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

Daniel J. Kim, James Kim, Katrina Spaunhurst, Javier Montoya, Rita Khodosh, Kalyani Chandra, Teresa Fu, Anita Gilliam, Monserrat Molgo, Philip A. Beachy, Jean Y. Tang

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)745-751
Number of pages7
JournalJournal of Clinical Oncology
Volume32
Issue number8
DOIs
StatePublished - Mar 10 2014

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Itraconazole
Basal Cell Carcinoma
Hedgehogs
Neoplasms
Therapeutics
HhAntag691
United States Food and Drug Administration
Tumor Biomarkers
Human Activities
Fatigue
Carcinogenesis
Heart Failure
Cell Proliferation
Messenger RNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. / Kim, Daniel J.; Kim, James; Spaunhurst, Katrina; Montoya, Javier; Khodosh, Rita; Chandra, Kalyani; Fu, Teresa; Gilliam, Anita; Molgo, Monserrat; Beachy, Philip A.; Tang, Jean Y.

In: Journal of Clinical Oncology, Vol. 32, No. 8, 10.03.2014, p. 745-751.

Research output: Contribution to journalArticle

Kim, DJ, Kim, J, Spaunhurst, K, Montoya, J, Khodosh, R, Chandra, K, Fu, T, Gilliam, A, Molgo, M, Beachy, PA & Tang, JY 2014, 'Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma', Journal of Clinical Oncology, vol. 32, no. 8, pp. 745-751. https://doi.org/10.1200/JCO.2013.49.9525
Kim, Daniel J. ; Kim, James ; Spaunhurst, Katrina ; Montoya, Javier ; Khodosh, Rita ; Chandra, Kalyani ; Fu, Teresa ; Gilliam, Anita ; Molgo, Monserrat ; Beachy, Philip A. ; Tang, Jean Y. / Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. In: Journal of Clinical Oncology. 2014 ; Vol. 32, No. 8. pp. 745-751.
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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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