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Phase I/II study with ruthenium compound NAMI-A and gemcitabine in patients with non-small cell lung cancer after first line therapy

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Summary

Background This phase I/II study determined the maximal tolerable dose, dose limiting toxicities, antitumor activity, the pharmacokinetics and pharmacodynamics of ruthenium compound NAMI-A in combination with gemcitabine in Non-Small Cell Lung Cancer patients after first line treatment. Methods Initial dose escalation of NAMI-A was performed in a 28 day cycle: NAMI-A as a 3 h infusion through a port-a-cath at a starting dose of 300 mg/m2 at day 1, 8 and 15, in combination with gemcitabine 1,000 mg/m2 at days 2, 9 and 16. Subsequently, dose escalation of NAMI-A in a 21 day schedule was explored. At the maximal tolerable dose level of this schedule an expansion group was enrolled of which 15 patients were evaluable for response. Results Due to frequent neutropenic dose interruptions in the third week, the 28 day schedule was amended into a 21 day schedule. The maximal tolerable dose was 300 and 450 mg/m2 of NAMI-A (21 day schedule). Main adverse events consisted of neutropenia, anemia, elevated liver enzymes, transient creatinine elevation, nausea, vomiting, constipation, diarrhea, fatigue, and renal toxicity. Conclusion NAMI-A administered in combination with gemcitabine is only moderately tolerated and less active in NSCLC patients after first line treatment than gemcitabine alone.

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Acknowledgments

We would like to thank Fondazione CRTrieste and Commissariato del Governo – Fondo Trieste for providing financial support. We are greatly indebted to Ms Lidwina Wever and Dr. O. Dalesio of the trial office of The Netherlands Cancer Institute. Finally, we are thankful for the support of G. Dastoli MD, Eudax SrL, Pavia Italy and R. Bianchi, Aquisitio S.p.A., Milan Italy.

Conflict of interest

Suzanne Leijen no conflict of interest

SjaakA. Burgers, no conflict of interest

Paul Baas, no conflict of interest

Dick Pluim, no conflict of interest

Matthijs Tibben, no conflict of interest

Erik van Werkhoven no conflict of interest

Enzo Alessio, no conflict of interest

Gianni Sava, researcher involved in discovery of NAMI-A

Jos H. Beijnen, no conflict of interest

Jan H.M. Schellens no conflict of interest

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Authors and Affiliations

  1. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Suzanne Leijen, Dick Pluim & Jan H. M. Schellens

  2. Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Sjaak A. Burgers & Paul Baas

  3. Department of Thoracic Oncology, Amsterdam Medical Center, Amsterdam, The Netherlands

    Paul Baas

  4. Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands

    Matthijs Tibben & Jos H. Beijnen

  5. Biometrics Department, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Erik van Werkhoven

  6. University of Trieste, Department of Chemical and Pharmaceutical Sciences, Trieste, Italy

    Enzo Alessio

  7. Callerio Foundation Onlus, Via A. Fleming 22-31, 34127, Trieste, Italy

    Gianni Sava

  8. Department of Life Sciences, University of Trieste, Trieste, Italy

    Gianni Sava

  9. Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Jan H. M. Schellens

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  1. Suzanne Leijen
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Leijen, S., Burgers, S.A., Baas, P. et al. Phase I/II study with ruthenium compound NAMI-A and gemcitabine in patients with non-small cell lung cancer after first line therapy. Invest New Drugs 33, 201–214 (2015). https://doi.org/10.1007/s10637-014-0179-1

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