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Phase I study of anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers

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Abstract

Purpose

Anti-angiogenic agents combined with histone deacetylase inhibitors act synergistically in vitro and in vivo. We conducted a phase I study of the combination of the anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers.

Methods

Bevacizumab was administered at escalating dosages of 2.5–11 mg/kg on days 1 and 15, and oral valproic acid at dosages of 5.3–10 mg/kg on days 1–28 every 28 days to determine the maximum tolerated dose. Pharmacodynamic parameters were assessed in peripheral blood mononuclear cells (histone H3 acetylation) and serum (valproic acid levels).

Results

Fifty-seven patients were enrolled. Dose-limiting toxicities were grade 3 altered mental status (n = 2), related to valproic acid. Bevacizumab 11 mg/kg given on days 1 and 15 and valproic acid 5.3 mg/kg daily were the recommended phase II dosages. Stable disease (SD) ≥6 months was reported in 4/57 (7 %) of patients, including two patients with colorectal cancer who had progressed previously on bevacizumab. Of the 39 patients evaluated for histone acetylation, 2 of 3 (67 %) patients with SD ≥6 months showed histone acetylation, while 8 of 36 (22 %) without SD ≥6 months demonstrated histone acetylation (p = 0.16). Patients with any grade of hypertension, compared to others, had a prolonged median survival (11.1 vs. 5.8 months; p = 0.012).

Conclusions

The combination of bevacizumab 11 mg/kg and valproic acid 5.3 mg/kg is safe in patients with advanced malignancies, with activity in colorectal, gastroesophageal junction, and prostate cancer. Patients with hypertension had improved overall survival.

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Acknowledgements

Supported by Grant Number RR024148 from the National Center for Research Resources, a component of the NIH Roadmap for Medical Research. (http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp).

Conflict of interest

FJ has served as a consultant/advisor for Trovagene and has funding from Novartis, Roche, Biocartis, Trovagene and Transgenomi. All authors have not conflicts to disclose.

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Authors and Affiliations

  1. Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jennifer J. Wheler, Filip Janku, Gerald S. Falchook, Tiffiny L. Jackson, Siqing Fu, Aung Naing, Apostalia M. Tsimberidou, David S. Hong, Sarina A. Piha-Paul & Johnique T. Atkins

  2. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Stacy L. Moulder

  3. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Hui Yang & Guillermo Garcia-Manero

  4. Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA

    Razelle Kurzrock

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  1. Jennifer J. Wheler
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  2. Filip Janku
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  3. Gerald S. Falchook
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Corresponding author

Correspondence to Jennifer J. Wheler.

Additional information

Jennifer J. Wheler and Filip Janku have contributed equally to this work.

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Wheler, J.J., Janku, F., Falchook, G.S. et al. Phase I study of anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers. Cancer Chemother Pharmacol 73, 495–501 (2014). https://doi.org/10.1007/s00280-014-2384-1

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  • DOI: https://doi.org/10.1007/s00280-014-2384-1

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