TY - JOUR
T1 - Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma
AU - Kim, Daniel J.
AU - Kim, James
AU - Spaunhurst, Katrina
AU - Montoya, Javier
AU - Khodosh, Rita
AU - Chandra, Kalyani
AU - Fu, Teresa
AU - Gilliam, Anita
AU - Molgo, Monserrat
AU - Beachy, Philip A.
AU - Tang, Jean Y.
PY - 2014/3/10
Y1 - 2014/3/10
N2 - Purpose: Itraconazole, a US Food and Drug Administration-approved antifungal drug, inhibits the Hedgehog (HH) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis, and reduces BCC growth in mice. We assessed the effect of itraconazole on the HH pathway and on tumor size in human BCC tumors. Patients and Methods: Patients with ≥ one BCC tumor > 4 mm in diameter were enrolled onto two cohorts to receive oral itraconazole 200 mg twice per day for 1 month (cohort A) or 100 mg twice per day for an average of 2.3 months (cohort B). The primary end point was change in biomarkers: Ki67 tumor proliferation and HH activity (GLI1 mRNA). Secondary end points included change in tumor size in a subset of patients with multiple tumors. Results: A total of 29 patients were enrolled, of whom 19 were treated with itraconazole. Itraconazole treatment was associated with two adverse events (grade 2 fatigue and grade 4 congestive heart failure). Itraconazole reduced cell proliferation by 45% (P = .04), HH pathway activity by 65% (P = .03), and reduced tumor area by 24% (95% CI, 18.2% to 30.0%). Of eight patients with multiple nonbiopsied tumors, four achieved partial response, and four had stable disease. Tumors from untreated control patients and from those previously treated with vismodegib showed no significant changes in proliferation or tumor size. Conclusion: Itraconazole has anti-BCC 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 HH pathway inhibitors.
AB - Purpose: Itraconazole, a US Food and Drug Administration-approved antifungal drug, inhibits the Hedgehog (HH) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis, and reduces BCC growth in mice. We assessed the effect of itraconazole on the HH pathway and on tumor size in human BCC tumors. Patients and Methods: Patients with ≥ one BCC tumor > 4 mm in diameter were enrolled onto two cohorts to receive oral itraconazole 200 mg twice per day for 1 month (cohort A) or 100 mg twice per day for an average of 2.3 months (cohort B). The primary end point was change in biomarkers: Ki67 tumor proliferation and HH activity (GLI1 mRNA). Secondary end points included change in tumor size in a subset of patients with multiple tumors. Results: A total of 29 patients were enrolled, of whom 19 were treated with itraconazole. Itraconazole treatment was associated with two adverse events (grade 2 fatigue and grade 4 congestive heart failure). Itraconazole reduced cell proliferation by 45% (P = .04), HH pathway activity by 65% (P = .03), and reduced tumor area by 24% (95% CI, 18.2% to 30.0%). Of eight patients with multiple nonbiopsied tumors, four achieved partial response, and four had stable disease. Tumors from untreated control patients and from those previously treated with vismodegib showed no significant changes in proliferation or tumor size. Conclusion: Itraconazole has anti-BCC 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 HH pathway inhibitors.
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U2 - 10.1200/JCO.2013.49.9525
DO - 10.1200/JCO.2013.49.9525
M3 - Article
C2 - 24493717
AN - SCOPUS:84897949607
SN - 0732-183X
VL - 32
SP - 745
EP - 751
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 8
ER -