Pilot LDE225 in Locally Advanced or Metastatic BCC + Previously Tx Non-LDE225 Smoothened Inhibitors

• Sponsor: Anne Chang (Other)
• Overall Status: Completed
• CT.gov ID: NCT01529450
• Collaborator: Novartis (Industry)
• Enrollment: 11
• Location: 1
• Arms: 2
• Duration (Months): 18
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This is a prospective single-center, open label, pilot study to investigate the safety and efficacy of LDE225 in patients with locally advanced or metastatic basal cell carcinoma.

Primary Objectives:

• To explore the effects of oral LDE225 on the Progression Free Survival (PFS) of individuals with locally advanced or metastatic BCC who have been previously treated with a non-LDE225 Smo inhibitor.

Secondary Objectives:

• To evaluate the effect of oral LDE225 on tumor tissue biomarkers of BCC activation (Gii 1, 2, Patched 1,2 and Ki67) in individuals which are non-na"ive to Smo inhibitors other than LDE225, at baseline and at end-of-treatment

• To describe adverse effects of oral LDE225 in individuals with a history of non-LDE225 Smo inhibitor usage

• To assess the overall survival rates of individuals with locally advanced BCC or metastatic BCC who have previously taken a non-LDE225 Smo inhibitor after treatment with LDE225

Condition or Disease	Intervention/Treatment	Phase
Basal Cell Carcinoma	Drug: LDE225	N/A

Detailed Description

This is a prospective single-center, open label, pilot study to investigate the safety and efficacy of LDE225 in patients with locally advanced or metastatic basal cell carcinoma.

Primary Objectives:

• To explore the effects of oral LDE225 on the Progression Free Survival (PFS) of individuals with locally advanced or metastatic BCC who have been previously treated with a non-LDE225 Smo inhibitor.

Secondary Objectives:

• To evaluate the effect of oral LDE225 on tumor tissue biomarkers of BCC activation (e.g. Gli and Ki67) in individuals which are non-naive to Smo inhibitors other than LDE225, at baseline and at end-of-treatment

• To describe adverse effects of oral LDE225 in individuals with a history of non-LDE225 Smo inhibitor usage

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Open-Label Study to Examine the Safety and Efficacy of Oral LDE225 in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma Who Have Been Previously Treated With Non-LDE225 Smoothened Inhibitor(s)
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Refractory Group Patients previously treated with non-LDE225 Smo inhibitor who were refractory.	Drug: LDE225; 800-mg (4 200-mg capsules/day) capsule; Other Names: NVP-LDE225
Active Comparator: Resistance Developed Group Patients previously treated with non-LDE225 Smo inhibitor who were initially responsive but became resistant with progressive disease.	Drug: LDE225; 800-mg (4 200-mg capsules/day) capsule; Other Names: NVP-LDE225

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) of All Participants [End of treatment or at time of disease progression (up to 58 weeks)]

Secondary Outcome Measures

1. Molecular Markers Associated With Clinical Response [Assessed on day 1]

   Following consent, historical biopsy samples were analyzed for molecular markers associated with clinical response. Tumors were analyzed and present of Smooth mutation (SMO [genetic changes which influence Ki 67 and Gli levels]). was determined. The number of participants with and without SMO were reported by clinical outcome (SD = stable disease; PD = progressive disease).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age 18 years or older.

2. Histologically documented diagnosis of basal cell carcinoma deemed to be locally advanced or metastatic who have previously received a non-LDE225 Smo inhibitor.

3. World Health Organization (WHO) performance status <= 2

4. At least one measurable site of disease (as defined by Response Evaluation Criteria in Solid Tumors), or other disease specific response assessment criteria, as appropriate. State age restriction and/or gender/race-ethnic restrictions.

5. Patients with adequate bone marrow, liver and renal function, as specified below:

• Absolute Neutrophil Count (ANC) >= 1.5 x 10^9/L

• Hemoglobin (Hgb) >= 9 g/dL

• Platelets >= 80 x 10^9/L

• Serum total bilirubin <= 1.5 x upper limit of normal (ULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.5 x ULN or <= 5 x ULN if liver metastases are present

• Plasma creatine phosphokinase (CK) < 1.5 x ULN

• Serum creatinine <= 1.5 x ULN or 24-hour clearance >= 50ml/min

1. Written informed consent obtained prior to any screening procedures

Exclusion Criteria:

1. Patients who have had major surgery within 4 weeks of initiation of study medication.

2. Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data.

