Clinical Trial of Patidegib Gel 2%, 4%, and Vehicle Applied Once or Twice Daily to Decrease the GLI1 Biomarker in Sporadic Nodular Basal Cell Carcinomas

Study Overview
=================
Brief Summary
-----------------
This is a double-blind, dose escalating, randomized, vehicle-controlled study designed to compare the efficacy and safety of patidegib gel 2% and 4% applied once or twice daily in comparison with that of vehicle in patients with Basal Cell Carcinoma. One investigational center (metasite) in the United States will participate in this study. Approximately 36 subjects who meet the study entry criteria will be enrolled into one of four sequential cohorts. Within each cohort subjects will be randomized in a 2:1 ratio to receive active or vehicle gel.

Detailed Description
-----------------
This is a double-blind, dose escalating, randomized, vehicle-controlled study designed to compare the efficacy and safety of patidegib gel 2% and 4% applied once or twice daily in comparison with that of vehicle. Approximately 36 subjects who meet the study entry criteria will be enrolled into one of four sequential cohorts. As soon as one cohort has been completely enrolled, the next cohort will be enrolled. Each subject will treat no more than two previously untreated biopsy confirmed treatment-targeted nodular BCCs. If the subject has additional non-treatment targeted BCCs they can be treated surgically prior to or during the trial. Within each cohort subjects will be randomized in a 2:1 ratio to receive active or vehicle gel. The sequential cohorts will be: Cohort 1: patidegib gel 2% or vehicle, once daily Cohort 2: patidegib gel 4% or vehicle, once daily Cohort 3: patidegib gel 2% or vehicle, twice daily Cohort 4: patidegib gel 4% or vehicle, twice daily The study drug will be applied topically to the treatment-targeted BCCs and a rim of adjacent skin for 12 weeks. Information on reported and observed adverse events (AEs) will be obtained at each visit. An abbreviated physical examination (PE) will be performed at Baseline and Week 12. The treatment-targeted BCCs will be identified by the Investigator at the Baseline visit and will be circled in ink at Baseline, Weeks 6 and 12 and photographed, and measured at all study visits (Baseline, Weeks 2, 6, 8, 10, and 12). Blood samples for complete blood count and serum chemistry and urine for urinalysis will be collected from subjects at Screening, Week 6, and Week 12. Subjects who terminate study participation early will be asked to complete all Week 12 assessments, as appropriate, prior to commencement of any alternative therapy for BCCs (if possible). Subjects who discontinue from the study during the treatment period will not be replaced.

Official Title
-----------------
Double-Blind, Dose Escalating, Randomized, Vehicle-Controlled Proof of Concept Clinical Trial of Patidegib Gel 2%, 4%, and Vehicle Applied Once or Twice Daily to Decrease the GLI1 Biomarker in Sporadic Nodular Basal Cell Carcinomas

