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Phase I study of the heat shock protein 90 (Hsp90) inhibitor onalespib (AT13387) administered on a daily for 2 consecutive days per week dosing schedule in patients with advanced solid tumors

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Summary

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. Thirty-one 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 oncoproteins.

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Acknowledgments

The 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 U.S. Government. John Lyons is an employee of Astex Pharmaceuticals; no potential conflicts of interest were disclosed by the other authors.

Ethical approval

All 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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Authors and Affiliations

  1. Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg 31, Rm 3A44, Bethesda, MD, 20892, USA

    Khanh Do, Giovanna Speranza, Lun-Ching Chang, Eric C. Polley, Larry Phillips, Jerry Collins, Woondong Jeong, Alice P. Chen, James H. Doroshow & Shivaani Kummar

  2. National Eye Institute, Bethesda, MD, USA

    Rachel Bishop

  3. Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA

    Weimin Zhu, Robert J. Kinders & Ramya Antony

  4. Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Jane B. Trepel, Sunmin Lee, Min-Jung Lee, Len Neckers & James H. Doroshow

  5. Astex Pharmaceuticals, Cambridge, UK

    John Lyons

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  1. Khanh Do
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  2. Giovanna Speranza
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  3. Lun-Ching Chang
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  11. Larry Phillips
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  14. Woondong Jeong
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  16. Alice P. Chen
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  18. James H. Doroshow
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  19. Shivaani Kummar
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Correspondence to Shivaani Kummar.

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Do, K., Speranza, G., Chang, LC. et al. Phase I study of the heat shock protein 90 (Hsp90) inhibitor onalespib (AT13387) administered on a daily for 2 consecutive days per week dosing schedule in patients with advanced solid tumors. Invest New Drugs 33, 921–930 (2015). https://doi.org/10.1007/s10637-015-0255-1

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  • DOI: https://doi.org/10.1007/s10637-015-0255-1

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