State restrictions regarding use of other Investigational Agents.

1. Patients unable to take oral drugs or with lack of physical integrity of the upper gastrointestinal tract or known malabsorption syndromes.

State exclusion requirements due to co-morbid disease or incurrent illness, as needed.

1. Patients who have previously been treated with systemic LDE225.

2. Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) inhibitors (statins), clofibrate and gemfibrozil, and that cannot be discontinued at least 2 weeks prior to starting LDE225 treatment. If it is essential that the patient stays on a statin to control hyperlipidemia, only pravastatin may be used with extra caution.

1. Patients who are planning on embarking on a new strenuous exercise regimen after initiation of study treatment. Note: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided whilst on LDE225 treatment.

1. Patients who have taken part in an experimental drug study within 4 weeks of initiating treatment with LDE225.

2. Patients who are receiving other anti-neoplastic therapy (e.g. chemotherapy, targeted therapy or radiotherapy) concurrently or within 2 weeks of starting treatment with LDE225.

3. Patients who are receiving treatment with medications known to be moderate and strong inhibitors or inducers of cytochrome (CYP)3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that have narrow therapeutic index, and that cannot be discontinued before starting treatment with LDE225. Medications that are strong CYP3A4/5 inhibitors should be discontinued at least 7 days and strong CYP3A/5 inducers for at least 2 weeks prior to starting treatment with LDE225.

4. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (> 5 mIU/mL).

10 Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method. Adequate barrier methods of contraception include:

• Diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent.

• Reliable contraception should be maintained throughout the study and for 3 months after study drug discontinuation.

11 Patients unwilling or unable to comply with the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University, School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• Anne Chang
• Novartis

Investigators

• Principal Investigator: Anne Chang, MD, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Anne Chang, Assistant Professor of Dermatology, Stanford University
• ClinicalTrials.gov Identifier: NCT01529450
• Other Study ID Numbers: SKIN0009; SU-09022011-8371; 21759
• First Posted: Feb 8, 2012
• Last Update Posted: Jan 16, 2017
• Last Verified: Nov 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Anne Chang, Assistant Professor of Dermatology, Stanford University: basal cell carcinoma, sonidegib, smoothened inhibitor, hedgehog
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Basal Cell

Study Results

Participant Flow

Arm/Group Title	Refractory Group	Resistance Developed Group
Arm/Group Description	Patients previously treated with non-LDE225 Smo inhibitor who were refractory. LDE225: 800-mg (4 200-mg capsules/day) capsule	Patients previously treated with non-LDE225 Smo inhibitor who were initially responsive but became resistant with progressive disease. LDE225: 800-mg (4 200-mg capsules/day) capsule
Period Title: Overall Study
STARTED	3	8
COMPLETED	3	6
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Refractory Group	Resistance Developed Group	Total
Arm/Group Description	Patients previously treated with non-LDE225 Smo inhibitor who were refractory. LDE225: 800-mg (4 200-mg capsules/day) capsule	Patients previously treated with non-LDE225 Smo inhibitor who were initially responsive but became resistant with progressive disease. LDE225: 800-mg (4 200-mg capsules/day) capsule	Total of all reporting groups
Overall Participants	3	6	9
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	3 100%	4 66.7%	7 77.8%
>=65 years	0 0%	2 33.3%	2 22.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65 (24)	54 (9)	57 (15)
Gender (Count of Participants)
Female	1 33.3%	0 0%	1 11.1%
Male	2 66.7%	6 100%	8 88.9%
Region of Enrollment (participants) [Number]
United States	3 100%	6 100%	9 100%
Size of disease by RECIST criteria (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	3.8 (1.3)	4.2 (2.4)	4.0 (2.0)

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) of All Participants
Time Frame	End of treatment or at time of disease progression (up to 58 weeks)

Outcome Measure Data

Analysis Population Description

Progression is defined using RECIST version 1.0 as a 20% increase in the sum of the longest diameter of target lesions, or a measureable increase in a non-target lesion or the appearance of new lesion.

