Antifungal Itraconazole Shows Activity in Basal Cell Carcinoma
In an open-label exploratory phase II trial reported in the Journal of Clinical Oncology, Kim et al found that the antifungal agent itraconazole, which inhibits the Hedgehog signaling pathway, reduced tumor cell proliferation, Hedgehog pathway activity, and tumor area in patients with basal cell carcinoma. The Hedgehog pathway is a central driver in basal cell cancer tumorigenesis.
Study Details
In the study, 19 patients with at least one basal cell carcinoma tumor > 4 mm in diameter received oral itraconazole at 200 mg twice per day for 1 month (cohort A, n = 15) or 100 mg twice per day for an average of 2.3 months (cohort B, n = 4). An additional 10 patients who were eligible but unwilling to receive itraconazole received no treatment and served as a control group.
The primary objective in cohort A was to assess changes in Ki67 tumor cell proliferation and Hedgehog activity (measured as GLI1 mRNA). The primary objective in cohort B was to assess whether a lower itraconazole dose over a longer period could produce clinically significant effects. Secondary endpoints included change in tumor size in patients with multiple tumors.
In the 19 treated patients, average age was 62 years, 79% were male, total tumor count was 90 (with an average of 4.8 per patient), most tumors were nodular (50%) or superficial (33%), and the most common tumor sites were face (39%), back (19%), and shoulder (14%). Three patients in cohort A had previously received the Hedgehog pathway antagonist vismodegib (Erivedge). Control patients were similar in age (average, 68.5 years), sex (80% male), tumor type (nodular in 43%, superficial in 29%), and tumor location (face for 55% and back for 18%) but had a lower average number of tumors per patient (1.1).
Reduced Cell Proliferation and Hedgehog Activity
Comparison of Ki67 activity and Hedgehog activity at baseline and at excision at 1 month in itraconazole-treated patients who had not received vismodegib showed a 35% reduction in cell proliferation (P = .079) and a 65% reduction in GLI1 mRNA (P = .028) in unpaired analysis and a 45% reduction in cell proliferation (P = .04) and 45% reduction in Hedgehog activity in paired analysis of tumors from the same patients (n = 8 for Ki67 activity; n = 4 for Hedgehog activity). Control patients and itraconazole-treated patients with previous vismodegib treatment showed no changes in cell proliferation, and no reduction in Hedgehog activity was seen in those with prior vismodegib treatment.
Tumor Reduction
Measurement of change in tumor area in patients from both cohort A and cohort B (8 patients with a total of 57 tumors) showed an average reduction in size of 24%. Reductions in tumors from the two cohorts were similar (P =.435), suggesting that itraconazole given at lower doses over longer duration can produce clinically significant reductions. Among eight itraconazole patients with multiple nonbiopsied tumors, four (50%) achieved partial response and four (50%) had stable disease. Tumors from control patients and from patients previously treated with vismodegib showed no change in size.
Toxicity
Two of 19 patients discontinued itraconazole due to adverse events; one patient with undiagnosed heart disease from doxorubicin treatment for Hodgkin lymphoma 20 years earlier developed grade 4 congestive heart failure, and one patient discontinued treatment due to grade 2 fatigue. Other adverse events were mild, and all were reversible with drug discontinuation. No elevations in liver function tests were observed.
The investigators concluded, “Itraconazole has anti-[basal cell carcinoma] activity in humans. These results provide the basis for larger trials of longer duration to measure the clinical efficacy of itraconazole, especially relative to other [Hedgehog pathway] inhibitors.”
Jean Y. Tang, MD, PhD, of Stanford University School of Medicine, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by the Stanford Clinical and Translational Science Institute and Damon Runyon Clinical Investigator Award. Dr. Tang reported a consultant or advisory role with Genentech.
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