeilla and Sen, Suman and Cameron, John and Cohen, Roger B (2012) A Phase I dose-escalation study of LCL161, an oral IAP inhibitor, in patients with advanced solid tumors. Journal of Clinical Oncology.

Official URL: http://jco.ascopubs.org/

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.

Patients and Methods
LCL161 was administered orally once-weekly on a 21-day cycle to adult patients with advanced solid tumors. An adaptive Bayesian Logistic Regression Model with overdose control guided dose escalation. A second part of the study assessed the relative bioavailability of tablet versus solution formulation.

Results
Fifty-three patients received at least one dose of LCL161 (range 10–3000 mg). LCL161 was well tolerated at doses up to 1800 mg, with cytokine release syndrome (CRS) the only dose-limiting toxicity (3/53; 6%) and most common grade 3/4 event (5/53; 9%). Although the MTD was not reached, a dose of 1800 mg was selected for further study given the occurrence of CRS at higher doses and evidence of pharmacodynamic activity at lower doses. LCL161 was rapidly absorbed. The tablet formulation of LCL161 was better tolerated than the solution with similar exposure, 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 consistent with LCL161’s mechanism of action.

Conclusion
Single-agent LCL161 administered in tablet formulation at a dose of 1800 mg once-weekly was well tolerated, with significant pharmacodynamic activity, warranting further investigation in future studies.

Item Type: Article
Keywords: IAP antagonist, TNFa, SMAC mimetic, cancer
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/8450

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