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
Overview
- Phase
- Phase 2
- Intervention
- LDE225 0.75%
- Conditions
- Treatment for Basal Cell Carcinomas (BCCs) in Gorlin Syndrome Patients
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 18
- Locations
- 2
- Primary Endpoint
- Percentage of BCCs With Complete and at Least Partial Clinical Clearance
- Status
- Completed
- Last Updated
- 10 years ago
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.
Investigators
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.
Arms & Interventions
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.
Intervention: LDE225 0.75%
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.
Intervention: Vehicle
LDE225 0.25% [Part II]
Participants were exposed to topically applied 0.25% LDE225 cream twice daily for 6 weeks.
Intervention: LDE225 0.25%
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.
Intervention: LDE225 0.75%
Outcomes
Primary Outcomes
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).
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 Outcomes
- Change From Baseline in Tumor Measurements (Part I)(4 weeks)
- Change From Baseline in Tumor Measurements (Part II)(4 weeks, 6 weeks, 9 weeks)
- Change From Baseline in Tumor Measurements (by Tumor) (Part I)(4 weeks)
- Change From Baseline in Tumor Measurements (by Tumor) (Part II)(4 weeks, 6 weeks, 9 weeks)