Study of Efficacy and Safety of LDE225 in Adult Patients With Relapsed/Refractory Acute Leukemia

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01826214
• Collaborator: (none)
• Enrollment: 70
• Locations: 23
• Arms: 2
• Duration (Months): 24
• Patients Per Site: 3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The study will evaluate the efficacy, safety and tolerability of two dosing schedules of LDE225 in patients with relapsed/refractory acute leukemia or elderly patients with untreated acute leukemia.

Condition or Disease	Intervention/Treatment	Phase
Acute Leukemias	Drug: LDE225	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Multi-center, Open Label, Randomized Study to Assess Safety and Efficacy of Two Different Schedules of Oral LDE225 in Adult Patients With Relapsed/Refractory or Untreated Elderly Patients With Acute Leukemia
• Study Start Date: May 1, 2013
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LDE225-400 Patients who were randomized to Schedule A, and received 400 mg LDE225 twice daily for the first two weeks only and then after two weeks, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.	Drug: LDE225; LDE225 will be supplied as 200 mg capsules by Novartis. Patients will receive study treatment on an outpatient basis. LDE225 will be dispensed every two weeks for the first four weeks and at the start of every four weeks thereafter, as needed.
Experimental: LDE225-800 Patients who were randomized to Schedule B, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.	Drug: LDE225; LDE225 will be supplied as 200 mg capsules by Novartis. Patients will receive study treatment on an outpatient basis. LDE225 will be dispensed every two weeks for the first four weeks and at the start of every four weeks thereafter, as needed.

Outcome Measures

Primary Outcome Measures

1. Rate of Complete Remission (CR) [at screening, every week up to Week 9, every 2 weeks thereafter until CR, every 4 weeks after CR up to 24 months]

   Complete Response (CR) was based on the International Working Group (IWG) criteria based on weekly peripheral blood count measurements and bone marrow biopsy/aspiration collection. Efficacy assessments were performed to determine CR. A treatment cycle was defined as 4 weeks. The outcome measure for the study is based on standardized response criteria as defined by the International Working Group (IWG) for AML. The IWG was established by a group of investigators interested in the design and conduct of clinical trials in acute myeloid leukemia (AML). The criteria established by this group (a set of recommendations for response assessment) are well established, endorsed by major institutions and Health Authorities, and are widely used in clinical trials. No statistical analysis was planned for this primary outcome.

2. Complete Remission With Incomplete Blood Count Recovery (CRi) [within 3 days after clearance of blasts from peripheral blood (PB), monthly thereafter until CR or reappearance of blasts in the PB, after CR every other month until discontination up to 24 months]

   The other primary efficacy endpoint was CRi based on the International Working Group (IWG) criteria based on weekly peripheral blood count measurements and bone marrow biopsy/aspiration collection. Efficacy assessments were performed to determine CRi. A treatment cycle was defined as 4 weeks. No statistical analysis was planned for this primary outcome.

Secondary Outcome Measures

1. Overall Response Rate (ORR) [Every 8 weeks for the first 6 months and every 12 weeks until 53 weeks after the last patient is enrolled or until relapse up to 24 months]

   ORR was the rate of complete remission (CR), complete remission with incomplete blood count recovery (CRi) or partial response (PR) according to IWG criteria. CR, CRi or PR will be assessed through bone marrow biopsy/aspirate and peripheral blood blasts counts.

2. Parmacokintics (PK) Parameter: Cmax [Week 1 Day 1, Week 9 Day 1]

   Cmax is the maximum observed plasma concentration after drug administration.The PK parameters were determined in plasma using non-compartmental methods. A PK sample was excluded from analyses if the patient vomited within the first 4 hours following the last oral dose of study drug. Other PK samples were excluded as deemed appropriate by the pharmacokineticist. Cmax was derived from the PK concentrations collected at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose on W1D1 and W9D1. The PK concentration at each time point is not an endpoint in the protocol, but these concentrations are used to derive the PK parameters.

