A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer
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.
KeywordsProstate cancer Castration-resistant Histone deacetylase inhibitor Panobinostat Docetaxel
- 7.Shao W, Growney J, O’Connor G, Feng Y, Scher H, Yao Y, Fawell S, Atadja P (2008) Efficacy of panobinostat (LBH589) in prostate cancer cell models: targeting the androgen receptor in hormone-refractory prostate cancer (HRPC). Presented at the Genitourinary Cancers Symposium, San FranciscoGoogle Scholar
- 8.Giles F, Fischer T, Cortes J, Garcia-Manero G, Beck J, Ravandi F, Masson E, Rae P, Laird G, Sharma S, Kantarjian H, Dugan M, Albitar M, Bhalla K (2006) A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 12:4628–4635CrossRefPubMedGoogle Scholar
- 9.Prince HM, George D, Patnaik A et al (2007) Phase I study of oral panobinostat (LBH589) in advanced solid tumors and non-Hodgkin’s lymphoma. Presented at the ECCO Poster, Barcelona, Spain, September 23–27, 2007 (abstr 701)Google Scholar
- 10.Sharma S, Vogelzang N, Beck J et al (2007) Phase I pharmacokinetic and pharmacodynamic study of once-weekly i.v. panobinostat (LBH589). Presented at the ECCO Poster, Barcelona, Spain, September 23–27, 2007 (abstr 702)Google Scholar
- 15.Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, Pruim J, Price P (1999) Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European organization for research and treatment of cancer (EORTC) PET study group. Eur J Cancer 35:1773–1782CrossRefPubMedGoogle Scholar
- 18.Kelloff GJ, Krohn KA, Larson SM, Weissleder R, Mankoff DA, Hoffman JM, Link JM, Guyton KZ, Eckelman WC, Scher HI, O’Shaughnessy J, Cheson BD, Sigman CC, Tatum JL, Mills GQ, Sullivan DC, Woodcock J (2005) The progress and promise of molecular imaging probes in oncologic drug development. Clin Cancer Res 11:7967–7985CrossRefPubMedGoogle Scholar
- 19.Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA, TAX 327 Investigators (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512CrossRefPubMedGoogle Scholar
- 24.Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA et al (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 26(7):1148–1159Google Scholar
- 26.Sharma S, Vogelzang NJ, Beck J et al (2007) Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of LBH589, a novel deacetylase (DAC) inhibitor given intravenously on a new once weekly schedule. J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20, 2007, Supplement) (abstr 14019)Google Scholar