Volume 13 Supplement 1

18th Scientific Symposium of the Austrian Pharmacological Society (APHAR)

Open Access

NKP-1339, a first-in-class anticancer drug showing mild side effects and activity in patients suffering from advanced refractory cancer

  • Robert Trondl1, 3,
  • Petra Heffeter2, 3,
  • Michael A Jakupec1, 3,
  • Walter Berger2, 3 and
  • Bernhard K Keppler1, 3Email author
BMC Pharmacology and Toxicology201213(Suppl 1):A82

DOI: 10.1186/2050-6511-13-S1-A82

Published: 17 September 2012

Background

NKP-1339 is one of the most promising investigational non-platinum metal drugs in clinical development against solid malignancies. Recently, NKP-1339 was evaluated in a clinical phase I trial regarding its safety, tolerability, maximum tolerated dose, pharmacokinetics, and pharmacodynamics. The high tumor targeting potential of NKP-1339 is probably based on delivery to tumor sites by serum proteins such as albumin and transferrin as well as on the activation of the compound in the reductive tumor milieu. The reduction of ruthenium(III) to ruthenium(II) is favoured under hypoxic condition (frequently occurring in solid tumors) and is followed by severe disruption of the cellular redox balance and induction of apoptosis via the mitochondrial pathway.

Methods

In the recently completed clinical phase I trial 34 patients with advanced solid tumors were enrolled for dose escalation [1]. NKP-1339 was infused on day 1, 8, and 15 of 28-day cycles. To gain further insight in the mechanism of action, protein expression studies in cancer cells exposed in vitro were performed.

Results

The maximum tolerated dose of NKP-1339 was determined at 625 mg/m2, and the most common drug-related side effects were nausea, vomiting, and fatigue. A long-lasting partial response was observed in 1 patient with a gastro-intestinal neuroendocrine tumor (NET), and 7 patients having experienced stable disease, including NET (2), non-small-cell lung cancer (2), colorectal cancer (1), sarcoma (1), and cancer of unknown primary (1). Moreover, NKP-1339 was found to down-regulate in cancer cell lines the ER chaperon GRP78, a key regulator of the unfolded protein response, which is associated with intrinsic and chemotherapy-induced resistance.

Conclusions

The very limited side effects of NKP-1339 and the activity observed in a variety of tumors so far are very promising. Further clinical phase I drug combination studies and single agent phase II studies are planned.

Authors’ Affiliations

(1)
Institute of Inorganic Chemistry, University of Vienna
(2)
Institute of Cancer Research, Medical University of Vienna
(3)
Research Platform Translational Cancer Therapy Research, University of Vienna

References

  1. Thompson D, Weiss GJ, Jones SF, Burris HA, Ramanathan K, Infante JR, Bendell JC, Ogden A, Von Hoff DD: NKP-1339: Maximum tolerated dose defined for first-in-human GRP78 targeted agent. ASCO Annual Meeting Abstract. 2012, : abstract ID 3033Google Scholar

Copyright

© Trondl et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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