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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01350115
• Collaborator: (none)
• Enrollment: 10
• Locations: 6
• Arms: 2
• Duration (Months): 18
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Basal Cell Carcinoma; Gorlin Syndrome; Nevoid Basal Cell Carcinoma Syndrome	Drug: LDE225; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: LDE225 Participants received 400 mg once daily.	Drug: LDE225; supplied as 100 mg capsules
Placebo Comparator: Placebo Participants received matching placebo.	Drug: Placebo; supplied in capsules

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Wien		Austria	A-1090
2	Novartis Investigative Site	Leuven		Belgium	3000
3	Novartis Investigative Site	Markham	Ontario	Canada	L3P 1A8
4	Novartis Investigative Site	Waterloo	Ontario	Canada	N2J 1C4
5	Novartis Investigative Site	Montreal	Quebec	Canada	H2K 4L5
6	Novartis Investigative Site	Kiel		Germany	24105

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01350115
• Other Study ID Numbers: CLDE225B2209; 2010-023819-34
• First Posted: May 9, 2011
• Last Update Posted: Oct 19, 2015
• Last Verified: Sep 1, 2015

• Keywords provided by Novartis Pharmaceuticals: 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
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Basal Cell; Basal Cell Nevus Syndrome; Syndrome

Study Results

Participant Flow

Pre-assignment Detail	Participants were assigned to one of the following 2 treatment arms in a ratio of 6:1,LDE225 400 mg QD and Placebo QD.

Arm/Group Title	LDE225	Placebo
Arm/Group Description	Participants received 400 mg once daily.	Participants received matching placebo.
Period Title: Core Study (All Patients)
STARTED	8	2
Safety Anlysis Set	8	2
Pharmacodynamic Set	7	2
COMPLETED	8	2
NOT COMPLETED	0	0
Period Title: Core Study (All Patients)
STARTED	8	2
COMPLETED	7	0
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	LDE225	Placebo	Total
Arm/Group Description	Participants received 400 mg once daily.	Participants received matching placebo.	Total of all reporting groups
Overall Participants	8	2	10
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	50.5 (9.90)	66 (2.00)	53.6 (10.95)
Sex: Female, Male (Count of Participants)
Female	4 50%	0 0%	4 40%
Male	4 50%	2 100%	6 60%

Outcome Measures

1. Primary Outcome

Title	Clinical Clearance Assessment of Main Target Basal Cell Carcinomas (BCCs)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	LDE225	Placebo
Arm/Group Description	Participants received 400 mg once daily.	Participants received matching placebo.
Measure Participants	7	2
Complete Clearance (100% Improvement)	3 37.5%	0 0%
Marked Clearance (76-99% Improvement)	3 37.5%	0 0%
Moderate Clearance (26-75% improvement)	1 12.5%	0 0%
Slight Clearance (1-25%)	0 0%	1 50%
Worsening	0 0%	1 50%

2. Secondary Outcome

Title	Histological Clearance Assessment of Main Target BCCs
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	LDE225	Placebo
Arm/Group Description	Participants received 400 mg once daily.	Participants received matching placebo.
Measure Participants	7	2
Histological clearance	57 712.5%	0 0%
Complete clinical (up to day 85) & histological	14 175%	0 0%
Complete clinical (up to day 113) & histological	29 362.5%	0 0%

3. Secondary Outcome

Title	Measure: Disease Burden by BCC Tumor Counts
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	LDE225	Placebo
Arm/Group Description	Participants received 400 mg once daily.	Participants received matching placebo.
Measure Participants	7	2
Baseline	566	510
Day 85	341	571
Day 113	309	619

Adverse Events

Arm/Group Title	LDE225 - Core		Placebo - Core		LDE225 - Long Term Follow-up		Placebo - Long Term Follow-up
Arm/Group Description	Participants received 400 mg once daily.		Participants received matching placebo.
All Cause Mortality
	LDE225 - Core		Placebo - Core		LDE225 - Long Term Follow-up		Placebo - Long Term Follow-up
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	LDE225 - Core		Placebo - Core		LDE225 - Long Term Follow-up		Placebo - Long Term Follow-up
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		1/2 (50%)		1/8 (12.5%)		0/2 (0%)
Infections and infestations
Cellulitis	0/8 (0%)		0/2 (0%)		1/8 (12.5%)		0/2 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/8 (0%)		1/2 (50%)		0/8 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	LDE225 - Core		Placebo - Core		LDE225 - Long Term Follow-up		Placebo - Long Term Follow-up
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/8 (87.5%)		1/2 (50%)		2/8 (25%)		0/2 (0%)
Cardiac disorders
Cardiovascular disorder	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Ear and labyrinth disorders
Vertigo positional	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Eye disorders
Eyelid irritation	0/8 (0%)		1/2 (50%)		0/8 (0%)		0/2 (0%)
Vision blurred	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Gastrointestinal disorders
Constipation	0/8 (0%)		1/2 (50%)		0/8 (0%)		0/2 (0%)
Diarrhoea	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Food poisoning	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Gingival pain	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Nausea	2/8 (25%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Vomiting	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
General disorders
Fatigue	2/8 (25%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Infections and infestations
Folliculitis	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Laryngitis	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Nasopharyngitis	2/8 (25%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Postoperative wound infection	0/8 (0%)		1/2 (50%)		0/8 (0%)		0/2 (0%)
Sinusitis	0/8 (0%)		0/2 (0%)		1/8 (12.5%)		0/2 (0%)
Wound infection	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Injury, poisoning and procedural complications
Electric shock	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Humerus fracture	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Investigations
Alanine aminotransferase increased	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Aspartate aminotransferase increased	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Blood creatine phosphokinase increased	2/8 (25%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Gamma-glutamyltransferase increased	1/8 (12.5%)		0/2 (0%)		1/8 (12.5%)		0/2 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Muscle spasms	3/8 (37.5%)		1/2 (50%)		0/8 (0%)		0/2 (0%)
Musculoskeletal pain	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Myalgia	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Osteoarthritis	0/8 (0%)		1/2 (50%)		0/8 (0%)		0/2 (0%)
Pain in extremity	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Nervous system disorders
Dizziness	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Dysgeusia	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Headache	2/8 (25%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Rhinitis allergic	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Skin and subcutaneous tissue disorders
Alopecia	2/8 (25%)		0/2 (0%)		0/8 (0%)		0/2 (0%)
Neurodermatitis	0/8 (0%)		0/2 (0%)		1/8 (12.5%)		0/2 (0%)
Night sweats	1/8 (12.5%)		0/2 (0%)		0/8 (0%)		0/2 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.