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Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination

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Summary

Purpose Combining proteasome and histone deacetylase (HDAC) inhibition has been seen to provide synergistic anti-tumor activity, with complementary effects on a number of signaling pathways. The novel bi-cyclic structure of marizomib with its unique proteasome inhibition, toxicology and efficacy profiles, suggested utility in combining it with an HDAC inhibitor such as vorinostat. Thus, in this study in vitro studies assessed the potential utility of combining marizomib and vorinostat, followed by a clinical trial with the objectives of assessing the recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), safety and preliminary anti-tumor activity of the combination in patients. Experimental Design Combinations of marizomib and vorinostat were assessed in vitro. Subsequently, in a Phase 1 clinical trial patients with melanoma, pancreatic carcinoma or Non-small Cell Lung Cancer (NSCLC) were given escalating doses of weekly marizomib in combination with vorinostat 300 mg daily for 16 days in 28 day cycles. In addition to standard safety studies, proteasome inhibition and pharmacokinetics were assayed. Results Marked synergy of marizomib and vorinostat was seen in tumor cell lines derived from patients with NSCLC, melanoma and pancreatic carcinoma. In the clinical trial, 22 patients were enrolled. Increased toxicity was not seen with the combination. Co-administration did not appear to affect the PK or PD of either drug in comparison to historical data. Although no responses were demonstrated using RECIST criteria, 61% of evaluable patients demonstrated stable disease with 39% having decreases in tumor measurements. Conclusions Treatment of multiple tumor cell lines with marizomib and vorinostat resulted in a highly synergistic antitumor activity. The combination of full dose marizomib with vorinostat is tolerable in patients with safety findings consistent with either drug alone.

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Acknowledgement

Presented in part at:

21st EORTC-NCI-AACR Symposium on Molecular targets and Cancer Therapeutics, 2009

We also acknowledge others instrumental in the preparation of these data and manuscript: Desmond McDonnell and Lada Keenan

Funding

This study was funded by Nereus Pharmaceuticals, Inc.

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Authors and Affiliations

  1. Sir Charles Gairdner Hospital, University of Western Australia, Perth, Australia

    Michael Millward

  2. The Queen Elizabeth Hospital, Adelaide, Australia

    Timothy Price, Amanda Townsend & Shawgi Sukumaran

  3. Royal Adelaide Hospital, Adelaide, Australia

    Christopher Sweeney

  4. The Alfred Hospital, Melbourne, Australia

    Andrew Spencer

  5. MD Anderson Cancer Center, Houston, TX, USA

    David J. McConkey

  6. Department of Medical University of South Carolina, Charleston, SC, USA

    Girish Sharma, Robert M. Gemmill & Harry A. Drabkin

  7. Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA, 92121, USA

    Angie Longenecker, Lonnie Lee, Ana Lay, G. Kenneth Lloyd, Saskia T. C. Neuteboom, Michael A. Palladino & Matthew A. Spear

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  1. Michael Millward
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  2. Timothy Price
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  11. Robert M. Gemmill
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  13. G. Kenneth Lloyd
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  14. Saskia T. C. Neuteboom
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  15. David J. McConkey
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  16. Michael A. Palladino
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Corresponding author

Correspondence to Matthew A. Spear.

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Millward, M., Price, T., Townsend, A. et al. Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination. Invest New Drugs 30, 2303–2317 (2012). https://doi.org/10.1007/s10637-011-9766-6

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  • DOI: https://doi.org/10.1007/s10637-011-9766-6

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