title: A phase I clinical study of high dose ketoconazole plus weekly docetaxel for metastatic castration resistant prostate cancer.
abstract: OBJECTIVE
  This phase I study of high dose ketoconazole and docetaxel was designed against castration resistant prostate cancer to determine the maximum tolerated doses, side effects, and pharmacokinetic interaction of co-administered docetaxel and ketoconazole.
  
  
  METHODS
  Patients with metastatic castration resistant prostate cancer received weekly docetaxel for 3 of every 4 weeks plus daily ketoconazole. Pharmacokinetic studies were performed on day 1 (docetaxel alone) and day 16 (after ketoconazole).
  
  
  RESULTS
  The study enrolled 42 patients at 9 different dose levels. The combination regimens investigated included docetaxel weekly, increasing from 5 to 43 mg/m(2), with starting doses of 600, 800 or 1,200 mg ketoconazole daily. Decreases in prostate specific antigen of 50% or greater were seen in 62% of patients. Of 25 patients with soft tissue disease 7 (28%) had a partial response. Median overall survival was 22.8 months and was significantly greater in docetaxel naïve patients than in patients pretreated with docetaxel (36.8 vs 10.3 months, p = 0.0001). The most frequently observed adverse events were anemia, edema, fatigue, diarrhea, nausea, sensory neuropathy and elevated liver function tests. The fractional change in docetaxel clearance correlated significantly with ketoconazole exposure (p <0.01). Concomitant ketoconazole increased docetaxel exposure 2.6-fold with 1,200 mg daily, 1.6-fold with 800 mg daily and approximately 1.3 to 1.5-fold with 600 mg daily.
  
  
  CONCLUSIONS
  Combination regimens using 600 mg ketoconazole daily were fairly well tolerated and the maximum tolerated dose of docetaxel was 32 mg/m(2). Results suggest that the combination has significant antitumor activity in castration resistant prostate cancer. The long survival in the docetaxel naïve cohort warrants additional, larger trials of docetaxel with ketoconazole or possibly CYP17A1 inhibitors such as abiraterone.
authors.affiliation: Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. wdfigg@helix.nih.gov
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Sukyung
authors.initials: S
authors.lastname: Woo
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zhu
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Chen
authors.forename: A Seun
authors.initials: AS
authors.lastname: Ajiboye
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Price
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Howard L
authors.initials: HL
authors.lastname: Parnes
authors.forename: Philip M
authors.initials: PM
authors.lastname: Arlen
authors.forename: James L
authors.initials: JL
authors.lastname: Gulley
authors.forename: William L
authors.initials: WL
authors.lastname: Dahut
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077143:Docetaxel; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D007654:Ketoconazole / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017211:Treatment Failure
chemical_list: D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D007654:Ketoconazole
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