Conditions
-----------------
Basal Cell Carcinomas

Intervention / Treatment
-----------------
* Drug: Patidegib
* Drug: Vehicle gel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The participant is from 18 to 85 years of age, inclusive. The participant must provide electronic informed consent prior to any study procedures. If the participant is a woman of childbearing potential, she is willing to use two effective methods of birth control during the duration of the trial and for one month after the last application of the gel. The two forms of birth control authorized are defined as the use of a barrier method of contraception (condom with spermicide) in association with one of the following methods of birth control: bilateral tubal ligation; combined oral contraceptives (estrogens and progesterone) or implanted or injectable contraceptives with a stable dose for at least 1 month prior to Baseline; hormonal intra-uterine device (IUD) inserted at least 1 month prior to Baseline. This proscription is based on the key role of the hedgehog (HH) pathway in embryogenesis, the known preclinical teratogenic effects of systemic cyclopamine, a naturally occurring inhibitor of smoothened (SMO), and the unknown level of systemic exposure following topical application of patidegib in humans. If the participant is a male with a female sexual partner who is of childbearing potential, the couple is willing to use two effective methods of birth control during the duration of the trial and for one month after the last application of the gel. Authorized birth control methods are outlined in Inclusion Criterion #3. Any woman of childbearing potential applying the gel to themselves, or assisting a subject, must comply with the same birth control measures. One or two previously untreated basal cell carcinomas (BCCs) with the clinical features of a nodular BCC confirmed by a biopsy done at or prior to screening confirming nodular BCC. These tumors must be suitable for surgical excision. The BCCs prior to biopsy must be no less than 5 millimeters (mm) or greater than 15 mm in greatest diameter on the face and no less than 9 mm or more than 20 mm in greatest diameter at sites other than the face. Tumors on the nose, periorbital skin, or on or below the knee are excluded. The participant is willing to abstain from application of non-study topical prescription and over the counter medications within 5 centimeters (cm) of a treatment-targeted BCC for the duration of the study except as prescribed by the Investigator. Moisturizers and emollients are allowable. Subjects will be encouraged to use sunscreen with a sunscreen protection factor (SPF 15 or higher) at least once daily on all exposed skin sites. Female participant must have negative serum pregnancy test at Screening. The participant is willing to contact the study center after each primary skin care physician (PSCP) visit to provide the study center details of the visit and any treatment of skin tumors. The participant is willing to forego alternative treatment of the treatment-targeted baseline BCC for the duration of the trial. Exclusion Criteria: Participants with basal cell nevus syndrome (BCNS, Gorlin syndrome, nevoid basal cell carcinoma syndrome; Online Mendelian Inheritance in Man [OMIM] #109400). The participant has used topical products within 5 cm of a treatment- targeted BCC or systemic therapies that might interfere with the evaluation of the study medication during the study. Specifically, these include the use of: Topical glucocorticoids 30 days prior to screening Retinoids (such as etretinate, isotretinoin, tazarotene, tretinoin, adapalene) systemically or topically, or > 5% of an alphahydroxy acid (such as glycolic acid, lactic acid), photodynamic therapy (PDT), or 5-fluorouracil or imiquimod (except as topical treatment to discrete BCCs) systemically or topically to the skin during the six months prior to entry. Systemic chemotherapy within one year prior to screening. (Note: field therapy with topically applied treatments can be done as long as they are not applied within 5 cm of a treatment-targeted tumor). Known inhibitors of the HH signaling pathway (such as vismodegib, patidegib, sonidegib, and itraconazole) topically or systemically within 6 months of entry into the study. The participant has a history of hypersensitivity to any of the ingredients in the study medication formulation. The participant is unable or unwilling to make a good faith effort to be present for all follow-up visits and tests. The participant is a woman who is currently nursing. The participant has any systemic disease that in the Investigator's opinion would interfere with the subject's ability to participate. The participant has a clinically significant history of liver disease, including viral hepatitis, current alcohol abuse, or cirrhosis, that in the investigator's opinion would interfere with the participant's ability to participate. The participant has any condition or situation which in the Investigator's opinion may put the subject at significant risk, could confound the study results, or could interfere significantly with the participant's participation in the study. This includes history of other skin conditions or diseases, metabolic dysfunction, physical examination findings, or clinical laboratory findings giving reasonable suspicion of a disease or condition that contraindicates use of this investigational drug or that might affect interpretation