Cancer Chemotherapy and Pharmacology

, Volume 66, Issue 1, pp 181–189 | Cite as

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

  • Dana Rathkopf
  • Bryan Y. Wong
  • Robert W. Ross
  • Aseem Anand
  • Erika Tanaka
  • Margaret M. Woo
  • Jing Hu
  • Andy Dzik-Jurasz
  • Wei Yang
  • Howard I. Scher
Clinical Trial Report



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).


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/m2 every 21 days.


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 ≥50% decline in prostate-specific antigen (PSA), including one patient whose disease had previously progressed on docetaxel.


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.


Prostate cancer Castration-resistant Histone deacetylase inhibitor Panobinostat Docetaxel 



This work was supported by Novartis; the Department of Defense Prostate Cancer Research Program (PC051382) and the Prostate Cancer Foundation; and the Sidney Kimmel Center for Prostate and Urologic Cancers.

Conflicts of interest

The authors declared no financial conflicts of interest beyond the aforementioned funding. The authors have full control of all primary data and agree to allow the journal to review their data if requested.


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Dana Rathkopf
    • 1
    • 2
  • Bryan Y. Wong
    • 3
  • Robert W. Ross
    • 4
  • Aseem Anand
    • 1
    • 2
  • Erika Tanaka
    • 1
    • 2
  • Margaret M. Woo
    • 5
  • Jing Hu
    • 5
  • Andy Dzik-Jurasz
    • 5
  • Wei Yang
    • 5
  • Howard I. Scher
    • 1
    • 2
  1. 1.Genitourinary Oncology Service, Department of MedicineSidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Department of MedicineJoan and Sanford I. Weill Medical College of Cornell UniversityNew YorkUSA
  3. 3.Mayo ClinicScottsdaleUSA
  4. 4.Dana-Farber Cancer InstituteBostonUSA
  5. 5.Novartis OncologyFlorham ParkUSA

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