A phase I clinical study of high dose ketoconazole plus weekly docetaxel for metastatic castration resistant prostate cancer

Abstract

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/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.

Figure 1

Progression-free survival (A) and overall survival (B) for patients with and without prior docetaxel therapy.

Figure 2

Pharmacokinetic interaction between docetaxel and ketoconazole. (A) Effects of docetaxel on exposure to ketoconazole in patients receiving 1200 mg/day, 800 mg/day, or 600 mg/day; (B) mean plasma concentration of docetaxel vs. time profiles at doses of 16 to 43 mg/m² in the absence (open circles) and presence (closed circles) of ketoconazole 600 mg/day; (C) fold-changes in docetaxel AUC by ketoconazole coadministration; (D) correlation between ketoconazole AUC and fold-changes in docetaxel CL. Solid line is generated from a linear regression and broken lines represent 95% confidence intervals.

Figure 3

Effects of ABCB1 polymorphism on pharmacokinetics of docetaxel alone (A–C) and in the presence of ketoconazole 600 mg/day (D–F).