A Trial to Evaluate the Safety, Local Tolerability, Pharmacokinetics and Pharmacodynamics of LDE225 on Skin Basal Cell Carcinomas in Gorlin Syndrome Patients

Study Overview
=================
Brief Summary
-----------------
Part I was a double-blind, randomized, vehicle-controlled Proof of Concept (PoC) study to evaluate the safety, local tolerability, pharmacokinetics and pharmacodynamics of multiple topical administrations of LDE225 (a specific Smoothened inhibitor) on skin basal cell carcinomas in Gorlin's syndrome patients. Following a 21-day screening period, patients were exposed to multiple doses of topically applied LDE225 twice daily for 4 weeks in a double-blind manner. The patients returned weekly for visits where each BCC was clinically evaluated and digital photographs taken. Local safety and tolerability was also assessed. After the last application of treatment, biopsies were taken from treated (both vehicle and LDE225) BCCs (three per patient) for histology, biomarker evaluation and for pharmacokinetics (skin exposure). In addition, a biopsy from LDE225-treated uninvolved perilesional skin was taken for pharmacokinetic evaluation. In total, 4 biopsies were taken: 2 for histology and biomarker and 2 for PK. Part II of this study consisted of a 21-day screening period, a baseline period (directly before commencing the treatment period) and a treatment period of 6 or 9 weeks, depending on randomization. A clinical assessment was performed on site on the last treatment day and if a full clinical response had been observed, approximately 3 weeks after the last treatment an excision of the BCC(s) would have been performed. The study completion visit occurred either 1 week after the excision (when this visit was planned) or 1 week after the last treatment. For a subset of patients, skin biopsies were collected on the last treatment day and an excision of a BCC was also performed at that same visit.

Official Title
-----------------
A Double-blind, Randomized, Vehicle-controlled Proof of Concept (PoC) Study to Evaluate the Safety, Local Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Topical Administrations of LDE225 (a Specific Smoothened Inhibitor) on Skin Basal Cell Carcinomas in Gorlin Syndrome Patients Followed by an Open Label, Randomized Expansion Group to Test Two Different Strengths of an Improved LDE225 Formulation for Extended Treatment Durations

Conditions
-----------------
Treatment for Basal Cell Carcinomas (BCCs) in Gorlin Syndrome Patients

Intervention / Treatment
-----------------
* Drug: Vehicle
* Drug: LDE225 0.25%
* Drug: LDE225 0.75%


