Abstract LB-223: An open-label, exploratory phase II study of oral itraconazole for the treatment of basal cell carcinoma

Abstract

Abstract Purpose: Itraconazole is an FDA-approved antifungal drug that has been recently shown to antagonize the Hedgehog (Hh) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis. As oral itraconazole reduced BCC growth in mice, we assessed itraconazole's efficacy in treating human BCC tumors in an open-label, exploratory phase II study. Patients and Methods: Patients with at least one BCC tumor greater than 4 mm in diameter and with no co-morbidities were eligible to enroll. Patients were enrolled in 2 cohorts to receive oral itraconazole 200 mg twice-daily for one month (Cohort A) or 100 mg twice-daily for a longer duration (Cohort B). The primary endpoint was to determine changes in tumor size, proliferation (Ki67 levels), and a target gene of the Hh pathway (GLI1 mRNA). Results: Of the 29 patients that enrolled in the clinical trial, 19 patients were treated with itraconazole. Itraconazole caused 2 treatment-related adverse events (grade 2 fatigue and grade 4 CHF). Tumors treated with itraconazole showed a 23% reduction in clinical tumor area (95% CI: 17.2% to 28.1%), a 45% reduction in cell proliferation (P=0.04), and a 65% reduction in Hedgehog activity (P=0.03). Eight subjects with multiple tumors were assessed for clinical size changes: 4 subjects had partial response and 4 had stable disease. Tumors from control patients and patients previously treated with other Hedgehog inhibitors saw no significant changes in cell proliferation or Hedgehog activity. Conclusion: Itraconazole reduced BCC tumor size, tumor proliferation, and Hedgehog pathway activity in this exploratory study. Additional studies with larger numbers of patients are needed to validate these findings, however this proof-of-concept study demonstrates the possibility of repurposing FDA approved drugs for the treatment of cancers driven by the Hedgehog signaling pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-223. doi:1538-7445.AM2012-LB-223