Arm/Group Title	Refractory Group	Resistance Developed Group
Arm/Group Description	Patients previously treated with non-LDE225 Smo inhibitor who were refractory. LDE225: 800-mg (4 200-mg capsules/day) capsule	Patients previously treated with non-LDE225 Smo inhibitor who were initially responsive but became resistant with progressive disease. LDE225: 800-mg (4 200-mg capsules/day) capsule
Measure Participants	3	6
Median (95% Confidence Interval) [weeks]	6	36

2. Secondary Outcome

Title	Molecular Markers Associated With Clinical Response
Description	Following consent, historical biopsy samples were analyzed for molecular markers associated with clinical response. Tumors were analyzed and present of Smooth mutation (SMO [genetic changes which influence Ki 67 and Gli levels]). was determined. The number of participants with and without SMO were reported by clinical outcome (SD = stable disease; PD = progressive disease).
Time Frame	Assessed on day 1

Outcome Measure Data

Analysis Population Description

Participants with tissue available for screening were analyzed.

Arm/Group Title	All Participants
Arm/Group Description	Participants received LDE225: 800-mg (4 200-mg capsules/day) capsule
Measure Participants	7
SMO Present (outcome SD)	1 33.3%
SMO absent (outcome SD)	1 33.3%
SMO Present (outcome PD)	4 133.3%
SMO absent (outcome PD)	1 33.3%

Adverse Events

Adverse Event Reporting Description	Participants with evaluable data are included for Adverse Events
Arm/Group Title	Refractory Group		Resistance Developed Group
Arm/Group Description	Patients previously treated with non-LDE225 Smo inhibitor who were refractory. LDE225: 800-mg (4 200-mg capsules/day) capsule		Patients previously treated with non-LDE225 Smo inhibitor who were initially responsive but became resistant with progressive disease. LDE225: 800-mg (4 200-mg capsules/day) capsule
All Cause Mortality
	Refractory Group		Resistance Developed Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Refractory Group		Resistance Developed Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		1/6 (16.7%)
Nervous system disorders
Altered mental status	0/3 (0%)	0	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	Refractory Group		Resistance Developed Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		6/6 (100%)
Cardiac disorders
palpitations	0/3 (0%)		1/6 (16.7%)
Ear and labyrinth disorders
ear canal stenosis	1/3 (33.3%)		0/6 (0%)
ear drainage	1/3 (33.3%)		0/6 (0%)
hearing loss	1/3 (33.3%)		0/6 (0%)
Gastrointestinal disorders
appetite decrease	1/3 (33.3%)		0/6 (0%)
dehydration	0/3 (0%)		1/6 (16.7%)
diarrhea	1/3 (33.3%)		0/6 (0%)
nausea	0/3 (0%)		2/6 (33.3%)
taste disturbance	0/3 (0%)		1/6 (16.7%)
vomit	1/3 (33.3%)		0/6 (0%)
General disorders
weight loss	1/3 (33.3%)		0/6 (0%)
Infections and infestations
candidiasis	1/3 (33.3%)		0/6 (0%)
Injury, poisoning and procedural complications
ecchymosis	0/3 (0%)		1/6 (16.7%)
laceration	0/3 (0%)		1/6 (16.7%)
Investigations
elevated creatine kinase	0/3 (0%)		1/6 (16.7%)
Musculoskeletal and connective tissue disorders
hip fracture	0/3 (0%)		1/6 (16.7%)
muscle cramps	0/3 (0%)		4/6 (66.7%)
restless arms and legs	0/3 (0%)		1/6 (16.7%)
rhabdomyolysis	0/3 (0%)		1/6 (16.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
neoplasm	1/3 (33.3%)		0/6 (0%)
Nervous system disorders
altered mental status	0/3 (0%)		1/6 (16.7%)
migraine	1/3 (33.3%)		0/6 (0%)
somnolence	1/3 (33.3%)		0/6 (0%)
Psychiatric disorders
agitation	0/3 (0%)		1/6 (16.7%)
Respiratory, thoracic and mediastinal disorders
cough	0/3 (0%)		1/6 (16.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.