Investigational New Drugs

, Volume 30, Issue 6, pp 2303–2317

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

Authors

  • Michael Millward
    • Sir Charles Gairdner HospitalUniversity of Western Australia
  • Timothy Price
    • The Queen Elizabeth Hospital
  • Amanda Townsend
    • The Queen Elizabeth Hospital
  • Christopher Sweeney
    • Royal Adelaide Hospital
  • Andrew Spencer
    • The Alfred Hospital
  • Shawgi Sukumaran
    • The Queen Elizabeth Hospital
  • Angie Longenecker
    • Nereus Pharmaceuticals, Inc
  • Lonnie Lee
    • Nereus Pharmaceuticals, Inc
  • Ana Lay
    • Nereus Pharmaceuticals, Inc
  • Girish Sharma
    • Department of Medical University of South Carolina
  • Robert M. Gemmill
    • Department of Medical University of South Carolina
  • Harry A. Drabkin
    • Department of Medical University of South Carolina
  • G. Kenneth Lloyd
    • Nereus Pharmaceuticals, Inc
  • Saskia T. C. Neuteboom
    • Nereus Pharmaceuticals, Inc
  • David J. McConkey
    • MD Anderson Cancer Center
  • Michael A. Palladino
    • Nereus Pharmaceuticals, Inc
    • Nereus Pharmaceuticals, Inc
PHASE I STUDIES

DOI: 10.1007/s10637-011-9766-6

Cite this article as:
Millward, M., Price, T., Townsend, A. et al. Invest New Drugs (2012) 30: 2303. doi:10.1007/s10637-011-9766-6

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.

Keywords

ProteasomeMarizomibNPI-0052MelanomaLung cancerPancreatic cancer

Copyright information

© Springer Science+Business Media, LLC 2011