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A randomized phase II study of two doses of vorinostat in combination with 5-FU/LV in patients with refractory colorectal cancer

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Abstract

Background

Vorinostat is synergistic with 5-FU in vitro and in vivo models. A combination of these two agents was associated with clinical activity in 5-FU refractory colorectal cancer patients in a phase I clinical trial, therefore warranting the conduct of this prospective phase II study.

Patients and methods

Patients with refractory metastatic colorectal cancer were randomized in a two-stage design to receive vorinostat at 800 or 1,400 mg/day once a day × 3, every 2 weeks. 5-FU, preceded by leucovorin, was administered as a bolus followed by a 46-h infusion on days 2 and 3 of vorinostat. A pre-specified 2-month progression-free survival (PFS) rate of 27/43 patients per arm was needed to deem an arm interesting for further investigation.

Results

The high-dose vorinostat arm did not reach the needed efficacy endpoint at completion of the first stage, with only 8 out of 15 patients being alive and progression free at 2 months. The low-dose vorinostat arm proceeded to accrue 43 patients with a 2-month PFS rate of 53% (23 out 43), including one partial response. The median PFS and overall survival on the low-dose arm were 2.4 and 6.5 months, respectively. Both treatment arms were well tolerated. No differences were noted in the pharmacokinetics of vorinostat at the 800- or 1,400-mg dose-levels, suggesting bioavailability saturation.

Conclusions

While the addition of vorinostat to 5-FU resulted in 1 partial response and in some disease stabilizations, the limited activity does not warrant the unselected use of this combination in chemotherapy-refractory colorectal cancer.

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Acknowledgments

The authors would like to acknowledge the late Dr. Merrill Egorin. Dr. Egorin made major contributions to the earlier vorinostat plus 5-FU phase I clinical trial, which formed the basis for the conduct of this phase II study. Dr. Egorin developed the clinical assay for vorinostat and his laboratory performed all vorinostat pharmacokinetic measurements on this study. This study was supported by a research grant from Merck Sharp and Dohme Corp.

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Authors and Affiliations

  1. Department of Medicine, University of Michigan, Ann Arbor, MI, USA

    M. G. Fakih

  2. Department of Biostatistics, University at Buffalo, Buffalo, NY, USA

    A. Groman & G. Wilding

  3. Clinical Research Services, Roswell Park Cancer Institute, Buffalo, NY, USA

    J. McMahon

  4. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

    J. R. Muindi

  5. Division of Hematology and Oncology, Department of Medicine, University of Michigan Cancer Center, 1500 E Medical Drive, Ann Arbor, MI, 48109, USA

    M. G. Fakih

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  1. M. G. Fakih
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  2. A. Groman
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  3. J. McMahon
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  4. G. Wilding
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  5. J. R. Muindi
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Correspondence to M. G. Fakih.

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Fakih, M.G., Groman, A., McMahon, J. et al. A randomized phase II study of two doses of vorinostat in combination with 5-FU/LV in patients with refractory colorectal cancer. Cancer Chemother Pharmacol 69, 743–751 (2012). https://doi.org/10.1007/s00280-011-1762-1

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  • DOI: https://doi.org/10.1007/s00280-011-1762-1

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