3. Parmacokintics (PK) Parameter: Tmax [Week 1 Day 1,Week 9 Day 1]

   Tmax is the time to reach Cmax. The PK parameters were determined in plasma using non-compartmental methods. A PK sample was excluded from analyses if the patient vomited within the first 4 hours following the last oral dose of study drug. Other PK samples were excluded as deemed appropriate by the Pharmacokineticist. Tmax was derived from the PK concentrations collected at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose on W1D1 and W9D1. The PK concentration at each time point is not an endpoint in the protocol, but these concentrations are used to derive the PK parameters.

4. Parmacokintics (PK) Parameter: AUC0-8h [Week 1 Day 1,Week 9 Day 1]

   AUC0-8h is the area under the concentration-time curve from time zero to 8 hours. The PK parameters were determined in plasma using non-compartmental methods. A PK sample was excluded from analyses if the patient vomited within the first 4 hours following the last oral dose of study drug. Other PK samples were excluded as deemed appropriate by the Pharmacokineticist. AUC0-8h was derived from the PK concentrations collected at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose on W1D1 and W9D1. The PK concentration at each time point is not an endpoint in the protocol, but these concentrations are used to derive the PK parameters.

5. Parmacokintics (PK) Parameter: AUC0-24h [Week 1 Day 1,Week 9 Day 1]

   AUC0-24 is the area under the concentration-time curve from time zero to 24 hours done only on 800 mg once a day schedule. The PK parameters were determined in plasma using non-compartmental methods. A PK sample was excluded from analyses if the patient vomited within the first 4 hours following the last oral dose of study drug. Other PK samples were excluded as deemed appropriate by the Pharmacokineticist. AUC0-24h was derived from the PK concentrations collected at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose on W1D1 and W9D1. The PK concentration at each time point is not an endpoint in the protocol, but these concentrations are used to derive the PK parameters.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subjects must have relapsed or primary refractory non-M3 acute myeloid leukemia or relapsed or refractory non-T-cell acute lymphoblastic leukemia or untreated acute myeloid leukemia in elderly patients.

• Performance status of 0, 1 or 2 per WHO classification.

• Adequate renal and liver function.

• Adequate blood creatine kinase value (CK < 1.5ULN)

Exclusion Criteria:

• Allogeneic stem cell transplantation within the last 4 months and/or active graft versus host disease requiring systemic immunosuppressant therapy, or autologous stem cell transplantation within the last 4 weeks.

• Patient for which immediate allogeneic stem cell transplantation is the treatment of choice.

• Pregnant or nursing (lactating) women.

• Active CNS leukemic involvement

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center SC-5	Durham	North Carolina	United States	27710
2	Novartis Investigative Site	Adelaide	South Australia	Australia	5000
3	Novartis Investigative Site	Prahran	Victoria	Australia	3181
4	Novartis Investigative Site	Salzburg		Austria	5020
5	Novartis Investigative Site	Wien		Austria	1090
6	Novartis Investigative Site	Leuven		Belgium	3000
7	Novartis Investigative Site	Yvoir		Belgium	5530
8	Novartis Investigative Site	Montreal	Quebec	Canada	H1T 2M4
9	Novartis Investigative Site	Montreal	Quebec	Canada	H3T 1E2
10	Novartis Investigative Site	Dresden		Germany	01307
11	Novartis Investigative Site	Frankfurt		Germany	60590
12	Novartis Investigative Site	Magdeburg		Germany	39120
13	Novartis Investigative Site	Ulm		Germany	89081
14	Novartis Investigative Site	Debrecen		Hungary	4032
15	Novartis Investigative Site	Amsterdam		Netherlands	1081 HV
16	Novartis Investigative Site	Nijmegen		Netherlands	6525 GA
17	Novartis Investigative Site	Rotterdam		Netherlands	3015 CE
18	Novartis Investigative Site	Rotterdam		Netherlands	3075 EA
19	Novartis Investigative Site	Bergen		Norway	NO-5021
20	Novartis Investigative Site	Trondheim		Norway	7006
21	Novartis Investigative Site	Salamanca	Castilla y Leon	Spain	37007
22	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46026
23	Novartis Investigative Site	London		United Kingdom	WC1E 6HX

