Open-Label, Exploratory Phase II Trial of Oral Itraconazole for the Treatment of Basal Cell Carcinoma

• Published in: Journal of clinical oncology Vol. 32; no. 8; pp. 745 - 751
• Main Authors: KIM, Daniel J, KIM, James, TANG, Jean Y, SPAUNHURST, Katrina, MONTOYA, Javier, KHODOSH, Rita, CHANDRA, Kalyani, FU, Teresa, GILLIAM, Anita, MOLGO, Monserrat, BEACHY, Philip A
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 10-03-2014
• Subjects: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Biological and medical sciences; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; California; Carcinoma, Basal Cell - chemistry; Carcinoma, Basal Cell - drug therapy; Carcinoma, Basal Cell - genetics; Carcinoma, Basal Cell - pathology; Cell Proliferation - drug effects; Chile; Dermatology; Disease Progression; Drug Administration Schedule; Female; Humans; Itraconazole - administration & dosage; Itraconazole - adverse effects; Ki-67 Antigen - analysis; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Remission Induction; RNA, Messenger - analysis; Skin Neoplasms - chemistry; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Time Factors; Transcription Factors - genetics; Treatment Outcome; Tumor Burden - drug effects; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Zinc Finger Protein GLI1; Skin disease; Antifungal agent; Cancerology; Basal cell carcinoma; Azole derivatives; Keratinocyte cancer; Phase II trial; Oral administration; Triazole derivatives; Malignant tumor; Cancer; Itraconazole
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2013.49.9525

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 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.
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.
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.