Neoplasms

All Conditions

Symptoms and General Pathology

Musculoskeletal Diseases

Mouth and Tooth Diseases

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Rare Diseases

Carcinoma

Syndrome

Carcinoma, Basal Cell

Basal Cell Nevus Syndrome

Nevus, Pigmented

Nevus

Focal Dermal Hypoplasia

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Basal Cell

Cysts

Odontogenic Cysts

Jaw Cysts

Bone Cysts

Neoplastic Syndromes, Hereditary

Bone Diseases

Bone Diseases, Developmental

Jaw Diseases

Stomatognathic Diseases

Congenital Abnormalities

Abnormalities, Multiple

Genetic Diseases, Inborn

Nevoid Basal Cell Carcinoma Syndrome

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.

Participants were exposed to topically applied 0.25% LDE225 cream twice daily for 6 weeks.

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.

Vehicle

LDE225 0.25%

LDE225 0.75%

Novartis Pharmaceuticals

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.

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

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

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).

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.

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.

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.

All Part I Participants

0.25% LDE225 [Part II]

Participants were exposed to topically applied 0.75% LDE225 cream twice daily where some basal cell carcinomas (BCCs) were treated for 6 weeks and some BCCs were treated for 9 weeks.

0.75% LDE225 [Part II]

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.

LDE225 0.75%

Participants were exposed to topically applied 0.25% LDE225 cream twice daily for 6 weeks.

LDE225 0.25%

LDE225 0.25% [Part II]

Participants were exposed to topically applied 0.75% LDE225 cream twice daily where some basal cell carcinomas (BCCs) were treated for 6 weeks and some BCCs were treated for 9 weeks.

LDE225 0.75%

LDE225 0.75% [Part II]

Total

Age, Continuous

Sex: Female, Male

Study Director

Week 4, at least partial

Week 4, complete

Week 6, at least partial

Week 6, complete

Week 9, at least partial (LDE 0.75%, n=10)

Week 9, complete (LDE 0.75%, n=10)

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.

Vehicle: Placebo cream

Vehicle Cream (Applied in Parallel With LDE225 [Part I]

Percentage of BCCs With Complete and at Least Partial Clinical Clearance

2D surface area

3D surface area

Height

Redness

Total volume

All part I participants were included in the analysis.

Change From Baseline in Tumor Measurements (Part I)

2D surface, week 4

2D surface, week 6

2D surface area, week 9

3D surface area , week 4

3D surface area, week 6

3D surface area, week 9

Total volume, week 4

Total volume, week 6

Total volume, week 9

Part II participants with evaluable data (n=3,6) were included in the analysis.

Change From Baseline in Tumor Measurements (Part II)

All part I participants were included in this analysis.

Change From Baseline in Tumor Measurements (by Tumor) (Part I)

2D surface area, week 4

2D surface area, week 6 (LDE 0.75%, n=21)

2D surface area, week 9 (LDE 0.75%, n=10)

3D surface area, week 4

3D surface area, week 6 (LDE 0.75%, n=21)

3D surface area, week 9 (LDE 0.75%, n=10)

Total volume, week 6 (LDE 0.75%, n=21)

Total volume, week 9 (LDE 0.75%, n=10)

Change From Baseline in Tumor Measurements (by Tumor) (Part II)

Day 8

Day 15

Day 22

Day 29

Number of Participants With at Least Partial Clinical Clearance (Part I)

Overall Study

LDE225

Placebo

This was a phase II, double-blind, randomized, proof-of-concept, dose-ranging trial evaluating the efficacy, safety and pharmacokinetics of oral LDE225 in treatment of adult patients with NBCCS. This was an exploratory study designed to demonstrate preliminary efficacy of LDE225 in this indication. This study included a Screening period of approximately 4 weeks, treatment period duration of 12 weeks with initial follow-up of approximately 6-8 weeks followed by a long-term follow-up period.

Efficacy, Safety and Pharmacokinetics of Oral LDE225 in Treatment of Patients With Nevoid Basal Cell Carcinoma Syndrome (NBCCS)

A Phase II, Double-blind, Randomized, Proof-of-Concept, Dose-ranging Trial Evaluating the Efficacy, Safety and Pharmacokinetics of Oral LDE225 in Treatment of Adult Patients With Nevoid Basal Cell Carcinoma Syndrome

The clinical response of the main target (and secondary target, as appropriate) BCC(s) to treatment was evaluated using the following 6-point scale comparing the assessment at the visit to the clinical presentation at Baseline: 0 = Worsening, 1 = No change, 2 = Slight clearance (1-25% improvement), 3 = Moderate clearance (26-75% improvement), 4 = Marked clearance (76-99% improvement),5 = Complete clearance (100% improvement) Complete clearance was defined as no clinical residual signs of carcinoma, as evaluated by the Investigator at a post-Baseline visit, with the exception of post-inflammatory changes such as minimal residual erythema or residual hyper-pigmentation or hypo-pigmentation or residual scarring.

The main (and secondary, if appropriate) target BCC tumor area(s) was/were excised surgically and sent to a central laboratory for histological examination.

BCC tumor counts were performed separately for five body regions: head and neck, trunk back, trunk front (including axillae and groin), upper extremities and lower extremities (including buttocks). During the counting, the BCC tumors, were categorized upon inspection by their longest diameter measurement (\<10 mm, 10-19 mm, 20-29 mm, and \>+30mm), and also by the type of BCC (superficial, nodular, other). The counts for all of the BCC type and size categories were determined (or estimated if many small lesions) for each body region. The body region counts were summated to provide the overall BCC tumor count.

LDE225 - Core

Placebo - Core

LDE225 - Long Term Follow-up

Placebo - Long Term Follow-up

Complete Clearance (100% Improvement)

Marked Clearance (76-99% Improvement)

Moderate Clearance (26-75% improvement)

Slight Clearance (1-25%)

Worsening

All participants, who had evaluable (or complete) pharmacodynamic (PD) or biomarker parameter data and were without protocol deviations with significant impact on the PD data, were included in the PD analysis set.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Trial to Evaluate the Safety, Local Tolerability, Pharmacokinetics and Pharmacodynamics of LDE225 on Skin Basal Cell Carcinomas in Gorlin Syndrome Patients	NCT00961896	Treatment for B...	Vehicle LDE225 0.25% LDE225 0.75%	18 Years - 75 Years	Novartis
A Trial to Evaluate the Safety, Local Tolerability, Pharmacokinetics and Pharmacodynamics of LDE225 on Skin Basal Cell Carcinomas in Gorlin Syndrome Patients	NCT00961896	Treatment for B...	Vehicle LDE225 0.25% LDE225 0.75%	18 Years - 75 Years	Novartis
Efficacy, Safety and Pharmacokinetics of Oral LDE225 in Treatment of Patients With Nevoid Basal Cell Carcinoma Syndrome (NBCCS)	NCT01350115	Basal Cell Carc... Gorlin Syndrome Nevoid Basal Ce...	LDE225 Placebo	18 Years -	Novartis

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