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: NCT01826214
• Other Study ID Numbers: CLDE225X2203
• First Posted: Apr 8, 2013
• Last Update Posted: Aug 30, 2016
• Last Verified: Jul 1, 2016

• Keywords provided by Novartis Pharmaceuticals: acute myeloid leukemia; AML; acute lymphoblastic leukemia; ALL; leukemia; acute; LDE225; adult patients; relapsed/refractory
• Additional relevant MeSH terms: Leukemia; Acute Disease

Study Results

Participant Flow

Pre-assignment Detail	35 patients were randomized but only 34 patients received at least one dose of study drug in the LDE225-800 (schedule B ) arm.

Arm/Group Title	LDE225-400	LDE225-800
Arm/Group Description	Patients who were randomized to Schedule A, and received 400 mg LDE225 twice daily for the first two weeks only and after two weeks, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.	Patients who were randomized to Schedule B, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.
Period Title: Overall Study
STARTED	35	34
Untreated	0	1
Treated	35	34
COMPLETED	0	0
NOT COMPLETED	35	34

Baseline Characteristics

Arm/Group Title	LDE225-400	LDE225-800	Total
Arm/Group Description	Patients who were randomized to Schedule A, and received 400 mg LDE225 twice daily for the first two weeks only and after two weeks, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.	Patients who were randomized to Schedule B, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.	Total of all reporting groups
Overall Participants	35	35	70
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	65.3 (12.31)	67.7 (11.65)	66.5 (11.96)
Sex: Female, Male (Count of Participants)
Female	18 51.4%	13 37.1%	31 44.3%
Male	17 48.6%	22 62.9%	39 55.7%

Outcome Measures

1. Primary Outcome

Title	Rate of Complete Remission (CR)
Description	Complete Response (CR) was based on the International Working Group (IWG) criteria based on weekly peripheral blood count measurements and bone marrow biopsy/aspiration collection. Efficacy assessments were performed to determine CR. A treatment cycle was defined as 4 weeks. The outcome measure for the study is based on standardized response criteria as defined by the International Working Group (IWG) for AML. The IWG was established by a group of investigators interested in the design and conduct of clinical trials in acute myeloid leukemia (AML). The criteria established by this group (a set of recommendations for response assessment) are well established, endorsed by major institutions and Health Authorities, and are widely used in clinical trials. No statistical analysis was planned for this primary outcome.
Time Frame	at screening, every week up to Week 9, every 2 weeks thereafter until CR, every 4 weeks after CR up to 24 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprised of all patients who were randomized to a study treatment. According to the intent-to-treat principle, patient data were analyzed according to the treatment to which they had been randomized. No statistical analysis were reported in this study.

Arm/Group Title	LDE225-400	LDE225-800
Arm/Group Description	Patients who were randomized to Schedule A, and received 400 mg LDE225 twice daily for the first two weeks only and after two weeks, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.	Patients who were randomized to Schedule B, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.
Measure Participants	35	35
Number [Participants]	0 0%	0 0%

2. Primary Outcome

Title	Complete Remission With Incomplete Blood Count Recovery (CRi)
Description	The other primary efficacy endpoint was CRi based on the International Working Group (IWG) criteria based on weekly peripheral blood count measurements and bone marrow biopsy/aspiration collection. Efficacy assessments were performed to determine CRi. A treatment cycle was defined as 4 weeks. No statistical analysis was planned for this primary outcome.
Time Frame	within 3 days after clearance of blasts from peripheral blood (PB), monthly thereafter until CR or reappearance of blasts in the PB, after CR every other month until discontination up to 24 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprised of all patients who were randomized to a study treatment. According to the intent-to-treat principle, patient data were analyzed according to the treatment to which they had been randomized.

