Journal
CANCER CHEMOTHERAPY AND PHARMACOLOGY
Volume 66, Issue 1, Pages 181-189Publisher
SPRINGER
DOI: 10.1007/s00280-010-1289-x
Keywords
Prostate cancer; Castration-resistant; Histone deacetylase inhibitor; Panobinostat; Docetaxel
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Funding
- NCI NIH HHS [PC051382] Funding Source: Medline
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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, >= 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.
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