title: Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study.
abstract: OBJECTIVE
  To determine the safety, toxicity, and maximum-tolerated dose of a sequence-specific combination of the histone deacetylase inhibitor (HDACi), valproic acid (VPA), and epirubicin in solid tumor malignancies and to define the clinical feasibility of VPA as an HDACi.
  
  
  METHODS
  Patients were treated with increasing doses of VPA (days 1 through 3) followed by epirubicin (day 3) in 3-week cycles. The study evaluated pharmacokinetic and pharmacodynamic end points, toxicities, and tumor response.
  
  
  RESULTS
  Forty-eight patients were enrolled, and 44 received at least one cycle of therapy. Patients (median age, 54 years; range, 39 to 78 years) received the following doses of VPA: 15, 30, 45, 60, 75, 90, 100, 120, 140, and 160 mg/kg/d. Dose-limiting toxicities were somnolence (n = 1), confusion (n = 3), and febrile neutropenia (n = 1). No exacerbation of epirubicin-related toxicities was observed. Partial responses were seen across different tumor types in nine patients (22%), and stable disease/minor responses were seen in 16 patients (39%), despite a median number of three prior regimens (range, zero to 10 prior regimens). Patients received a median number of four treatment cycles (range, one to 10 cycles), and treatment was stopped after reaching maximal epirubicin doses rather than progression in 13 (32%) of 41 patients patients. Total and free VPA plasma concentrations increased linearly with dose and correlated with histone acetylation in peripheral-blood mononuclear cells.
  
  
  CONCLUSIONS
  The maximum-tolerated dose and recommended phase II dose was VPA 140 mg/kg/d for 48 hours followed by epirubicin 100 mg/m2. Sustained plasma concentrations of VPA exceeding those required for in vitro synergy were achieved with acceptable toxicity. Noteworthy antitumor activity was observed in heavily pretreated patients and historically anthracycline-resistant tumors.
authors.affiliation: Experimental Therapeutics, Breast Medical Oncology Program, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. pamela.munster@moffitt.org
authors.forename: Pamela
authors.initials: P
authors.lastname: Münster
authors.forename: Douglas
authors.initials: D
authors.lastname: Marchion
authors.forename: Elona
authors.initials: E
authors.lastname: Bicaku
authors.forename: Morgen
authors.initials: M
authors.lastname: Schmitt
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Ronald
authors.initials: R
authors.lastname: DeConti
authors.forename: George
authors.initials: G
authors.lastname: Simon
authors.forename: Mayer
authors.initials: M
authors.lastname: Fishman
authors.forename: Susan
authors.initials: S
authors.lastname: Minton
authors.forename: Chris
authors.initials: C
authors.lastname: Garrett
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiappori
authors.forename: Richard
authors.initials: R
authors.lastname: Lush
authors.forename: Daniel
authors.initials: D
authors.lastname: Sullivan
authors.forename: Adil
authors.initials: A
authors.lastname: Daud
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D015251:Epirubicin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D059005:Topoisomerase II Inhibitors; D016896:Treatment Outcome; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D059005:Topoisomerase II Inhibitors; D015251:Epirubicin; D014635:Valproic Acid