Arm/Group Title	LDE225-400	LDE225-800
Arm/Group Description	Patients who were randomized to Schedule A, and received 400 mg LDE225 twice daily for the first two weeks only and after two weeks, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.	Patients who were randomized to Schedule B, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.
Measure Participants	35	35
Number [Participants]	1 2.9%	0 0%

3. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	ORR was the rate of complete remission (CR), complete remission with incomplete blood count recovery (CRi) or partial response (PR) according to IWG criteria. CR, CRi or PR will be assessed through bone marrow biopsy/aspirate and peripheral blood blasts counts.
Time Frame	Every 8 weeks for the first 6 months and every 12 weeks until 53 weeks after the last patient is enrolled or until relapse up to 24 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprised of all patients who were randomized to a study treatment. According to the intent-to-treat principle, patient data were analyzed according to the treatment to which they had been randomized.

Arm/Group Title	LDE225-400	LDE225-800
Arm/Group Description	Patients who were randomized to Schedule A, and received 400 mg LDE225 twice daily for the first two weeks only and after two weeks, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.	Patients who were randomized to Schedule B, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.
Measure Participants	35	35
Number [Participants]	1 2.9%	0 0%

4. Secondary Outcome

Title	Parmacokintics (PK) Parameter: Cmax
Description	Cmax is the maximum observed plasma concentration after drug administration.The PK parameters were determined in plasma using non-compartmental methods. A PK sample was excluded from analyses if the patient vomited within the first 4 hours following the last oral dose of study drug. Other PK samples were excluded as deemed appropriate by the pharmacokineticist. Cmax was derived from the PK concentrations collected at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose on W1D1 and W9D1. The PK concentration at each time point is not an endpoint in the protocol, but these concentrations are used to derive the PK parameters.
Time Frame	Week 1 Day 1, Week 9 Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set (PAS): consisted of all patients who received at least one dose of sonidegib and provided at least one evaluable PK blood sample.

Arm/Group Title	LDE225-400	LDE225-800
Arm/Group Description	Patients who were randomized to Schedule A, and received 400 mg LDE225 twice daily for the first two weeks only and after two weeks, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.	Patients who were randomized to Schedule B, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.
Measure Participants	29	33
Week 1 Day 1	237 (158)	343 (275)
Week 9 Day 1(n: 7, 7)	1640 (612)	1500 (874)

5. Secondary Outcome

Title	Parmacokintics (PK) Parameter: Tmax
Description	Tmax is the time to reach Cmax. The PK parameters were determined in plasma using non-compartmental methods. A PK sample was excluded from analyses if the patient vomited within the first 4 hours following the last oral dose of study drug. Other PK samples were excluded as deemed appropriate by the Pharmacokineticist. Tmax was derived from the PK concentrations collected at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose on W1D1 and W9D1. The PK concentration at each time point is not an endpoint in the protocol, but these concentrations are used to derive the PK parameters.
Time Frame	Week 1 Day 1,Week 9 Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set (PAS): consisted of all patients who received at least one dose of sonidegib and provided at least one evaluable PK blood sample.

Arm/Group Title	LDE225-400	LDE225-800
Arm/Group Description	Patients who were randomized to Schedule A, and received 400 mg LDE225 twice daily for the first two weeks only and after two weeks, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.	Patients who were randomized to Schedule B, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.
Measure Participants	29	33
Week 1 Day 1	2.13 (NA)	2.12 (NA)
Week 9 Day 1 (n: 7, 7)	1.88 (NA)	2.02 (NA)

