Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Daniel J. Kim, James Kim, Katrina Spaunhurst, Rita Khodosh, Kalyani Chandra, Teresa Fu, Philip A. Beachy, and Jean Y. Tang, Stanford University, Stanford; Anita Gilliam, Palo Alto Medical Foundation, Palo Alto, CA; James Kim, University of Texas Southwestern, Dallas, TX; Javier Montoya and Monserrat Molgo, Universidad Católica de Chile, Santiago, Chile.
Daniel J
DJ
Kim
James
J
Kim
Katrina
K
Spaunhurst
Javier
J
Montoya
Rita
R
Khodosh
Kalyani
K
Chandra
Teresa
T
Fu
Anita
A
Gilliam
Monserrat
M
Molgo
Philip A
PA
Beachy
Jean Y
JY
Tang
D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002140:California; D002280:Basal Cell Carcinoma / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002677:Chile; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage* / Q000009:adverse effects; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D012074:Remission Induction; D012878:Skin Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D000071676:Zinc Finger Protein GLI1
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C400551:GLI1 protein, human; D019394:Ki-67 Antigen; D012333:RNA, Messenger; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D017964:Itraconazole