A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer

Cancer Chemother Pharmacol. 2010 May;66(1):181-9. doi: 10.1007/s00280-010-1289-x. Epub 2010 Mar 9.

Abstract

Purpose: 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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Administration, Oral
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Docetaxel
  • Drug Resistance, Neoplasm
  • Fluorodeoxyglucose F18
  • Histone Deacetylase Inhibitors* / administration & dosage
  • Histone Deacetylase Inhibitors* / adverse effects
  • Histone Deacetylase Inhibitors* / pharmacokinetics
  • Histones / blood
  • Humans
  • Hydroxamic Acids / administration & dosage*
  • Hydroxamic Acids / adverse effects
  • Hydroxamic Acids / pharmacokinetics
  • Indoles
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplastic Cells, Circulating / drug effects
  • Panobinostat
  • Positron-Emission Tomography
  • Prostate-Specific Antigen / blood
  • Prostate-Specific Antigen / drug effects
  • Prostatic Neoplasms / diagnostic imaging
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Taxoids / administration & dosage*
  • Treatment Outcome

Substances

  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Indoles
  • Taxoids
  • Fluorodeoxyglucose F18
  • Docetaxel
  • Panobinostat
  • Prostate-Specific Antigen