6. Secondary Outcome

Title	Parmacokintics (PK) Parameter: AUC0-8h
Description	AUC0-8h is the area under the concentration-time curve from time zero to 8 hours. The PK parameters were determined in plasma using non-compartmental methods. A PK sample was excluded from analyses if the patient vomited within the first 4 hours following the last oral dose of study drug. Other PK samples were excluded as deemed appropriate by the Pharmacokineticist. AUC0-8h was derived from the PK concentrations collected at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose on W1D1 and W9D1. The PK concentration at each time point is not an endpoint in the protocol, but these concentrations are used to derive the PK parameters.
Time Frame	Week 1 Day 1,Week 9 Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set (PAS): consisted of all patients who received at least one dose of sonidegib and provided at least one evaluable PK blood sample.

Arm/Group Title	LDE225-400	LDE225-800
Arm/Group Description	Patients who were randomized to Schedule A, and received 400 mg LDE225 twice daily for the first two weeks only and after two weeks, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.	Patients who were randomized to Schedule B, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.
Measure Participants	27	33
Week 1 Day1	988 (542)	1560 (1230)
Week 9 Day1 (n: 7, 7)	9750 (2830)	7910 (5090)

7. Secondary Outcome

Title	Parmacokintics (PK) Parameter: AUC0-24h
Description	AUC0-24 is the area under the concentration-time curve from time zero to 24 hours done only on 800 mg once a day schedule. The PK parameters were determined in plasma using non-compartmental methods. A PK sample was excluded from analyses if the patient vomited within the first 4 hours following the last oral dose of study drug. Other PK samples were excluded as deemed appropriate by the Pharmacokineticist. AUC0-24h was derived from the PK concentrations collected at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose on W1D1 and W9D1. The PK concentration at each time point is not an endpoint in the protocol, but these concentrations are used to derive the PK parameters.
Time Frame	Week 1 Day 1,Week 9 Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set (PAS): consisted of all patients who received at least one dose of sonidegib and provided at least one evaluable PK blood sample.

Arm/Group Title	LDE225-400	LDE225-800
Arm/Group Description	Patients who were randomized to Schedule A, and received 400 mg LDE225 twice daily for the first two weeks only and after two weeks, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.	Patients who were randomized to Schedule B, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.
Measure Participants	7	32
Week 1 Day 1	0 (0)	3110 (2620)
Week 9 Day 1 (n: 7, 6)	26500 (6650)	24000 (11500)

