Basal Cell Carcinoma (BCC), Skin Cancer
Conditions
Brief summary
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
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.
Interventions
DRUGItraconazole
* 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
Sponsors
Stanford University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ki67 Tumor Proliferation Biomarker | 1 month | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of GLI1 Tumor Biomarker | 1 month | 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. |
| Tumor Size | Up to 3 months | 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. |
| Tumor Response | End of treatment period: 1 month (Cohort A) or 2.3 months (mean for Cohort B) | 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. |
Countries
United States
Participant flow
Recruitment details
* Cohort A enrolled at the Stanford University Medical Center (SUMC). Subjects participated in biopsy studies. * Cohort B was enrolled and participated at the Universidad Catolica de Chile. No biopsy studies were conducted for these participants. * Untreated Control cohort was enrolled at SUMC. Subjects participated in biopsy studies.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) Oral itraconazole 400 mg as 200 mg twice daily, for 1 month, for participants without prior vismodegib treatment (vismodegib-naïve) and more than 1 lesion at baseline. | 12 |
| Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) Oral itraconazole 400 mg as 200 mg twice daily, for 1 month, for participants without prior vismodegib treatment (vismodegib-naïve) and more than 1 lesion at baseline. | 68 |
| Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) Oral itraconazole 400 mg as 200 mg twice daily, for 1 month, for participants with prior vismodegib treatment, and more than 1 lesion at baseline. | 3 |
| Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) Oral itraconazole 400 mg as 200 mg twice daily, for 1 month, for participants with prior vismodegib treatment, and more than 1 lesion at baseline. | 8 |
| Cohort B - Itraconazole 200 mg (Vismodegib-naïve) Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months treatment. All Cohort B participants were vismodegib-naïve. | 4 |
| Cohort B - Itraconazole 200 mg (Vismodegib-naïve) Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months treatment. All Cohort B participants were vismodegib-naïve. | 14 |
| Untreated Control Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment | 10 |
| Untreated Control Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment | 11 |
| Total | 130 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) | Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) | Cohort B - Itraconazole 200 mg (Vismodegib-naïve) | Untreated Control | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.2 years | 57.7 years | 61.7 years | 68.5 years | 65.35 years |
| Number of Tumor Lesions at Baseline > 1 Tumor Lesion at Baseline | 4 Participants | 0 Participants | 4 Participants | 1 Participants | 9 Participants |
| Number of Tumor Lesions at Baseline 1 Tumor Lesion at Baseline | 8 Participants | 3 Participants | 0 Participants | 10 Participants | 21 Participants |
| Region of Enrollment Chile | 0 participants | 0 participants | 4 participants | 0 participants | 4 participants |
| Region of Enrollment United States | 12 participants | 3 participants | 0 participants | 10 participants | 25 participants |
| Sex: Female, Male Female | 3 Participants | 0 Participants | 1 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 9 Participants | 3 Participants | 3 Participants | 8 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 3 | 0 / 4 |
| other Total, other adverse events | 1 / 12 | 0 / 3 | 0 / 4 |
| serious Total, serious adverse events | 1 / 12 | 0 / 3 | 0 / 4 |
Outcome results
Primary
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.
Time frame: 1 month
Population: Ki67 tumor proliferation biomarker assessment was not performed for Cohorts A2 (itraconazole 400 mg \& prior vismodegib) and B (itraconazole 100 mg twice daily).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) | Ki67 Tumor Proliferation Biomarker | Unpaired Analysis | 18 Mean percent change | Standard Deviation 17 |
| Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) | Ki67 Tumor Proliferation Biomarker | Paired Analysis | -19 Mean percent change | Standard Deviation 15 |
| Untreated Control | Ki67 Tumor Proliferation Biomarker | Unpaired Analysis | 0 Mean percent change | Standard Deviation 15 |
| Untreated Control | Ki67 Tumor Proliferation Biomarker | Paired Analysis | 13 Mean percent change | Standard Deviation 12 |
Comparison: Percent change in Ki67 tumor proliferation biomarker from baseline to 1 month, for Cohort A1 (vismodegib-naive patients, n = 8).~Paired analysis of tumors shows percent change between baseline (prior to treatment) and post-itraconazole treatment in individual patients.~% change was calculated from the difference between the mean of baseline Ki67 levels and the mean Ki67 levels after 1 month of treatment.p-value: 0.04t-test, 2 sided
Comparison: Percent change in Ki67 tumor proliferation biomarker - baseline vs 1 month - Cohort A, vismodegib-naive (n = 8) vs control patients Unpaired analysis shows percent change between individual tumors from control patients and itraconazole treated patients.~% change was calculated from the difference between the mean of baseline Ki67 levels and the mean Ki67 levels after 1 month of treatment.p-value: 0.079t-test, 1 sided
Comparison: Percent change in Ki67 tumor proliferation biomarker - baseline vs 1 month - control patients Paired analysis of tumors shows percent change between baseline and after 1 month in individual patients.~% change was calculated from the difference between the mean of baseline Ki67 levels and the mean Ki67 levels after 1 month.p-value: 0.652t-test, 2 sided
Secondary
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.
