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

Abstract

Purpose High-dose ketoconazole and docetaxel have shown activity as single agents against castration-resistant prostate cancer (CRPC). The goal of this phase I study was to determine the maximum tolerated doses, side effects, and pharmacokinetic interaction of coadministered docetaxel and ketoconazole. Experimental Design Patients with metastatic CRPC 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 for three weeks out of four escalating from 5 to 43 mg/m2, with starting doses of ketoconazole of 600, 800, or 1200 mg/day. Declines in prostate-specific antigen of ≥ 50% were seen in 62% of patients. Of 25 patients with soft tissue disease, 7 (28%) had 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 1200 mg/day, 1.6-fold with 800 mg/day, and 1.3- to 1.5-fold with 600 mg/day. Conclusions Results suggest that the combination of weekly docetaxel and ketoconazole has significant antitumor activity in CRPC with manageable toxicities. The extremely long survival in the docetaxel-naïve cohort (36.8 months) warrants additional larger trials of docetaxel with ketoconazole or possibly CYP17A1 inhibitors such as abiraterone.

Antidermatophyte and antioxidant activities of Nigella sativa alone and in combination with enilconazole in treatment of dermatophytosis in cattle

“…Some studies have reported clinical adverse effects after therapy with various systemic anti-fungal agents (Kim et al 2003;Figg et al 2010). Several case reports of mild-to-severe hepatic injury, including icteric and fatal cases, have been published (Kim et al 2003;Figg et al 2010). For instance, the adverse effects of griseofulvin include gastrointestinal symptoms, allergic reactions, photodermatitis, hepatic and renal dysfunctions.…”

“…For instance, the adverse effects of griseofulvin include gastrointestinal symptoms, allergic reactions, photodermatitis, hepatic and renal dysfunctions. Similarly, the adverse effects of ketoconazole include hepatic dysfunction or asymptomatic increases in the activities of serum transaminases (Figg et al 2010). In addition, nausea and vomiting are observed in response to itraconazole treatment and flucanozole treatment can trigger severe gastro-intestinal complications (Gupta and Gregurek 2001).…”

“…In another study, one month after the last treatment with enilconazole, all animals were cured as assessed by clinical and mycological evaluation (Schepens and Spanoghe 1981). Some researchers reported that several systemic antifungal agents have adverse effects resulting in mild-tosevere hepatic injuries and renal syndromes in cats (Kim et al 2003;Figg et al 2010). Enilconazole is generally well tolerated but has also been associated with hypersalivation, anorexia, weight loss, emesis, idiopathic muscle weakness, and slightly elevated serum alanine aminotransferase (ALT) concentrations (Dejaham 1998;Hnilica and Medleau 2002 Nigella sativa (NS), an annual herbaceous plant of the Ranunculaceae, has been used traditionally in the Middle East, Northern Africa, Far East and Asia for the treatment of various diseases for over 2000 years (Phillips 1992).…”

Overcoming Chemotherapy Resistance in Prostate Cancer

“…Median OS of chemotherapy-naive patients (n ¼ 27) in this study was 36.8 months. It is interesting to note, however, that patients who had previously progressing disease on docetaxel (n ¼ 15) had a median survival of 10.3 months when docetaxel was reintroduced with ketoconazole (67). Although this was a small trial, the OS of taxane-naive patients compares favorably with contemporary studies.…”

Medical strategies for treatment of castration resistant prostate cancer (CRPC) docetaxel resistant

“…may be feasible as well as the possible combination with chemotherapy. 27,28 MDV3100. MDV3100 is an orally bioavailable, organic, nonsteroidal small molecule targeting the androgen receptor with potential antineoplastic activity.…”