Adverse Events

Arm/Group Title	LDE225-400		LDE225-800
Arm/Group Description	Patients who were randomized to Schedule A, and received 400 mg LDE225 twice daily for the first two weeks only and after two weeks, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.		Patients who were randomized to Schedule B, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study.
All Cause Mortality
	LDE225-400		LDE225-800
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	LDE225-400		LDE225-800
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/35 (71.4%)		25/34 (73.5%)
Blood and lymphatic system disorders
ANAEMIA	0/35 (0%)		2/34 (5.9%)
FEBRILE NEUTROPENIA	9/35 (25.7%)		7/34 (20.6%)
LEUKOCYTOSIS	1/35 (2.9%)		0/34 (0%)
PANCYTOPENIA	1/35 (2.9%)		0/34 (0%)
Gastrointestinal disorders
ABDOMINAL PAIN	0/35 (0%)		1/34 (2.9%)
ABDOMINAL PAIN UPPER	1/35 (2.9%)		0/34 (0%)
COLITIS	0/35 (0%)		1/34 (2.9%)
CONSTIPATION	1/35 (2.9%)		0/34 (0%)
DIARRHOEA	1/35 (2.9%)		0/34 (0%)
GASTRIC HAEMORRHAGE	0/35 (0%)		1/34 (2.9%)
GASTROINTESTINAL HAEMORRHAGE	0/35 (0%)		1/34 (2.9%)
GINGIVAL HYPERTROPHY	1/35 (2.9%)		0/34 (0%)
NAUSEA	0/35 (0%)		1/34 (2.9%)
OESOPHAGEAL ULCER	1/35 (2.9%)		0/34 (0%)
STOMATITIS	0/35 (0%)		1/34 (2.9%)
VOMITING	0/35 (0%)		1/34 (2.9%)
General disorders
ASTHENIA	2/35 (5.7%)		1/34 (2.9%)
FATIGUE	1/35 (2.9%)		1/34 (2.9%)
GENERAL PHYSICAL HEALTH DETERIORATION	4/35 (11.4%)		1/34 (2.9%)
MULTI-ORGAN FAILURE	1/35 (2.9%)		0/34 (0%)
PYREXIA	1/35 (2.9%)		4/34 (11.8%)
Infections and infestations
ANAL ABSCESS	0/35 (0%)		1/34 (2.9%)
ARTHRITIS INFECTIVE	1/35 (2.9%)		0/34 (0%)
BACTERAEMIA	0/35 (0%)		1/34 (2.9%)
CLOSTRIDIAL INFECTION	1/35 (2.9%)		0/34 (0%)
DEVICE RELATED INFECTION	1/35 (2.9%)		0/34 (0%)
ENTEROCOCCAL BACTERAEMIA	1/35 (2.9%)		0/34 (0%)
EPIGLOTTITIS	1/35 (2.9%)		0/34 (0%)
INFECTION	1/35 (2.9%)		0/34 (0%)
INFLUENZA	1/35 (2.9%)		0/34 (0%)
LUNG INFECTION	2/35 (5.7%)		0/34 (0%)
NEUTROPENIC INFECTION	1/35 (2.9%)		0/34 (0%)
PNEUMONIA	3/35 (8.6%)		3/34 (8.8%)
SEPSIS	2/35 (5.7%)		4/34 (11.8%)
STAPHYLOCOCCAL SEPSIS	1/35 (2.9%)		0/34 (0%)
URINARY TRACT INFECTION	1/35 (2.9%)		0/34 (0%)
Injury, poisoning and procedural complications
FALL	0/35 (0%)		1/34 (2.9%)
SUBDURAL HAEMORRHAGE	0/35 (0%)		1/34 (2.9%)
Investigations
BLOOD CREATINE PHOSPHOKINASE INCREASED	2/35 (5.7%)		2/34 (5.9%)
MYOGLOBIN BLOOD INCREASED	1/35 (2.9%)		0/34 (0%)
Metabolism and nutrition disorders
DEHYDRATION	1/35 (2.9%)		0/34 (0%)
FLUID OVERLOAD	0/35 (0%)		1/34 (2.9%)
GOUT	0/35 (0%)		1/34 (2.9%)
Musculoskeletal and connective tissue disorders
