title: A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer.
abstract: OBJECTIVE
  Histone deacetylase inhibitors have demonstrated anticancer activity against a range of tumors. We aimed to define the maximum tolerated dose, toxicity, activity, and pharmacokinetics of oral panobinostat, a pan-deacetylase inhibitor, alone and in combination with docetaxel for the treatment of castration-resistant prostate cancer (CRPC).
  
  
  METHODS
  Sixteen patients were enrolled, eight in each arm. Eligible patients had CRPC and adequate organ function. In arm I, oral panobinostat (20 mg) was administered on days 1, 3, and 5 for 2 consecutive weeks followed by a 1-week break. In arm II, oral panobinostat (15 mg) was administered on the same schedule in combination with docetaxel 75 mg/m(2) every 21 days.
  
  
  RESULTS
  Dose-limiting toxicities were grade 3 dyspnea (arm I) and grade 3 neutropenia >7 days (arm II). In arm I, all patients developed progressive disease despite accumulation of acetylated histones in peripheral blood mononuclear cells. In arm II, five of eight patients (63%) had a >or=50% decline in prostate-specific antigen (PSA), including one patient whose disease had previously progressed on docetaxel.
  
  
  CONCLUSIONS
  Oral panobinostat with and without docetaxel is feasible, and docetaxel had no apparent effect on the pharmacokinetics of panobinostat. Since preclinical studies suggest a dose-dependent effect of panobinostat on PSA expression, and other phase I data demonstrate that intravenous panobinostat produces higher peak concentrations (>20- to 30-fold) and area under the curve (3.5x-5x), a decision was made to focus the development of panobinostat on the intravenous formulation to treat CRPC.
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. rathkopd@mskcc.org
authors.forename: Dana
authors.initials: D
authors.lastname: Rathkopf
authors.forename: Bryan Y
authors.initials: BY
authors.lastname: Wong
authors.forename: Robert W
authors.initials: RW
authors.lastname: Ross
authors.forename: Aseem
authors.initials: A
authors.lastname: Anand
authors.forename: Erika
authors.initials: E
authors.lastname: Tanaka
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Woo
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.forename: Andy
authors.initials: A
authors.lastname: Dzik-Jurasz
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D019788:Fluorodeoxyglucose F18; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006657:Histones / Q000097:blood; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007211:Indoles; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000187:drug effects; D000077767:Panobinostat; D049268:Positron-Emission Tomography; D017430:Prostate-Specific Antigen / Q000097:blood / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D043823:Taxoids; D019788:Fluorodeoxyglucose F18; D000077143:Docetaxel; D000077767:Panobinostat; D017430:Prostate-Specific Antigen