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Cancer Chemotherapy and Pharmacology

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01-03-2018 | Original Article

Phase 1 summary of plasma concentration–QTc analysis for idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors and AML

Authors: Steven Blotner, Lin-Chi Chen, Cristiano Ferlini, Jianguo Zhi

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2018

Abstract

Purpose

Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval.

Method

Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from baseline (Δ) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed effect model. Categorical analysis was also performed.

Results

A total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma concentration. There was no apparent increase of QTcF or ΔQTcF in a wide idasanutlin plasma concentration range, even at concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical analysis did not detect a potential signal of QT prolongation.

Conclusion

The concentration–QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted concentration range currently in consideration for clinical development.

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RO5503781 Evaluation of actions on K+ currents through recombinant hERG channels expressed in CHO cells. Un-published

RO5503781 A 2-cycle oral gavage toxicity and toxicokinetic study with RO5503781 in cynomolgus monkeys with a 32-day recovery phase. Un-published

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Title: Phase 1 summary of plasma concentration–QTc analysis for idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors and AML
Authors: Steven Blotner
Lin-Chi Chen
Cristiano Ferlini
Jianguo Zhi
Publication date: 01-03-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-018-3534-7

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Abstract

Purpose

Method

Results

Conclusion

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