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A phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy

  • Clinical Trial Report
  • Published:
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Abstract

Purpose

We conducted a phase I/II clinical trial to determine the safety and feasibility of combining vorinostat with 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer (mCRC) and elevated intratumoral thymidylate synthase (TS).

Methods

Patients with mCRC who had failed all standard therapeutic options were eligible. Intratumoral TS mRNA expression and peripheral blood mononuclear cell (PBMC) histone acetylation were measured before and after 6 consecutive days of vorinostat treatment at 400 mg PO daily. 5-FU/LV were given on days 6 and 7 and repeated every 2 weeks, along with continuous daily vorinostat. Dose escalation occurred in cohorts of three to six patients.

Results

Ten patients were enrolled. Three dose levels were explored in the phase I portion of the study. Two dose-limiting toxicities (DLTs) were observed at the starting dose level, which resulted in dose de-escalation to levels −1 and −2. Given the occurrence of two DLTs at each of the dose levels, we were unable to establish a maximum tolerated dose (MTD). Two patients achieved significant disease stabilization for 4 and 6 months. Grade 3 and 4 toxicities included fatigue, thrombocytopenia and mucositis. Intratumoral TS downregulation ≥50% was observed in one patient only. Acetylation of histone 3 was observed in PBMCs following vorinostat treatment.

Conclusions

The study failed to establish a MTD and was terminated. The presence of PBMC histone acetylation indicates biological activity of vorinostat, however, consistent reductions in intratumoral TS mRNA were not observed. Alternate vorinostat dose-scheduling may alleviate the toxicity and achieve optimal TS downregulation.

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Fig. 1
Fig. 2

Abbreviations

CRC:

Colorectal cancer

HDACi:

Histone deacetylase inhibitor

TS:

Thymidylate synthase

5-FU:

5-Fluorouracil

LV:

Leucovorin

DLT:

Dose-limiting toxicity

MTD:

Maximum tolerated dose

PBMC:

Peripheral blood mononuclear cell

CBC:

Complete blood count

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Acknowledgments

This study was funded by Merck & Co; NIH grant 5 P30CA14089-27I, the V Foundation for Cancer Research and the Dhont Family Foundation.

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Authors and Affiliations

  1. Department of Pathology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA

    Peter M. Wilson, William Fazzone, Melissa J. LaBonte, Margaret Kornacki & Robert D. Ladner

  2. Division of Medical Oncology, Sharon A. Carpenter Laboratory, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Room 5410, 1441 Eastlake Avenue, Los Angeles, CA, 90089, USA

    Anthony El-Khoueiry, Syma Iqbal, Sarah Cole & Heinz-Josef Lenz

  3. Biostatistics Core, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA

    Susan Groshen & Dongyun Yang

  4. Response Genetics, Inc., Los Angeles, CA, 90033, USA

    Kathy D. Danenberg

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  1. Peter M. Wilson
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  2. Anthony El-Khoueiry
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  9. Sarah Cole
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Corresponding author

Correspondence to Heinz-Josef Lenz.

Additional information

Peter M. Wilson and Anthony El-Khoueiry contributed equally in the preparation of this manuscript.

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Wilson, P.M., El-Khoueiry, A., Iqbal, S. et al. A phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy. Cancer Chemother Pharmacol 65, 979–988 (2010). https://doi.org/10.1007/s00280-009-1236-x

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  • DOI: https://doi.org/10.1007/s00280-009-1236-x

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