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: - Patients with multiple basal cell carcinomas and Gorlin syndrome, or patients with multiple basal cell carcinomas and a mutation in the PTCH1 gene at chromosome 9q22.3 Exclusion Criteria: Previous treatment of the BCC's that are selected for treatment. Any systemic treatment which is known to affect BCCs esp. cytostatic treatments, retinoids and photodynamic treatments. Other protocol defined Incl./Excl. criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 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 |
| --- | --- |
| Active Comparator: LDE225 (applied in parallel with vehicle) [Part I]<br>Participants were exposed to both topically applied 0.75% LDE225 cream and LDE225 vehicle cream twice daily for 28 days where each treatment was randomized to two different test areas on each participant. | Drug: LDE225 0.75%<br> <br> |
| Placebo Comparator: Vehicle cream (applied in parallel with LDE225 [Part I]<br>Participants were exposed to both topically applied 0.75% LDE225 cream and LDE225 vehicle cream twice daily for 28 days where each treatment was randomized to two different test areas on each participant. | Drug: Vehicle<br>* Placebo cream<br>|
| Active Comparator: LDE225 0.25% [Part II]<br>Participants were exposed to topically applied 0.25% LDE225 cream twice daily for 6 weeks. | Drug: LDE225 0.25%<br> <br> |
| Active Comparator: LDE225 0.75% [Part II]<br>Participants were exposed to topically applied 0.75% LDE225 cream twice daily where some basal cell carcinomas (BCCs) were teated for 6 weeks and some BCCs were treated for 9 weeks. | Drug: LDE225 0.75%<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of BCCs With Complete and at Least Partial Clinical Clearance | Clinical response parameters were defined as (i) complete response (i.e., there is no longer any visible evidence of a lesion consistent with BCC at this site), (ii) partial response (i.e., although a BCC still remains at this site, it has demonstrated a visible decrease in size compared with baseline), and (iii) no response / worsening (i.e., the BCC has not demonstrated any visible decrease in size compared with baseline). | 4 weeks, 6 weeks, 9 weeks | 
| Number of Participants With at Least Partial Clinical Clearance (Part I) | Clinical response parameters were defined as (i) complete response (i.e., there is no longer any visible evidence of a lesion consistent with BCC at this site), (ii) partial response (i.e., although a BCC still remains at this site, it has demonstrated a visible decrease in size compared with baseline), and (iii) no response / worsening (i.e., the BCC has not demonstrated any visible decrease in size compared with baseline). | day 8, day 15, day 22, day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Tumor Measurements (Part I) | Measurement of the tumor size, volume and color by standardized digital photography, using dermatoscopic, macroscopic and 3D images of the BCCs was done by participant where if a participant had more than one tumor, for each of these tumors, the change from baseline was calculated (% change). From these values, the mean was calculated to get only one result per participant. Then for all the participants (n=8 both for LDE and vehicle), the mean was calculated. Photographic analysis was conducted by QuantifiCare. The volume of a lesion was measured with a special device, the 3D LIFEVIZ Micro system, which uses a lens splitter to produce two images of the skin surface, captured at the same time, with viewing angle differences close to human vision. A stereovision algorithm is then applied to reconstruct and quantitatively analyze the skin surface in 3D. A negative change from baseline indicates improvement. | 4 weeks | 
| Change From Baseline in Tumor Measurements (Part II) | Measurement of the tumor size, volume and color by standardized digital photography, using dermatoscopic, macroscopic and 3D images of the BCCs was done by participant where if a participant had more than one tumor, for each of these tumors, the change from baseline was calculated (% change). From these values, the mean was calculated to get only one result per participant. Then for all the participants (n=8 both for LDE and vehicle), the mean was calculated.. Photographic analysis was conducted by QuantifiCare. The volume of a lesion was measured with a special device, the 3D LIFEVIZ Micro system, which uses a lens splitter to produce two images of the skin surface, captured at the same time, with viewing angle differences close to human vision. A stereovision algorithm is then applied to reconstruct and quantitatively analyze the skin surface in 3D. A negative change from baseline indicates improvement. | 4 weeks, 6 weeks, 9 weeks | 
| Change From Baseline in Tumor Measurements (by Tumor) (Part I) | Measurement of the tumor size, volume and color by standardized digital photography, using dermatoscopic, macroscopic and 3D images of the BCCs. Photographic analysis was conducted by QuantifiCare. The volume of a lesion was measured with a special device, the 3D LIFEVIZ Micro system, which uses a lens splitter to produce two images of the skin surface, captured at the same time, with viewing angle differences close to human vision. A stereovision algorithm is then applied to reconstruct and quantitatively analyze the skin surface in 3D. A negative change from baseline indicates improvement. | 4 weeks | 
| Change From Baseline in Tumor Measurements (by Tumor) (Part II) | Measurement of the tumor size, volume and color by standardized digital photography, using dermatoscopic, macroscopic and 3D images of the BCCs. Photographic analysis was conducted by QuantifiCare. The volume of a lesion was measured with a special device, the 3D LIFEVIZ Micro system, which uses a lens splitter to produce two images of the skin surface, captured at the same time, with viewing angle differences close to human vision. A stereovision algorithm is then applied to reconstruct and quantitatively analyze the skin surface in 3D. A negative change from baseline indicates improvement. | 4 weeks, 6 weeks, 9 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Basal Cell Carcinoma, Gorlin Syndrome,, Gorlin-Goltz Syndrome,, Basal Cell Nevus Syndrome,, Nevoid Basal Cell Carcinoma Syndrome,, Basal Cell Carcinoma Nevus Syndrome