A pilot trial of itraconazole pharmacokinetics in patients with metastatic breast cancer.

Abstract

e13565 Background: Preclinical studies show that itraconazole (ITRA) has inhibitory activity against human umbilical vein endothelial cells. It also decreases angiogenesis with 67.5% reduction in new blood vessel formation in ITRA-treated mice vs. controls. The aim of this study is to determine the pharmacokinetics (PK) of ITRA in patients with metastatic breast cancer (MBC) and correlate measures of angiogenesis with plasma levels of the drug and its metabolite hydroxyitraconazole. Methods: ITRA was administered orally at 200mg daily to patients with MBC. A cycle consists of 28 days. Plasma levels of ITRA and hydroxyitraconazole were obtained at 2 and 4 weeks for PK. Plasma VEGF-A and TSP-1, serum bFGF and PlGF levels were obtained at baseline, 2, and 4 weeks. Spearman correlations (rs) of angiogenesis factors with plasma levels of ITRA and hydroxyitraconazole were computed. Toxicities, OS, TTP were determined. Results: 14 patients were enrolled, median age 62.5, with 13 being evaluable. 8 were hormone receptor-positive; 1 was HER2-positive. Median follow-up was 13.7 months. Median number of cycles was 2. Frequent AEs were fatigue (30.8%), anorexia (23.1%), insomnia (23.1%). Gr 3/4 toxicity was observed in only 1 patient (fatigue, insomnia, nausea/vomiting, dyspnea, hemorrhage, and pain). Median ITRA levels at 2 and 4 weeks were 181 and 202 ng/mL. Median hydroxyitraconazole levels were 331.5 and 337 ng/mL. Median bFGF and PlGF levels decreased with administration of ITRA from baseline to weeks 2 and 4. bFGF displayed high correlations with ITRA and hydroxyitraconazole at weeks 2 and 4 although not statistically significant (rs= -0.54 to -0.70). Plasma TSP-1 increased at weeks 2 and 4. VEGF-A levels increased from baseline to week 2, but decreased with drug administration during weeks 2 to 4. PlGF, TSP-1, VEGF-A did not correlate with drug levels. 1 patient had a PR, 3 SD, and 9 PD. Estimated TTP and OS were 1.8 and 19.3 months respectively. Conclusions: This is the first study evaluating PK of ITRA and effects on angiogenesis in MBC. Whilst reductions in pro-angiogenic factors and increases in TSP-1 (angiogenesis inhibitor) were observed with ITRA administration, our pilot study suggests a lack of correlation with drug or metabolite levels.