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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00961896
First received: August 18, 2009
Last updated: October 5, 2015
Last verified: October 2015
  Purpose

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 Intervention Phase
Treatment for Basal Cell Carcinomas (BCCs) in Gorlin Syndrome Patients
Drug: Vehicle
Drug: LDE225 0.25%
Drug: LDE225 0.75%
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Percentage of BCCs With Complete and at Least Partial Clinical Clearance [ Time Frame: 4 weeks, 6 weeks, 9 weeks ] [ Designated as safety issue: No ]
    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).

  • Number of Participants With at Least Partial Clinical Clearance (Part I) [ Time Frame: day 8, day 15, day 22, day 29 ] [ Designated as safety issue: No ]
    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:
  • Change From Baseline in Tumor Measurements (Part I) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Tumor Measurements (Part II) [ Time Frame: 4 weeks, 6 weeks, 9 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Tumor Measurements (by Tumor) (Part I) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Tumor Measurements (by Tumor) (Part II) [ Time Frame: 4 weeks, 6 weeks, 9 weeks ] [ Designated as safety issue: No ]
    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.


Enrollment: 18
Study Start Date: July 2009
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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%

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00961896

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     History of Changes
Other Study ID Numbers: CLDE225B2203  EudraCT 2008 005506-40 
Study First Received: August 18, 2009
Results First Received: August 19, 2015
Last Updated: October 5, 2015
Health Authority: Austria: Agency for Health and Food Safety
Switzerland: Swissmedic

Keywords provided by Novartis:
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:
Basal Cell Nevus Syndrome
Syndrome
Carcinoma
Carcinoma, Basal Cell
Eye Abnormalities
Foot Deformities, Congenital
Syndactyly
Tooth Abnormalities
Craniofacial Abnormalities
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
Eye Diseases
Foot Deformities

ClinicalTrials.gov processed this record on July 24, 2016