Original Article

Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 3, pp 495-501

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

  • Jennifer J. WhelerAffiliated withDepartment of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center Email author 
  • , Filip JankuAffiliated withDepartment of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center
  • , Gerald S. FalchookAffiliated withDepartment of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center
  • , Tiffiny L. JacksonAffiliated withDepartment of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center
  • , Siqing FuAffiliated withDepartment of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center
  • , Aung NaingAffiliated withDepartment of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center
  • , Apostalia M. TsimberidouAffiliated withDepartment of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center
  • , Stacy L. MoulderAffiliated withDepartment of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center
  • , David S. HongAffiliated withDepartment of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center
    • , Hui YangAffiliated withDepartment of Leukemia, The University of Texas MD Anderson Cancer Center
    • , Sarina A. Piha-PaulAffiliated withDepartment of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center
    • , Johnique T. AtkinsAffiliated withDepartment of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center
    • , Guillermo Garcia-ManeroAffiliated withDepartment of Leukemia, The University of Texas MD Anderson Cancer Center
    • , Razelle KurzrockAffiliated withMoores Cancer Center, University of California at San Diego

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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.

Keywords

Bevacizumab Histone deacetylase Hypertension VEGF Valproic acid