BACK PAIN	2/35 (5.7%)		0/34 (0%)
MUSCLE SPASMS	0/35 (0%)		1/34 (2.9%)
MYALGIA	1/35 (2.9%)		0/34 (0%)
MYOPATHY	0/35 (0%)		1/34 (2.9%)
OSTEONECROSIS OF JAW	1/35 (2.9%)		0/34 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
CANCER PAIN	0/35 (0%)		1/34 (2.9%)
LEUKAEMIC INFILTRATION	1/35 (2.9%)		0/34 (0%)
Nervous system disorders
CEREBRAL HAEMORRHAGE	1/35 (2.9%)		1/34 (2.9%)
DYSGEUSIA	0/35 (0%)		1/34 (2.9%)
HAEMORRHAGE INTRACRANIAL	0/35 (0%)		1/34 (2.9%)
QUADRIPLEGIA	0/35 (0%)		1/34 (2.9%)
Respiratory, thoracic and mediastinal disorders
EPISTAXIS	1/35 (2.9%)		2/34 (5.9%)
IDIOPATHIC PNEUMONIA SYNDROME	1/35 (2.9%)		0/34 (0%)
LARYNGEAL INFLAMMATION	0/35 (0%)		1/34 (2.9%)
PLEURAL EFFUSION	0/35 (0%)		1/34 (2.9%)
RESPIRATORY FAILURE	1/35 (2.9%)		0/34 (0%)
Vascular disorders
CIRCULATORY COLLAPSE	0/35 (0%)		1/34 (2.9%)
Other (Not Including Serious) Adverse Events
	LDE225-400		LDE225-800
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/35 (100%)		34/34 (100%)
Blood and lymphatic system disorders
ANAEMIA	5/35 (14.3%)		6/34 (17.6%)
FEBRILE NEUTROPENIA	3/35 (8.6%)		2/34 (5.9%)
LEUKOCYTOSIS	1/35 (2.9%)		4/34 (11.8%)
LEUKOPENIA	2/35 (5.7%)		3/34 (8.8%)
NEUTROPENIA	3/35 (8.6%)		2/34 (5.9%)
THROMBOCYTOPENIA	7/35 (20%)		5/34 (14.7%)
Cardiac disorders
ATRIAL FIBRILLATION	1/35 (2.9%)		2/34 (5.9%)
Gastrointestinal disorders
ABDOMINAL PAIN	4/35 (11.4%)		3/34 (8.8%)
ABDOMINAL PAIN UPPER	2/35 (5.7%)		1/34 (2.9%)
APHTHOUS STOMATITIS	0/35 (0%)		2/34 (5.9%)
CONSTIPATION	6/35 (17.1%)		8/34 (23.5%)
DIARRHOEA	7/35 (20%)		8/34 (23.5%)
DYSPEPSIA	3/35 (8.6%)		3/34 (8.8%)
DYSPHAGIA	0/35 (0%)		2/34 (5.9%)
GINGIVAL BLEEDING	0/35 (0%)		3/34 (8.8%)
HAEMORRHOIDS	2/35 (5.7%)		1/34 (2.9%)
MOUTH HAEMORRHAGE	0/35 (0%)		3/34 (8.8%)
MOUTH ULCERATION	2/35 (5.7%)		1/34 (2.9%)
NAUSEA	11/35 (31.4%)		10/34 (29.4%)
ORAL DISORDER	2/35 (5.7%)		0/34 (0%)
ORAL PAIN	1/35 (2.9%)		3/34 (8.8%)
VOMITING	7/35 (20%)		12/34 (35.3%)
General disorders
ASTHENIA	1/35 (2.9%)		2/34 (5.9%)
CHILLS	2/35 (5.7%)		0/34 (0%)
FATIGUE	8/35 (22.9%)		10/34 (29.4%)
FEELING COLD	2/35 (5.7%)		0/34 (0%)
GENERAL PHYSICAL HEALTH DETERIORATION	1/35 (2.9%)		3/34 (8.8%)
MALAISE	1/35 (2.9%)		2/34 (5.9%)
NON-CARDIAC CHEST PAIN	0/35 (0%)		2/34 (5.9%)
OEDEMA PERIPHERAL	4/35 (11.4%)		5/34 (14.7%)
PAIN	0/35 (0%)		3/34 (8.8%)
PYREXIA	7/35 (20%)		10/34 (29.4%)
Infections and infestations
INFECTION	0/35 (0%)		2/34 (5.9%)
NASOPHARYNGITIS	1/35 (2.9%)		2/34 (5.9%)
ORAL HERPES	2/35 (5.7%)		1/34 (2.9%)
SKIN INFECTION	2/35 (5.7%)		1/34 (2.9%)
