Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 3, pp 495–501 | Cite as

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

  • Jennifer J. Wheler
  • Filip Janku
  • Gerald S. Falchook
  • Tiffiny L. Jackson
  • Siqing Fu
  • Aung Naing
  • Apostalia M. Tsimberidou
  • Stacy L. Moulder
  • David S. Hong
  • Hui Yang
  • Sarina A. Piha-Paul
  • Johnique T. Atkins
  • Guillermo Garcia-Manero
  • Razelle Kurzrock
Original Article



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.


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).


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).


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.


Bevacizumab Histone deacetylase Hypertension VEGF Valproic acid 



Supported by Grant Number RR024148 from the National Center for Research Resources, a component of the NIH Roadmap for Medical Research. (

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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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jennifer J. Wheler
    • 1
  • Filip Janku
    • 1
  • Gerald S. Falchook
    • 1
  • Tiffiny L. Jackson
    • 1
  • Siqing Fu
    • 1
  • Aung Naing
    • 1
  • Apostalia M. Tsimberidou
    • 1
  • Stacy L. Moulder
    • 2
  • David S. Hong
    • 1
  • Hui Yang
    • 3
  • Sarina A. Piha-Paul
    • 1
  • Johnique T. Atkins
    • 1
  • Guillermo Garcia-Manero
    • 3
  • Razelle Kurzrock
    • 4
  1. 1.Department of Investigational Cancer Therapeutics (Phase I Program)The University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Breast Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Department of LeukemiaThe University of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Moores Cancer CenterUniversity of California at San DiegoLa JollaUSA

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