Pilot Biomarker Trial to Evaluate the Efficacy of Itraconazole in Patients w/ Basal Cell Carcinomas

Study Overview
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Brief Summary
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Basal cell carcinomas (BCCs) are the most common human cancer in the US and affect over 1 million people. There is no effective drug to prevent basal cell carcinomas of the skin. We hope to learn if an oral anti-fungal drug, itraconazole, might inhibit a marker of proliferation and a biomarker (tumor signaling pathway) of BCC development. Itraconazole is an FDA-approved drug for the treatment of fungal infections of the skin, and has been used for the past 25 years with relatively few side effects. It has been shown in mice to reduce a BCC biomarker and to reduce growth of BCCs. Thus, it may reduce BCC growth in humans.

Detailed Description
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Participants with at least one BCC tumor measuring 4 mm or greater in diameter will be enrolled onto 1 of 2 treatment cohorts to receive oral itraconazole. Cohort A - 400 mg itraconazole (as 200 mg twice daily for 30 days), stratified by: Cohort A1 - Participants are vismodegib-naive. Cohort A2 - Participants had received prior vismodegib treatment. Cohort B - 200 mg itraconazole (as 100 mg twice daily, for up to 4 months). The objective of this cohort is to assess the anti-cancer efficacy of lower-dose extended treatment. Control Group - Tumors from untreated participants.

Official Title
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Pilot Biomarker Trial to Evaluate the Efficacy of Itraconazole in Patients With Basal Cell Carcinomas

Conditions
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Basal Cell Carcinoma (BCC), Skin Cancer

Intervention / Treatment
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* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA At least one BCC tumor (greater than 4 mm in diameter) at any skin location, to be biopsied and surgically removed. Had at least one liver function test [eg, aspartate aminotransferase (AST), alanine aminotransferase (ALT)] with normal results in the last year. Consent to research use of their BCC tissue. Cohort A or B: Willing to take itraconazole during the 2 to 3 weeks between biopsy and surgical removal of BCC EXCLUSION CRITERIA History or current hepatitis or other liver disease. Currently taking systemic medications that would affect BCC tumors (oral retinoids) or metabolism of itraconazole (anti-convulsants, corticosteroids) History or current evidence of malabsorption or liver disease within the one year prior to enrollment. History or current evidence of hyperthyroidism increasing metabolism of itraconazole Unable to attend to 2nd study visit at Stanford for Mohs surgical excision Current immunosuppression disease (cancer, autoimmune disease) Receiving immunosuppressive drugs Pregnant Lactating Any female actively trying to become pregnant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A - Itraconazole 400 mg<br>Oral itraconazole 400 mg as 200 mg twice daily, for 1 month, stratified by prior vismodegib history | Drug: Itraconazole<br>* Cohort A: oral itraconazole 400 mg as 200 mg twice daily; for 1 month Cohort B: oral itraconazole 200 mg as 100 mg twice daily; for up to 3 months<br>* Other names: Sporanox;|
| Experimental: Cohort B - Itraconazole 200 mg<br>Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months | Drug: Itraconazole<br>* Cohort A: oral itraconazole 400 mg as 200 mg twice daily; for 1 month Cohort B: oral itraconazole 200 mg as 100 mg twice daily; for up to 3 months<br>* Other names: Sporanox;|
| No Intervention: Untreated Control<br>Patients otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ki67 Tumor Proliferation Biomarker | Percent change in Ki67 tumor proliferation biomarker was assessed at baseline and after 1 month of treatment, for Cohort A1 (vismodegib-naïve participants receiving 400 mg as 200 mg twice daily) vs control patients. The outcome is expressed as the % change from baseline of cells with a positive signal after staining for Ki67. Paired analysis of tumors shows percent change between baseline (prior to treatment) and post itraconazole treatment in individual patients, & is reported as the mean of the changes observed for those lesions for which both baseline and treated valued are available. Unpaired analysis shows percent change between individual tumors from control patients and itraconazole treated patients, and is reported as the change in mean of the group of baseline basal cell carcinoma (BCC) lesion measurements and the group of treated BCC lesion measurements. | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of GLI1 Tumor Biomarker | Tumor biomarker GLI1 (glioma-associated oncogene 1), part of the Hedgehog (HH) pathway, was assessed in vismodegib-naïve participants at baseline and after 1 month of treatment by quantitative polymerase chain reaction (qPCR). The relative expression of the biomarker was measured as the fold increase of GLI1 expression compared to that of housekeeping gene hypoxanthine-guanine phosphoribosyltransferase (HPRT), and the outcome was assessed as the percent change from the mean of the pre-treatment measurements to the mean of the post-treatment measurements. A negative mean indicates an overall reduction in GLI1 expression. | 1 month | 
| Tumor Size | Tumor size was assessed by caliper measurement of the longest perpendicular diameters before and after itraconazole treatment, and determination of tumor area by multiplication of the measurements for each tumor. The outcome is expressed as the mean percent change in tumor area from baseline, with standard deviation. A negative value indicates a reduction in size. | Up to 3 months | 
| Tumor Response | The following criteria for basal cell carcinoma (BCC) tumor response were used. Complete response (CR) means no visible evidence of any lesion consistent with BCC Partial response (PR) means less than CR, but there was a visible decrease in BCC tumor size No response (NR) / Stable Disease (SD) means no visible decrease in BCC tumor size Progressive disease (PD) means an increase in size or number of BCC tumor lesions Treatment assessment was conducted on the basis of lesion photographs by a dermatologist investigator who was blinded to the assigned treatment. | End of treatment period: 1 month (Cohort A) or 2.3 months (mean for Cohort B) |