A Phase I Clinical Study of High Dose Ketoconazole Plus Weekly Docetaxel for Metastatic Castration Resistant Prostate Cancer

Received 8 October 2009 published online 16 April 2010.

Purpose

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.

Materials and 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/m2, 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/m2. 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.

Key Words: prostatic neoplasms, docetaxel, ketoconazole, drug interactions

a Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

b Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

c Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

d Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

e Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

f Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Correspondence and requests for reprints: Medical Oncology Branch, Building 10/Room 5A01, 9000 Rockville Pike, Bethesda, Maryland 20892 (telephone: 301-402-3623; FAX: 301-402-8606)

Study received institutional review board approval.

Supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The results and discussions presented herein do not represent the views of these federal agencies.

For another article on a related topic see page 2409.

PII: S0022-5347(10)00261-2

doi:10.1016/j.juro.2010.02.020

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