A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer.
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.
Rathkopf
Dana
D
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
Wong
Bryan Y
BY
Ross
Robert W
RW
Anand
Aseem
A
Tanaka
Erika
E
Woo
Margaret M
MM
Hu
Jing
J
Dzik-Jurasz
Andy
A
Yang
Wei
W
Scher
Howard I
HI
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
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D043823:Taxoids; D019788:Fluorodeoxyglucose F18; D000077143:Docetaxel; D000077767:Panobinostat; D017430:Prostate-Specific Antigen