Basal Cell Carcinoma, Gorlin Syndrome, Nevoid Basal Cell Carcinoma Syndrome
Conditions
Keywords
Basal Cell Carcinoma, Gorlin Syndrome,, Gorlin-Goltz Syndrome,, Basal Cell Nevus Syndrome,, Nevoid Basal Cell Carcinoma Syndrome,, Basal Cell Carcinoma Nevus Syndrome, Smo inhibitor,, Hedgehog pathway inhibitor, BCCs
Brief summary
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.
Interventions
DRUGLDE225
supplied as 100 mg capsules
DRUGPlacebo
supplied in capsules
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with multiple basal cell carcinomas (at least two) and typical presentation of NBCCS. * Female patients must be women of non-childbearing potential (WONCBP).
Exclusion criteria
* Use of any topical treatment to treat BCCs, including prescription and over the counter in the 4 weeks prior to first dose of study drug. * Use of photodynamic therapy (PDT), radiation or systemic treatment known to affect BCCs or neoplasm in the 12 weeks prior to first dose of study drug. * Patients receiving medications that are recognized to cause rhabdomyolysis or patients with a prior history of rhabdomyolysis. * Patients with a histologically confirmed diagnosis of locally advanced or metastatic BCC. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Clearance Assessment of Main Target Basal Cell Carcinomas (BCCs) | Day 113 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Histological Clearance Assessment of Main Target BCCs | day 113 | The main (and secondary, if appropriate) target BCC tumor area(s) was/were excised surgically and sent to a central laboratory for histological examination. |
| Measure: Disease Burden by BCC Tumor Counts | Baseline, day 85, and day 113 | 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. |
Countries
Austria, Belgium, Canada, Germany
Participant flow
Pre-assignment details
Participants were assigned to one of the following 2 treatment arms in a ratio of 6:1,LDE225 400 mg QD and Placebo QD.
Participants by arm
| Arm | Count |
|---|---|
| LDE225 Participants received 400 mg once daily. | 8 |
| Placebo Participants received matching placebo. | 2 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Long Term Follow-Up (All Patients) | Adverse Event | 0 | 1 |
| Long Term Follow-Up (All Patients) | Lost to Follow-up | 0 | 1 |
| Long Term Follow-Up (All Patients) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | LDE225 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 50.5 Years STANDARD_DEVIATION 9.9 | 66 Years STANDARD_DEVIATION 2 | 53.6 Years STANDARD_DEVIATION 10.95 |
| Sex: Female, Male Female | 4 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 8 | 1 / 2 | 2 / 8 | 0 / 2 |
| serious Total, serious adverse events | 0 / 8 | 1 / 2 | 1 / 8 | 0 / 2 |
Outcome results
Primary
Clinical Clearance Assessment of Main Target Basal Cell Carcinomas (BCCs)
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.
Time frame: Day 113
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDE225 | Clinical Clearance Assessment of Main Target Basal Cell Carcinomas (BCCs) | Marked Clearance (76-99% Improvement) | 3 Participants |
| LDE225 | Clinical Clearance Assessment of Main Target Basal Cell Carcinomas (BCCs) | Slight Clearance (1-25%) | 0 Participants |
| LDE225 | Clinical Clearance Assessment of Main Target Basal Cell Carcinomas (BCCs) | Moderate Clearance (26-75% improvement) | 1 Participants |
| LDE225 | Clinical Clearance Assessment of Main Target Basal Cell Carcinomas (BCCs) | Worsening | 0 Participants |
| LDE225 | Clinical Clearance Assessment of Main Target Basal Cell Carcinomas (BCCs) | Complete Clearance (100% Improvement) | 3 Participants |
| Placebo | Clinical Clearance Assessment of Main Target Basal Cell Carcinomas (BCCs) | Worsening | 1 Participants |
| Placebo | Clinical Clearance Assessment of Main Target Basal Cell Carcinomas (BCCs) | Complete Clearance (100% Improvement) | 0 Participants |
| Placebo | Clinical Clearance Assessment of Main Target Basal Cell Carcinomas (BCCs) | Marked Clearance (76-99% Improvement) | 0 Participants |
| Placebo | Clinical Clearance Assessment of Main Target Basal Cell Carcinomas (BCCs) | Moderate Clearance (26-75% improvement) | 0 Participants |
| Placebo | Clinical Clearance Assessment of Main Target Basal Cell Carcinomas (BCCs) | Slight Clearance (1-25%) | 1 Participants |
Secondary
Histological Clearance Assessment of Main Target BCCs
The main (and secondary, if appropriate) target BCC tumor area(s) was/were excised surgically and sent to a central laboratory for histological examination.
Time frame: day 113
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDE225 | Histological Clearance Assessment of Main Target BCCs | Histological clearance | 57 Percentage of participants |
| LDE225 | Histological Clearance Assessment of Main Target BCCs | Complete clinical (up to day 85) & histological | 14 Percentage of participants |
| LDE225 | Histological Clearance Assessment of Main Target BCCs | Complete clinical (up to day 113) & histological | 29 Percentage of participants |
| Placebo | Histological Clearance Assessment of Main Target BCCs | Histological clearance | 0 Percentage of participants |
| Placebo | Histological Clearance Assessment of Main Target BCCs | Complete clinical (up to day 85) & histological | 0 Percentage of participants |
| Placebo | Histological Clearance Assessment of Main Target BCCs | Complete clinical (up to day 113) & histological | 0 Percentage of participants |
Secondary
Measure: Disease Burden by BCC Tumor Counts
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.
Time frame: Baseline, day 85, and day 113
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDE225 | Measure: Disease Burden by BCC Tumor Counts | Day 113 | 309 Number of BCC tumors |
| LDE225 | Measure: Disease Burden by BCC Tumor Counts | Baseline | 566 Number of BCC tumors |
| LDE225 | Measure: Disease Burden by BCC Tumor Counts | Day 85 | 341 Number of BCC tumors |
| Placebo | Measure: Disease Burden by BCC Tumor Counts | Baseline | 510 Number of BCC tumors |
| Placebo | Measure: Disease Burden by BCC Tumor Counts | Day 85 | 571 Number of BCC tumors |
| Placebo | Measure: Disease Burden by BCC Tumor Counts | Day 113 | 619 Number of BCC tumors |