Trial Outcomes & Findings for Pilot Biomarker Trial to Evaluate the Efficacy of Itraconazole in Patients w/ Basal Cell Carcinomas (NCT NCT01108094)

NCT ID: NCT01108094

Last Updated: 2018-11-13

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 29 participants
• Primary outcome timeframe: 1 month
• Results posted on: 2018-11-13

Participant Flow

• 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.

Participant milestones

Measure	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.	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.	Cohort B - Itraconazole 200 mg Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months	Untreated Control Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment
Overall Study STARTED	12	3	4	10
Overall Study COMPLETED	9	3	4	10
Overall Study NOT COMPLETED	3	0	0	0

Reasons for withdrawal

Measure	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.	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.	Cohort B - Itraconazole 200 mg Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months	Untreated Control Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment
Overall Study Adverse Event	2	0	0	0
Overall Study Withdrawal by Subject	1	0	0	0

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) n=68 Basal cell carcinoma lesions 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 A2 - Itraconazole 400 mg (Prior Vismodegib) n=8 Basal cell carcinoma lesions 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.	Cohort B - Itraconazole 200 mg (Vismodegib-naïve) n=14 Basal cell carcinoma lesions Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months treatment. All Cohort B participants were vismodegib-naïve.	Untreated Control n=11 Basal cell carcinoma lesions Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment	Total n=101 Basal cell carcinoma lesions Total of all reporting groups
Age, Continuous	62.2 years n=5 Participants	57.7 years n=7 Participants	61.7 years n=5 Participants	68.5 years n=4 Participants	65.35 years n=21 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	6 Participants n=21 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	8 Participants n=4 Participants	23 Participants n=21 Participants
Region of Enrollment United States	12 participants n=5 Participants	3 participants n=7 Participants	0 participants n=5 Participants	10 participants n=4 Participants	25 participants n=21 Participants
Region of Enrollment Chile	0 participants n=5 Participants	0 participants n=7 Participants	4 participants n=5 Participants	0 participants n=4 Participants	4 participants n=21 Participants
Number of Tumor Lesions at Baseline 1 Tumor Lesion at Baseline	8 Participants n=5 Participants	3 Participants n=7 Participants	0 Participants n=5 Participants	10 Participants n=4 Participants	21 Participants n=21 Participants
Number of Tumor Lesions at Baseline > 1 Tumor Lesion at Baseline	4 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants	1 Participants n=4 Participants	9 Participants n=21 Participants

PRIMARY outcome

Timeframe: 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).

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.

Outcome measures

Measure	Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) n=31 Basal Cell Carcinoma (BCC) lesions 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 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.	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.	Untreated Control n=23 Basal Cell Carcinoma (BCC) lesions 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 Unpaired Analysis	18 Mean percent change Standard Deviation 17	—	—	0 Mean percent change Standard Deviation 15
Ki67 Tumor Proliferation Biomarker Paired Analysis	-19 Mean percent change Standard Deviation 15	—	—	13 Mean percent change Standard Deviation 12

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) n=18 Basal Cell Carcinoma (BCC) lesions 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 A2 - Itraconazole 400 mg (Prior Vismodegib) n=6 Basal Cell Carcinoma (BCC) lesions 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.	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.	Untreated Control Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment.
Change of GLI1 Tumor Biomarker	-40.3 Percent change Standard Deviation 35.6	-16.2 Percent change Standard Deviation 13.1	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) n=42 Basal Cell Carcinoma (BCC) lesions 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 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.	Cohort B - Itraconazole 200 mg (Vismodegib-naïve) n=14 Basal Cell Carcinoma (BCC) lesions Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months treatment. All Cohort B participants were vismodegib-naïve.	Untreated Control Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment.
Tumor Size	-25.4 Mean percent change Standard Deviation 21.8	—	-20 Mean percent change Standard Deviation 24.4	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) n=4 Participants 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 A2 - Itraconazole 400 mg (Prior Vismodegib) n=3 Participants 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.	Cohort B - Itraconazole 200 mg (Vismodegib-naïve) n=4 Participants Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months treatment. All Cohort B participants were vismodegib-naïve.	Untreated Control n=10 Participants Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment.
Tumor Response Complete Response (CR)	0 Participants	0 Participants	0 Participants	0 Participants
Tumor Response Partial Response (PR)	4 Participants	0 Participants	0 Participants	0 Participants
Tumor Response No Response (NR) / Stable Disease (SD)	0 Participants	3 Participants	4 Participants	10 Participants
Tumor Response Disease Progression (PD)	0 Participants	0 Participants	0 Participants	0 Participants

Adverse Events

Cohort A1 - Itraconazole 400 mg +/- Prior Vismodegib

Serious events: 1 serious events

Other events: 1 other events

Deaths: 0 deaths

Cohort A2 - Itraconazole 400 mg (Prior Vismodegib)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Cohort B - Itraconazole 200 mg (Vismodegib-naïve)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Measure	Cohort A1 - Itraconazole 400 mg +/- Prior Vismodegib n=12 participants at risk Oral itraconazole 400 mg as 200 mg twice daily, for 1 month.	Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) n=3 participants at risk Oral itraconazole 400 mg as 200 mg twice daily, for 1 month.	Cohort B - Itraconazole 200 mg (Vismodegib-naïve) n=4 participants at risk Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months treatment. All Cohort B participants were vismodegib-naïve.
Cardiac disorders Congestive heart failure	8.3% 1/12 • Number of events 1 • 2.3 months (average) All patients treated with itraconazole were monitored for adverse events ≥ Grade 2. Only adverse events (AEs) grade 2 or greater were collected and reported.	0.00% 0/3 • 2.3 months (average) All patients treated with itraconazole were monitored for adverse events ≥ Grade 2. Only adverse events (AEs) grade 2 or greater were collected and reported.	0.00% 0/4 • 2.3 months (average) All patients treated with itraconazole were monitored for adverse events ≥ Grade 2. Only adverse events (AEs) grade 2 or greater were collected and reported.

Other adverse events

Measure	Cohort A1 - Itraconazole 400 mg +/- Prior Vismodegib n=12 participants at risk Oral itraconazole 400 mg as 200 mg twice daily, for 1 month.	Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) n=3 participants at risk Oral itraconazole 400 mg as 200 mg twice daily, for 1 month.	Cohort B - Itraconazole 200 mg (Vismodegib-naïve) n=4 participants at risk Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months treatment. All Cohort B participants were vismodegib-naïve.
General disorders Grade 2 Fatigue	8.3% 1/12 • Number of events 1 • 2.3 months (average) All patients treated with itraconazole were monitored for adverse events ≥ Grade 2. Only adverse events (AEs) grade 2 or greater were collected and reported.	0.00% 0/3 • 2.3 months (average) All patients treated with itraconazole were monitored for adverse events ≥ Grade 2. Only adverse events (AEs) grade 2 or greater were collected and reported.	0.00% 0/4 • 2.3 months (average) All patients treated with itraconazole were monitored for adverse events ≥ Grade 2. Only adverse events (AEs) grade 2 or greater were collected and reported.

Additional Information

Jean Tang MD PhD, Associate Professor of Dermatology

Stanford University Medical Center

Phone: 650-723-6316

Email: tangy@stanford.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place