of the results of the study or render the participant at high risk from treatment complications. The participant has a history of invasive cancer within the past five years excluding non-melanoma skin cancer, Stage I cervical cancer, ductal carcinoma in situ of breast, or chronic lymphocytic lymphoma (CLL) (Stage 0). The participant is currently participating in an experimental drug study (within 4 weeks of Baseline visit) or plans to participate in an experimental drug study while enrolled in this study. The participant is on a concomitant medication that is a strong CYP3A4 inhibitor. These include, but are not limited to: larithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patidegib gel 2% - Cohort 1<br>Patidegib gel 2%, applied topically, once daily for 12 weeks (Cohort 1) | Drug: Patidegib<br> <br> * Other names: Study drug;|
| Experimental: Patidegib gel 4% - Cohort 2<br>Patidegib gel 4%, applied topically, once daily for 12 weeks (Cohort 2) | Drug: Patidegib<br> <br> * Other names: Study drug;|
| Placebo Comparator: Vehicle gel - Cohort 1<br>Vehicle gel, applied topically, once daily for 12 weeks (Cohort 1) | Drug: Vehicle gel<br> <br> * Other names: Placebo;|
| Experimental: Patidegib gel 2% - Cohort 3<br>Patidegib gel 2%, applied topically, twice daily for 12 weeks (Cohort 3) | Drug: Patidegib<br> <br> * Other names: Study drug;|
| Experimental: Patidegib gel 4% - Cohort 4<br>Patidegib gel 4%, applied topically, twice daily for 12 weeks (Cohort 4) | Drug: Patidegib<br> <br> * Other names: Study drug;|
| Placebo Comparator: Vehicle gel - Cohort 2<br>Vehicle gel, applied topically, once daily for 12 weeks (Cohort 2) | Drug: Vehicle gel<br> <br> * Other names: Placebo;|
| Placebo Comparator: Vehicle gel - Cohort 3<br>Vehicle gel, applied topically, twice daily for 12 weeks (Cohort 3) | Drug: Vehicle gel<br> <br> * Other names: Placebo;|
| Placebo Comparator: Vehicle gel - Cohort 4<br>Vehicle gel, applied topically, twice daily for 12 weeks (Cohort 4) | Drug: Vehicle gel<br> <br> * Other names: Placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment-emergent Adverse Events (Including Both Serious and Non-Serious) Causally Related to Study Drug | All serious adverse events (SAEs) and all other non-serious adverse events (AEs) regardless of causality are located in the Reported AE Module. The number of AEs (including both serious and non-serious) considered related to study drug by the Investigator are presented below. Treatment-emergent AEs are those with an onset after use of study drug. | Baseline through Week 12 | 
| Molecular Efficacy: Percent Change From Baseline in the Hedgehog (HH) Signaling Pathway Target Gene Glioma-associated Oncogene Homolog 1 (GLI1) Messenger Ribonucleic Acid (mRNA) Levels at Week 12 | GLI1 change is a biomarker of the HH signaling pathway. A change in GLI1 mRNA levels reflect a change in the HH pathway. Surgically eligible basal cell carcinomas (SEBs) were defined as clinically diagnosed basal cell carcinoma (BCC) 5 to 20 millimeters (mm) in diameter on the face, excluding the nose and periorbital skin, and 9 to 20 mm at sites other than the face. A single baseline BCC designated as a treatment-targeted tumor at Baseline was biopsied first at Baseline and again following 12 weeks of treatment. This was used to assess percent change in GLI1 mRNA levels as follows: (Baseline - Week 12) / Baseline * 100, with positive numbers to represent increases and negative numbers to represent decreases. Any missing values were not imputed; all available data is summarized. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Efficacy: Percent Change From Baseline in Tumor Size of Treatment-targeted SEBs at Week 12 | SEBs were defined as clinically diagnosed BCC 5 to 20 mm in diameter on the face, excluding the nose and periorbital skin, and 9 to 20 mm at sites other than the face. The percent change in greatest diameters of treatment-targeted surgically eligible basal cell carcinomas (SEBs) from Baseline to Week 12 was calculated as follows: (sum [Baseline] - sum [Week 12] / sum [Baseline] * 100), where sum = the greatest diameters of treatment-targeted SEBs and positive numbers to represent increases and negative numbers to represent decreases. Missing values were imputed using Last-Observation Carried Forward (LOCF). | Baseline, Week 12 | 
| Clinical Efficacy: Percentage of SEBs Showing Complete or Partial Response at Week 12 as Determined by Blinded Photographic Review | SEBs were defined as clinically diagnosed BCC 5 to 20 mm in diameter on the face, excluding the nose and periorbital skin, and 9 to 20 mm at sites other than the face. The percentage of tumors showing a complete or partial response at Week 12 was calculated as follows: (Number of baseline treatment-targeted SEBs showing complete or partial response at Week 12) / (Number of Baseline treatment-targeted SEBs) * 100. Missing values were not imputed.Complete Response is determined when there is no longer any visible evidence of a lesion consistent with BCC at the site, and Partial Response is determined when although a BCC still remains at this site, it has demonstrated a visible decrease in size compared with baseline. | Baseline, Week 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
High Frequency Basal Cell Carcinomas, Gorlin Syndrome, Basal Cell Nevus Syndrome BCNS, nevoid basal cell carcinoma syndrome, Basal cell carcinoma, Hedgehog inhibitor, Surgically Eligible Basal Cell Carcinomas