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A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells

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Summary

Background: We tested the hypothesis that 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®) may enhance response to re-treatment with gemcitabine by enhancing intracellular uptake of gemcitabine in a phase II study. Method: Patients who had prior exposure to gemcitabine as a first-line treatment of advanced non-small-cell lung cancer (NSCLC) were given weekly infusions of 3-AP and gemcitabine for 3 weeks followed by 1 week of rest, repeated every 28 days. Plasma and peripheral blood mononuclear cells (PBMCs) were collected to evaluate the effect of 3-AP on pharmacokinetics and intracellular uptake of gemcitabine. Result: Twelve patients were treated with a median of two treatment cycles without objective response, hence the study was terminated at interim analysis. Four patients had stable disease and the median time to progression was 3 months (95% confidence interval, CI: 1.7 to 9.1 months). Grade 3 toxicities included neutropenia (two patients), hypoxia (three patients) and dyspnea (one patient). Four patients developed reversible symptomatic methemoglobinemia during 3-AP infusion, with mild to moderately elevated methemoglobin levels that ranged from 7.8 to 17.6% of the total hemoglobin concentration. Limited pharmacokinetic data did not suggest any clinically relevant pharmacological influence of 3-AP on gemcitabine. Conclusion: 3-AP did not enhance clinical response to gemcitabine in this cohort of patients with prior exposure to gemcitabine for advanced NSCLC. Further development of 3-AP in lung cancer is challenged by its potential of causing methemoglobinemia and hypoxia, which could be problematic in patients with compromised pulmonary reserves.

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Acknowledgement

This study was sponsored by the National Cancer Institute, Bethesda, USA (NCI protocol #6256).

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Authors and Affiliations

  1. Department of Clinical Oncology at the Sir Y.K. Pao Center for Cancer, Hong Kong Cancer Institute, State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Ngan Shing Street, Shatin, New Territories, Hong Kong

    Brigette Ma, Kwok Chi Lam, Frankie Mo, Anthony T. C. Chan, Benny Zee & Tony Mok

  2. National University Hospital, Singapore, Singapore

    Boon Cher Goh, Ross Soo & Ling Zhi Wang

  3. National Cancer Center, Singapore, Singapore

    Eng Huat Tan & Swan Swan Leong

Authors
  1. Brigette Ma
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  2. Boon Cher Goh
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  3. Eng Huat Tan
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  4. Kwok Chi Lam
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  5. Ross Soo
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  6. Swan Swan Leong
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  7. Ling Zhi Wang
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  8. Frankie Mo
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  9. Anthony T. C. Chan
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  10. Benny Zee
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  11. Tony Mok
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Correspondence to Brigette Ma.

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Ma, B., Goh, B.C., Tan, E.H. et al. A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells. Invest New Drugs 26, 169–173 (2008). https://doi.org/10.1007/s10637-007-9085-0

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  • DOI: https://doi.org/10.1007/s10637-007-9085-0

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