Phase I study of the heat shock protein 90 Hsp90

Authors: Khanh Do Giovanna Speranza LunChing Chang Eric C Polley Rachel Bishop Weimin Zhu Jane B Trepel Sunmin Lee MinJung Lee Robert J Kinders Larry Phillips Jerry Collins John Lyons Woondong Jeong Ramya Antony Alice P Chen Len Neckers James H Doroshow Shivaani Kummar

Publish Date: 2015/06/18

Volume: 33, Issue: 4, Pages: 921-930

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Abstract

Inhibition of heat shock 90 Hsp90 molecular chaperones allows targeting of multiple proteins involved in tumorigenesis We investigated the safety recommended phase 2 dose RP2D and pharmacokinetic and pharmacodynamic profile of onalespib AT13387 a potent synthetic Hsp90 inhibitor administered on days 1 2 8 9 15 and 16 of 28 day cycles QDx2/week in a phase I trial This study followed an accelerated titration design with a starting dose of 20 mg/m2/dose and a standard 3 + 3 dose escalation design for dose level 4 120 mg/m2/dose and above Additional patients were enrolled at the RP2D with mandatory paired tumor biopsies to assess modulation of 210 client proteins using reverse phase protein array analysis Thirtyone patients were treated RP2D was established at 160 mg/m2/dose on the QDx2/week schedule Common toxicities were gastrointestinal hepatic and hematologic Pharmacokinetic profile was linear and plasma levels increased proportionally with dose T½ ~8 h No responses were observed eight patients had stable disease for 2 cycles with one patient remaining on study for 6 cycles Target engagement was demonstrated by transcriptional upregulation of Hsp70 and Hsp27 in PBMCs Statistically significant modulation of client proteins was not achieved in the 9 paired tumor biopsies evaluated however hierarchical clustering revealed two subgroups of patients with differential patterns of protein expression Further combination studies are needed in order to target prospective driver oncoproteinsThe authors thank Dr Andrea Regier Voth Leidos Biomedical Research Inc for medical writing support in the preparation of this manuscript and Ms Tracy Webb Leidos Biomedical Research Inc for pharmacokinetic technical assistance This project has been funded in whole or in part with federal funds from the National Cancer Institute National Institutes of Health under Contract No HHSN261200800001E and Core grant CA16672 The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names commercial products or organizations imply endorsement by the US Government John Lyons is an employee of Astex Pharmaceuticals no potential conflicts of interest were disclosed by the other authorsAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards

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