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Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

  • Clinical Trial Report
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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To determine the maximum tolerated dose (MTD) of trabectedin plus gemcitabine administered on a weekly schedule in patients with advanced solid tumors.

Methods

Patients with ECOG performance status 0–1 and adequate organ function were enrolled. On days 1, 8, and 15 of a 28-day cycle, patients received gemcitabine (starting dose, 800 mg/m2) followed by trabectedin (starting dose, 0.3 mg/m2). Strict liver function test treatment criteria were employed to avoid hepatic toxicity seen in previous trabectedin studies. Plasma samples were collected during cycles 1 and 2 for pharmacokinetic analyses.

Results

Fifteen patients received ≥1 dose, with a median of two treatment cycles (range 1–10). The most common drug-related toxicity was hepatic. Dose reductions were required for trabectedin in four (27%) patients and gemcitabine in six (40%) patients. Cycle delays/dose holds were required in 11 (73%) patients and doses above trabectedin 0.4 mg/m2 and gemcitabine 1,000 mg/m2, which is the recommended phase II dose, were not feasible. Seven patients maintained stable disease after two cycles. Gemcitabine and trabectedin pharmacokinetics were not altered substantially with concomitant administration.

Conclusions

Given the lack of pharmacokinetic interaction and potential efficacy of trabectedin and gemcitabine combination therapy, further study is warranted with alternate schedules.

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Acknowledgments

This clinical trial (Study ET-743-USA-7) was sponsored by Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ and PharmaMar S.A.U., Madrid, Spain. We would like to thank Tom Verhaeghe for overseeing the bioanalysis of trabectedin and gemcitabine. We would also like to thank Lisa Shannon, PharmD, of Scientific Connexions, for providing medical co-writing and editing services.

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Authors and Affiliations

  1. University of Colorado Cancer Center, P.O. Box 6511, Mail Stop 8117, Aurora, CO, 80045, USA

    Wells A. Messersmith

  2. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    Antonio Jimeno, David Ettinger, Dan Laheru, Julie Brahmer, Dina Lansey, Yasmin Khan, Ross C. Donehower & Manuel Hidalgo

  3. Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, USA

    Yusri Elsayed & Peter Zannikos

Authors
  1. Wells A. Messersmith
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  2. Antonio Jimeno
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  3. David Ettinger
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Correspondence to Wells A. Messersmith.

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Messersmith, W.A., Jimeno, A., Ettinger, D. et al. Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors. Cancer Chemother Pharmacol 63, 181–188 (2008). https://doi.org/10.1007/s00280-008-0733-7

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  • DOI: https://doi.org/10.1007/s00280-008-0733-7

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