A phase I clinical study of high dose ketoconazole plus weekly docetaxel for metastatic castration resistant prostate cancer.
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.
Figg
William D
WD
Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. wdfigg@helix.nih.gov
Woo
Sukyung
S
Zhu
Wenhui
W
Chen
Xiaohong
X
Ajiboye
A Seun
AS
Steinberg
Seth M
SM
Price
Douglas K
DK
Wright
John J
JJ
Parnes
Howard L
HL
Arlen
Philip M
PM
Gulley
James L
JL
Dahut
William L
WL
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
D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D007654:Ketoconazole
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