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

• ClinicalTrials.gov Identifier: NCT00961896
• Recruitment Status: Completed
• First Posted: August 19, 2009
• Results First Posted: September 21, 2015
• Last Update Posted: November 3, 2015
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Treatment for Basal Cell Carcinomas (BCCs) in Gorlin Syndrome Patients	Drug: Vehicle; Drug: LDE225 0.25%; Drug: LDE225 0.75%	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Study Start Date: July 2009
• Actual Primary Completion Date: August 2010

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: LDE225 (applied in parallel with vehicle) [Part I]; 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%
Placebo Comparator: Vehicle cream (applied in parallel with LDE225 [Part I]; 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; Placebo cream
Active Comparator: LDE225 0.25% [Part II]; Participants were exposed to topically applied 0.25% LDE225 cream twice daily for 6 weeks.	Drug: LDE225 0.25%
Active Comparator: LDE225 0.75% [Part II]; 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%

Outcome Measures

Primary Outcome Measures :

1. Percentage of BCCs With Complete and at Least Partial Clinical Clearance [ Time Frame: 4 weeks, 6 weeks, 9 weeks ]
   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).
2. Number of Participants With at Least Partial Clinical Clearance (Part I) [ Time Frame: day 8, day 15, day 22, day 29 ]
   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).

Secondary Outcome Measures :

1. Change From Baseline in Tumor Measurements (Part I) [ Time Frame: 4 weeks ]
   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.
2. Change From Baseline in Tumor Measurements (Part II) [ Time Frame: 4 weeks, 6 weeks, 9 weeks ]
   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.
3. Change From Baseline in Tumor Measurements (by Tumor) (Part I) [ Time Frame: 4 weeks ]
   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. Change From Baseline in Tumor Measurements (by Tumor) (Part II) [ Time Frame: 4 weeks, 6 weeks, 9 weeks ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Austria

Novartis Investigative Site

Graz, Austria

Novartis Investigator Site

Vienna, Austria

Switzerland

Novartis Investigative Site

Zurich, Switzerland

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00961896
• Other Study ID Numbers: CLDE225B2203; EudraCT 2008 005506-40
• First Posted: August 19, 2009
• Results First Posted: September 21, 2015
• Last Update Posted: November 3, 2015
• Last Verified: October 2015

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Basal Cell Carcinoma; Gorlin Syndrome,; Gorlin-Goltz Syndrome,; Basal Cell Nevus Syndrome,; Nevoid Basal Cell Carcinoma Syndrome,; Basal Cell Carcinoma Nevus Syndrome

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Basal Cell; Basal Cell Nevus Syndrome; Syndrome; Disease; Pathologic Processes; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Basal Cell; Odontogenic Cysts; Jaw Cysts; Bone Cysts; Cysts; Neoplastic Syndromes, Hereditary; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Jaw Diseases; Stomatognathic Diseases; Abnormalities, Multiple; Congenital Abnormalities; Genetic Diseases, Inborn