title: Phase I study of anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA, jjwheler@mdanderson.org.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.forename: Tiffiny L
authors.initials: TL
authors.lastname: Jackson
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Apostalia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Moulder
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
authors.forename: Johnique T
authors.initials: JT
authors.lastname: Atkins
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D000068258:Bevacizumab; D004305:Dose-Response Relationship, Drug; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D056572:Histone Deacetylase Inhibitors; D000068258:Bevacizumab; D014635:Valproic Acid