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

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ClinicalTrials.gov Identifier: NCT01108094
Recruitment Status : Completed
First Posted : April 21, 2010
Results First Posted : November 12, 2018
Last Update Posted : November 12, 2018
Sponsor:
Information provided by (Responsible Party):
Jean Yuh Tang, Stanford University

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Basal Cell Carcinoma (BCC)
Skin Cancer
Intervention Drug: Itraconazole
Enrollment 29
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.
Pre-assignment Details  
Arm/Group Title Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) Cohort B - Itraconazole 200 mg Untreated Control
Hide Arm/Group Description 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. 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. Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment
Period Title: Overall Study
Started 12 3 4 10
Completed 9 3 4 10
Not Completed 3 0 0 0
Reason Not Completed
Adverse Event             2             0             0             0
Withdrawal by Subject             1             0             0             0
Arm/Group Title Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) Cohort B - Itraconazole 200 mg (Vismodegib-naïve) Untreated Control Total
Hide Arm/Group Description 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. 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. Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months treatment. All Cohort B participants were vismodegib-naïve. Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment Total of all reporting groups
Overall Number of Baseline Participants 12 3 4 10 29
Overall Number of Units Analyzed
Type of Units Analyzed: Basal cell carcinoma lesions
68 8 14 11 101
Hide Baseline Analysis Population Description
Patients with one or more BCC tumors measuring 4 mm or greater in diameter were enrolled.
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 12 participants 3 participants 4 participants 10 participants 29 participants
62.2
(44 to 85)
57.7
(55 to 62)
61.7
(51 to 78)
68.5
(53 to 81)
65.35
(44 to 85)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 3 participants 4 participants 10 participants 29 participants
Female
3
  25.0%
0
   0.0%
1
  25.0%
2
  20.0%
6
  20.7%
Male
9
  75.0%
3
 100.0%
3
  75.0%
8
  80.0%
23
  79.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 12 participants 3 participants 4 participants 10 participants 29 participants
United States 12 3 0 10 25
Chile 0 0 4 0 4
Number of Tumor Lesions at Baseline  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 3 participants 4 participants 10 participants 29 participants
1 Tumor Lesion at Baseline
8
  66.7%
3
 100.0%
0
   0.0%
10
 100.0%
21
  72.4%
> 1 Tumor Lesion at Baseline
4
  33.3%
0
   0.0%
4
 100.0%
1
  10.0%
9
  31.0%
1.Primary Outcome
Title Ki67 Tumor Proliferation Biomarker
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Ki67 tumor proliferation biomarker assessment was not performed for Cohorts A2 (itraconazole 400 mg & prior vismodegib) and B (itraconazole 100 mg twice daily).
Arm/Group Title Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) Cohort B - Itraconazole 200 mg (Vismodegib-naïve) Untreated Control
Hide Arm/Group Description:
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.
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.
Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months treatment. All Cohort B participants were vismodegib-naïve.
Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment.
Overall Number of Participants Analyzed 8 0 0 10
Overall Number of Units Analyzed
Type of Units Analyzed: Basal Cell Carcinoma (BCC) lesions
31 0 0 23
Mean (Standard Deviation)
Unit of Measure: Mean percent change
Unpaired Analysis Number Analyzed 20 Basal Cell Carcinoma (BCC) lesions 0 Basal Cell Carcinoma (BCC) lesions 0 Basal Cell Carcinoma (BCC) lesions 23 Basal Cell Carcinoma (BCC) lesions
18  (17) 0  (15)
Paired Analysis Number Analyzed 16 Basal Cell Carcinoma (BCC) lesions 0 Basal Cell Carcinoma (BCC) lesions 0 Basal Cell Carcinoma (BCC) lesions 23 Basal Cell Carcinoma (BCC) lesions
-19  (15) 13  (12)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve)
Comments

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.

Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.04
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve)
Comments

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.

Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.079
Comments [Not Specified]
Method t-test, 1 sided
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Untreated Control
Comments

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.

Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.652
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
2.Secondary Outcome
Title Change of GLI1 Tumor Biomarker
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) Cohort B - Itraconazole 200 mg (Vismodegib-naïve) Untreated Control
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 3 3 0 0
Overall Number of Units Analyzed
Type of Units Analyzed: Basal Cell Carcinoma (BCC) lesions
18 6 0 0
Mean (Standard Deviation)
Unit of Measure: Percent change
-40.3  (35.6) -16.2  (13.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve)
Comments

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.

Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.028
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Other Statistical Analysis Wilcoxon signed rank test
3.Secondary Outcome
Title Tumor Size
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve) Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) Cohort B - Itraconazole 200 mg (Vismodegib-naïve) Untreated Control
Hide Arm/Group Description:
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.
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.
Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months treatment. All Cohort B participants were vismodegib-naïve.
Participants otherwise eligible but unwilling to take itraconazole were enrolled onto the control arm of the study and received no treatment.
Overall Number of Participants Analyzed 4 0 4 0
Overall Number of Units Analyzed
Type of Units Analyzed: Basal Cell Carcinoma (BCC) lesions
42 0 14 0
Mean (Standard Deviation)
Unit of Measure: Mean percent change
-25.4  (21.8) -20  (24.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve), Cohort B - Itraconazole 200 mg (Vismodegib-naïve)
Comments 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.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 24
Confidence Interval (2-Sided) 95%
18.2 to 30
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohort A1 - Itraconazole 400 mg (Vismodegib-naïve), Cohort B - Itraconazole 200 mg (Vismodegib-naïve)
Comments Average tumor size reductions were compared between Cohort A1 and Cohort B.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.435
Comments [Not Specified]
Method t-test, 1 sided
Comments [Not Specified]
4.Secondary Outcome
Title Tumor Response
Hide Description

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)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cohort A1 - Itraconazole 400 mg, (Vismodegib-naïve) Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) Cohort B - Itraconazole 200 mg (Vismodegib-naïve) Untreated Control
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 4 3 4 10
Measure Type: Count of Participants
Unit of Measure: Participants
Complete Response (CR)
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Partial Response (PR)
4
 100.0%
0
   0.0%
0
   0.0%
0
   0.0%
No Response (NR) / Stable Disease (SD)
0
   0.0%
3
 100.0%
4
 100.0%
10
 100.0%
Disease Progression (PD)
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Time Frame 2.3 months (average)
Adverse Event Reporting Description All patients treated with itraconazole were monitored for adverse events ≥ Grade 2. Only adverse events (AEs) grade 2 or greater were collected and reported.
 
Arm/Group Title Cohort A1 - Itraconazole 400 mg +/- Prior Vismodegib Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) Cohort B - Itraconazole 200 mg (Vismodegib-naïve)
Hide Arm/Group Description Oral itraconazole 400 mg as 200 mg twice daily, for 1 month. Oral itraconazole 400 mg as 200 mg twice daily, for 1 month. Oral itraconazole 200 mg as 100 mg twice daily, for up to 3 months treatment. All Cohort B participants were vismodegib-naïve.
All-Cause Mortality
Cohort A1 - Itraconazole 400 mg +/- Prior Vismodegib Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) Cohort B - Itraconazole 200 mg (Vismodegib-naïve)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/12 (0.00%)      0/3 (0.00%)      0/4 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Cohort A1 - Itraconazole 400 mg +/- Prior Vismodegib Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) Cohort B - Itraconazole 200 mg (Vismodegib-naïve)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/12 (8.33%)      0/3 (0.00%)      0/4 (0.00%)    
Cardiac disorders       
Congestive heart failure * [1]  1/12 (8.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
[1]
One grade 4 congestive heart failure occurred in a patient who had undiagnosed heart disease from prior adriamycin treatment for Hodgkin lymphoma 20 years previously.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Cohort A1 - Itraconazole 400 mg +/- Prior Vismodegib Cohort A2 - Itraconazole 400 mg (Prior Vismodegib) Cohort B - Itraconazole 200 mg (Vismodegib-naïve)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/12 (8.33%)      0/3 (0.00%)      0/4 (0.00%)    
General disorders       
Grade 2 Fatigue *  1/12 (8.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Jean Tang MD PhD, Associate Professor of Dermatology
Organization: Stanford University Medical Center
Phone: 650-723-6316
EMail: tangy@stanford.edu
Layout table for additonal information
Responsible Party: Jean Yuh Tang, Stanford University
ClinicalTrials.gov Identifier: NCT01108094     History of Changes
Other Study ID Numbers: IRB-17365
SU-04162010-5722 ( Other Identifier: Stanford University )
SKIN0004-TX ( Other Identifier: OnCore )
First Submitted: April 19, 2010
First Posted: April 21, 2010
Results First Submitted: November 22, 2016
Results First Posted: November 12, 2018
Last Update Posted: November 12, 2018