Time frame: 1 month
Population: Analysis conducted for Cohorts A1 - Itraconazole 400 mg (Vismodegib-naive) and A2 - Itraconazole 400 mg (Prior Vismodegib) only. GLI1 tumor biomarker assessment was not performed for the Cohort B (100 mg twice daily); or Control Group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) | Change of GLI1 Tumor Biomarker | -40.3 Percent change | Standard Deviation 35.6 |
| Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) | Change of GLI1 Tumor Biomarker | -16.2 Percent change | Standard Deviation 13.1 |
Comparison: Percentage change in GLI1 messenger RNA (mRNA) expression Paired analysis of tumors shows percent change between baseline (prior to treatment) and post itraconazole treatment in individual patients.~% change was calculated from the difference between the mean of baseline Gli levels and the mean Gli level after 1 month of treatment.p-value: 0.028t-test, 2 sided
Secondary
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.
Time frame: End of treatment period: 1 month (Cohort A) or 2.3 months (mean for Cohort B)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) | Tumor Response | Partial Response (PR) | 4 Participants |
| Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) | Tumor Response | Disease Progression (PD) | 0 Participants |
| Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) | Tumor Response | No Response (NR) / Stable Disease (SD) | 0 Participants |
| Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) | Tumor Response | Complete Response (CR) | 0 Participants |
| Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) | Tumor Response | Complete Response (CR) | 0 Participants |
| Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) | Tumor Response | Disease Progression (PD) | 0 Participants |
| Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) | Tumor Response | Partial Response (PR) | 0 Participants |
| Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) | Tumor Response | No Response (NR) / Stable Disease (SD) | 3 Participants |
| Cohort B - Itraconazole 200 mg (Vismodegib-naïve) | Tumor Response | Partial Response (PR) | 0 Participants |
| Cohort B - Itraconazole 200 mg (Vismodegib-naïve) | Tumor Response | Disease Progression (PD) | 0 Participants |
| Cohort B - Itraconazole 200 mg (Vismodegib-naïve) | Tumor Response | Complete Response (CR) | 0 Participants |
| Cohort B - Itraconazole 200 mg (Vismodegib-naïve) | Tumor Response | No Response (NR) / Stable Disease (SD) | 4 Participants |
| Untreated Control | Tumor Response | Disease Progression (PD) | 0 Participants |
| Untreated Control | Tumor Response | Complete Response (CR) | 0 Participants |
| Untreated Control | Tumor Response | Partial Response (PR) | 0 Participants |
| Untreated Control | Tumor Response | No Response (NR) / Stable Disease (SD) | 10 Participants |
Secondary
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.
Time frame: Up to 3 months
Population: Change in tumor area was assessed for only for Cohort A1 or B participants who had \> 1 basal cell carcinoma (BCC) tumor (42 and 14 lesions respectively). No Cohort A2 participants had \> 1 BCC tumor. No data were collected from untreated patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) | Tumor Size | -25.4 Mean percent change | Standard Deviation 21.8 |
| Cohort B - Itraconazole 200 mg (Vismodegib-naïve) | Tumor Size | -20 Mean percent change | Standard Deviation 24.4 |
Comparison: Only tumors from 4 patients from cohort A (n = 42 BCCs) and all tumors from the 4 patients (n = 14 BCCs) in cohort B were observed for tumor size change. Percent change in tumor area from both cohorts (eight patients total with 57 tumors) was calculated only.95% CI: [18.2, 30]
Comparison: Average tumor size reductions were compared between Cohort A1 and Cohort B.p-value: 0.435t-test, 1 sided