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Exploratory study of carboplatin plus the copper-lowering agent trientine in patients with advanced malignancies

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Summary

Purpose Preclinical data showed that trientine, a copper-lowering agent, re-sensitized cancer cells to carboplatin through enhanced human copper transporter 1 (hCtr1) -mediated platinum uptake. Experimental Design We studied carboplatin and trientine in patients (n = 55; 45 who had failed platinum) with advanced malignancies (Phase I, modified 3 + 3 design). Results The most common cancers were head and neck (n = 13), non-small cell lung (n = 10) and epithelial ovarian (n = 8). The median number of prior regimens was four. No dose-limiting toxicity or treatment-related deaths were observed at doses up to carboplatin AUC 6 given with trientine. Eight patients achieved stable disease (SD) ≥ 6 months (six platinum failures) and one patient with platinum-resistant ovarian cancer, partial response (PR) (total SD ≥ 6 months/PR = 9, 16.4 %). The mean nadir serum copper level in the nine patients with SD ≥ 6 months/PR was 0.55 μg/mL (95 % CI, 0.34–0.75) versus 1.22 μg/mL (95 % CI, 1.02–1.42) (p < 0.001) in 38 tested patients with progression. In patients who maintained their ceruloplasmin (major copper-carrying protein) levels at 5–15 mg/dL (n = 9), the median progression-free and overall survivals were 9.2 and 15.2 months versus 1.9 (p = 0.001) and 5.7 months (p = 0.033) in patients who did not (n = 38), respectively. Conclusions The combination of a copper-lowering agent with carboplatin was well tolerated and associated with antitumor activity, especially in patients in whom copper and/or ceruloplasmin levels were lowered. Further investigation of this strategy for reversing platinum resistance is warranted.

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Acknowledgments

The authors thank Thuan Nguyen and Jing Gong in the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center for coordinating this clinical trial, and Diane Hackett and Jill Delsigne in the Department of Scientific Publications at MD Anderson for editing the manuscript.

Conflicts of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Investigational Cancer Therapeutics, Unit 0455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Siqing Fu, Ming-Mo Hou, Jennifer Wheler, David Hong, Aung Naing, Apostolia Tsimberidou, Filip Janku, Ralph Zinner, Sarina Piha-Paul & Gerald Falchook

  2. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Macus Tien Kuo

  3. University of California San Diego, Moores Cancer Center, La Jolla, CA, USA

    Razelle Kurzrock

  4. Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan

    Ming-Mo Hou

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Fu, S., Hou, MM., Wheler, J. et al. Exploratory study of carboplatin plus the copper-lowering agent trientine in patients with advanced malignancies. Invest New Drugs 32, 465–472 (2014). https://doi.org/10.1007/s10637-013-0051-8

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  • DOI: https://doi.org/10.1007/s10637-013-0051-8

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