UPPER RESPIRATORY TRACT INFECTION	0/35 (0%)		3/34 (8.8%)
URINARY TRACT INFECTION	1/35 (2.9%)		2/34 (5.9%)
Injury, poisoning and procedural complications
FALL	0/35 (0%)		2/34 (5.9%)
Investigations
ASPARTATE AMINOTRANSFERASE INCREASED	2/35 (5.7%)		1/34 (2.9%)
BLOOD CREATINE PHOSPHOKINASE INCREASED	8/35 (22.9%)		7/34 (20.6%)
BLOOD CREATININE INCREASED	1/35 (2.9%)		5/34 (14.7%)
BLOOD MAGNESIUM DECREASED	1/35 (2.9%)		2/34 (5.9%)
MYOGLOBIN BLOOD INCREASED	2/35 (5.7%)		0/34 (0%)
NEUTROPHIL COUNT DECREASED	1/35 (2.9%)		2/34 (5.9%)
PLATELET COUNT DECREASED	2/35 (5.7%)		2/34 (5.9%)
WEIGHT DECREASED	2/35 (5.7%)		2/34 (5.9%)
WHITE BLOOD CELL COUNT DECREASED	1/35 (2.9%)		2/34 (5.9%)
Metabolism and nutrition disorders
DECREASED APPETITE	7/35 (20%)		5/34 (14.7%)
HYPERKALAEMIA	0/35 (0%)		3/34 (8.8%)
HYPOALBUMINAEMIA	2/35 (5.7%)		0/34 (0%)
HYPOCALCAEMIA	3/35 (8.6%)		0/34 (0%)
HYPOKALAEMIA	4/35 (11.4%)		6/34 (17.6%)
HYPOMAGNESAEMIA	0/35 (0%)		2/34 (5.9%)
Musculoskeletal and connective tissue disorders
BACK PAIN	3/35 (8.6%)		2/34 (5.9%)
BONE PAIN	2/35 (5.7%)		2/34 (5.9%)
MUSCLE SPASMS	8/35 (22.9%)		5/34 (14.7%)
MUSCULAR WEAKNESS	1/35 (2.9%)		2/34 (5.9%)
MUSCULOSKELETAL PAIN	1/35 (2.9%)		2/34 (5.9%)
MYALGIA	4/35 (11.4%)		8/34 (23.5%)
MYOPATHY	2/35 (5.7%)		0/34 (0%)
PAIN IN EXTREMITY	1/35 (2.9%)		4/34 (11.8%)
Nervous system disorders
DIZZINESS	2/35 (5.7%)		5/34 (14.7%)
DYSGEUSIA	3/35 (8.6%)		5/34 (14.7%)
HEADACHE	3/35 (8.6%)		5/34 (14.7%)
Psychiatric disorders
ANXIETY	4/35 (11.4%)		0/34 (0%)
CONFUSIONAL STATE	4/35 (11.4%)		0/34 (0%)
INSOMNIA	2/35 (5.7%)		2/34 (5.9%)
Renal and urinary disorders
DYSURIA	2/35 (5.7%)		0/34 (0%)
Respiratory, thoracic and mediastinal disorders
COUGH	3/35 (8.6%)		4/34 (11.8%)
DYSPNOEA	7/35 (20%)		6/34 (17.6%)
EPISTAXIS	4/35 (11.4%)		3/34 (8.8%)
OROPHARYNGEAL PAIN	1/35 (2.9%)		2/34 (5.9%)
PRODUCTIVE COUGH	0/35 (0%)		3/34 (8.8%)
Skin and subcutaneous tissue disorders
ALOPECIA	2/35 (5.7%)		0/34 (0%)
NIGHT SWEATS	0/35 (0%)		2/34 (5.9%)
PETECHIAE	1/35 (2.9%)		6/34 (17.6%)
RASH	4/35 (11.4%)		2/34 (5.9%)
SKIN LESION	2/35 (5.7%)		0/34 (0%)
Vascular disorders
HAEMATOMA	0/35 (0%)		2/34 (5.9%)
HYPERTENSION	0/35 (0%)		2/34 (5.9%)
ORTHOSTATIC HYPOTENSION	2/35 (5.7%)		0/34 (0%)

Limitations/Caveats

Only 34 of the 35 patients in the LDE225 800 mg once daily arm received at least dose of study drug were analyzed for safety.

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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 pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.