Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Carcinoma

Carcinoma, Basal Cell

Skin Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Basal Cell

Anti-Infective Agents

All Drugs and Chemicals

Itraconazole

Hydroxyitraconazole

Clotrimazole

Miconazole

Antifungal Agents

Enzyme Inhibitors

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

Oral itraconazole 400 mg as 200 mg twice daily, for 1 month, stratified by prior vismodegib history

Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months

Patients otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment

* 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

Jean Y Tang, MD

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.

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.

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

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

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.

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 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.

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.

Stanford University

Associate Professor of Dermatology

All patients treated with itraconazole were monitored for adverse events ≥ Grade 2. Only adverse events (AEs) grade 2 or greater were collected and reported.

Oral itraconazole 400 mg as 200 mg twice daily, for 1 month.

Cohort A1 - Itraconazole 400 mg +/- Prior Vismodegib

Cohort A2 - Itraconazole 400 mg (Prior Vismodegib)

Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months treatment. All Cohort B participants were vismodegib-naïve.

Cohort B - Itraconazole 200 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.

Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve)

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.

Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment

Untreated Control

Total

Age, Continuous

Sex: Female, Male

United States

Chile

Region of Enrollment

1 Tumor Lesion at Baseline

> 1 Tumor Lesion at Baseline

Number of Tumor Lesions at Baseline

Patients with one or more BCC tumors measuring 4 mm or greater in diameter were enrolled.

Jean Tang MD PhD, Associate Professor of Dermatology

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.

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.

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.

Unpaired Analysis

Paired Analysis

Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment.

Ki67 tumor proliferation biomarker assessment was not performed for Cohorts A2 (itraconazole 400 mg \& prior vismodegib) and B (itraconazole 100 mg twice daily).

Ki67 Tumor Proliferation Biomarker

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.

Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months treatment. All Cohort B participants were vismodegib-naïve, and had more than 1 lesion at baseline.

Participants otherwise eligible but unwilling to take itraconazole were enrolled onto this study control arm, and received no treatment.

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.

Change of GLI1 Tumor Biomarker

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.

Average tumor size reductions were compared between Cohort A1 and Cohort B.

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.

Tumor Size

Cohort A1 - Itraconazole 400 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, and had more than 1 lesion at baseline..

Spots Global Cancer Trial Database for Pilot Biomarker Trial to Evaluate the Efficacy of Itraconazole in Patients w/ Basal Cell Carcinomas

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