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Phase I and pharmacokinetic study of cisplatin and troxacitabine administered intravenously every 28 days in patients with advanced solid malignancies

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Abstract

Purpose

To assess the feasibility of administering troxacitabine, an l-nucleoside analog that is not a substrate for deoxycytidine deaminase, in combination with cisplatin, to identify pharmacokinetic interactions, and to seek preliminary evidence of antitumor activity.

Methods

Patients with advanced solid malignancies were treated with cisplatin intravenously over an hour followed by troxacitabine intravenously over 30 min on day 1 every 28 days at the following cisplatin/troxacitabine (mg/m2) dose levels 50/4.8, 75/4.8, 50/6.4, 75/6.4, and 75/8.0. Plasma and urine sampling were performed to characterize the pharmacokinetic parameters of troxacitabine in combination with cisplatin.

Results

Thirty-one patients received 77 courses of cisplatin/troxacitabine at five dose levels. Grade 4 neutropenia lasting more than 5 days and/or grade 4 thrombocytopenia were consistently experienced by minimally pretreated (MP) and heavily pretreated (HP) patients at doses exceeding 75/6.4 and 50/4.8 mg/m2, respectively. Mean values for the volume of distribution at steady state and clearance of troxacitabine were 196–396 L and 7.2–9.8 L/h, respectively. A patient with metastatic non-small cell lung cancer experienced a 42% reduction in extent of disease for 6 months.

Conclusions

The combination of cisplatin and troxacitabine produces dose-limiting myelosuppression at lower doses of troxacitabine than single agent doses. The recommended phase II doses of cisplatin/troxacitabine are 75/6.4 and 50/4.8 mg/m2, every 4 weeks, for MP and HP patients, respectively. The addition of cisplatin did not substantially alter the pharmacokinetic behavior of troxacitabine.

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Author information

Author notes

  1. Chia-Chi Lin

    Present address: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

  2. Muralidhar Beeram

    Present address: South Texas Oncology and Hematology, San Antonio, TX, USA

  3. Eric K. Rowinsky

    Present address: ImClone Systems Inc, Branchburg, NJ, USA

  4. Chris H. Takimoto

    Present address: OrthoBiotech Oncology Research and Development, Radnor, PA, USA

  5. Chee M. Ng

    Present address: Bristol-Myers Squibb, Inc, Princeton, NJ, USA

  6. Charles E. Geyer Jr

    Present address: Allegheny General Hospital, Pittsburgh, PA, USA

  7. Louis J. Denis

    Present address: Pfizer Oncology, New London, CT, USA

  8. Sun-Young Rha

    Present address: College of Medicine, Yonsei University, Seoul, South Korea

  9. Jacques Jolivet

    Present address: Aegera Therapeutics Inc, Montreal, QC, Canada

  10. Johann S. De Bono

    Present address: Royal Marsden Hospital and Institute of Cancer Research, Sutton, UK

  11. Desiree Hao

    Present address: Tom Baker Cancer Center, Calgary, AB, Canada

  12. Anthony W. Tolcher & Amita Patnaik

    Present address: South Texas Accelerated Research Therapeutics, 4383 Medical Dr, 4th Floor, San Antonio, TX, 78229, USA

Authors and Affiliations

  1. The Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA

    Chia-Chi Lin, Muralidhar Beeram, Eric K. Rowinsky, Chris H. Takimoto, Chee M. Ng, Louis J. Denis, Johann S. De Bono, Desiree Hao, Anthony W. Tolcher, Sun-Young Rha & Amita Patnaik

  2. University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Muralidhar Beeram, Eric K. Rowinsky, Chris H. Takimoto, Chee M. Ng, Anthony W. Tolcher & Amita Patnaik

  3. Joe Arrington Cancer Research and Treatment Center, Lubbock, TX, USA

    Charles E. Geyer Jr

  4. Shire Pharmaceuticals, Wayne, PA, USA

    Jacques Jolivet

Authors
  1. Chia-Chi Lin
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  2. Muralidhar Beeram
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Corresponding author

Correspondence to Amita Patnaik.

Additional information

C.-C. Lin and M. Beeram contributed equally to this work.

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Lin, CC., Beeram, M., Rowinsky, E.K. et al. Phase I and pharmacokinetic study of cisplatin and troxacitabine administered intravenously every 28 days in patients with advanced solid malignancies. Cancer Chemother Pharmacol 65, 167–175 (2009). https://doi.org/10.1007/s00280-009-1020-y

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  • DOI: https://doi.org/10.1007/s00280-009-1020-y

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