MACS1271: Efficacy of Panobinostat in Patients With Relapsed and Bortezomib-refractory Multiple Myeloma

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01083602
• Collaborator: (none)
• Enrollment: 55
• Locations: 13
• Arm: 1
• Duration (Months): 44.1
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is designed to assess the effectiveness of the combination of Panobinostat plus Bortezomib and Dexamethasone in patients with relapsed and bortezomib refractory Multiple Myeloma.

Condition or Disease	Intervention/Treatment	Phase
Relapsed and Bortezomib Refractory Multiple Myeloma; Refractory Multiple Myeloma; Multiple Myeloma in Relapse	Drug: panobinostat; Drug: bortezomib; Drug: dexamethasone	Phase 2

Detailed Description

This is a phase II, two stage, single arm, open label, multi-center study of oral PAN in combination with BTZ/Dex in patients with relapsed and refractory multiple myeloma, who are bortezomib-refractory and have received at least 2 prior lines of therapy. Patients must have been exposed to an iMID (lenalidomide or thalidomide) and progressed on or within 60 days of their last BTZ-containing line of therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Multi-center, Single Arm, Open Label Study of Panobinostat in Combination With Bortezomib and Dexamethasone in Patients With Relapsed and Bortezomib-refractory Multiple Myeloma
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Feb 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: panobinostat + bortezomib & dexamethasone panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma	Drug: panobinostat; PAN 20 mg PO given TIW, weeks 1&2 of each 3-week cycle;• BTZ 1.3 mg/m2 IV push given BIW weeks 1&2 of each 3 week cycle (days 1,4,8 and 11);• Dex 20 mg PO given QIW, weeks 1&2 of each 3-week cycle (days 1,2,4,5,8,9,11 and 12); Other Names: LBH589 PAN ; Drug: bortezomib; Other Names: BTZ ; Drug: dexamethasone; Other Names: DEX

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (PR+nCR+CR) [after eight cycyles of treatment (24 weeks)]

   Overall response rate=(PR+nCR+CR) CR= < 5% plasma cells in bone marrow. No confirmation on bone marrow plasma cell (additional assessment) is needed to document CR except patients with non-secretory myeloma where the bone marrow examination must be repeated after an interval of at least 6 weeks, Absence of M-protein in serum and urine by immunofixation,nCR same as CR without out Absence of M-protein in serum and urine by immunofixation,PR+ 50% reduction of serum M-protein and sofft tissue Plasmacytomas all for more than 6 weeks.

Secondary Outcome Measures

1. Responders to Treatment [after eight cycyles of treatment (24 weeks)]

   The primary endpoint for this phase II study of patients with bortezomib-refractory MM is response after a maximum of 8 cycles of therapy as defined by the modified EBMT criteria.

2. Time to Response (Greater Than or Equal to PR) Based on Investigator Assessment [after eight cycyles of treatment (24 weeks)]

   Time to response is defined as the time from the date of first administration of study treatment to the date of first documented evidence of CR or nCR or PR (whichever status is recorded first). Patients who do not have a response of PR or better by the data cut-off date are censored.

3. Progression-free Survival [24 weeks]

   Progression-free survival (PFS) was defined as the time from the date of first study treatment to first occurrence of documented progressive disease /relapse or death. Time from randomization until disease progression or death by Kaplan-Meier estimates

4. Time to Progression [24 weeks]

   Time from randomization until objective tumor progression; does not include deaths-- Kaplan-Meier estimates

5. Over All Survival [24 weeks]

   Kaplan Meier estimates- median time to event

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Patient has a previous diagnosis of multiple myeloma, based on IMWG 2003 definitions.

All three of the following criteria must have been met:

• Monoclonal immunoglobulin (M component) on electrophoresis, and on immunofixation on serum or on total 24 hour urine

• Bone marrow (clonal) plasma cells ≥ 10% or biopsy proven plasmacytoma

• Related organ or tissue impairment (CRAB symptoms: anemia, hypercalcemia, lytic bone lesions, renal insufficiency, hyperviscosity, amyloidosis or recurrent infections)

1. Patient must have relapsed and refractory MM and must require treatment for the relapsed disease

2. Patients must have received at least 2 prior lines of therapy which include an IMiD (thalidomide or lenalidomide)

3. Patient must be refractory to the last bortezomib containing line of therapy given in the relapsed and refractory setting defined as:

• having progressed on or within 60 days of the last bortezomib-containing line of therapy

1. Patient has measurable disease on M protein at study screening defined by at least one of the following measurements as per thresholds clarified in IMWG 2003 disease definitions (Kyle, et al 2003):

• Serum M-protein ≥ 1 g/dL (≥ 10 g/L)

• Urine M-protein ≥ 200 mg/24 h

1. Patients treated with local radiotherapy with or without concomitant exposure to steroids for pain control or management of cord/nerve root compression, are eligible. Two weeks must have lapsed since last date of radiotherapy, which is recommended to be a limited field. Patients who require concurrent radiotherapy should have entry to the protocol deferred until the radiotherapy is completed and 2 weeks have passed since the last date of therapy

2. Patient's age is ≥ 18 years at time of signing the informed consent

3. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2

4. Patient has the following laboratory values within 3 weeks before starting study drug (lab tests may be repeated, as clinically indicated, to obtain acceptable values before screen fail is concluded but supportive therapies are not to be administered within the week prior to screening tests for absolute neutrophil count or platelet counts)

• Absolute neutrophil count (ANC) ≥ 1.0 x 109 /L

• Platelet count ≥ 70 x 109 /L

• Serum potassium, magnesium, phosphorus, within normal limits (WNL) for institution

• Total calcium (corrected for serum albumin) or ionized calcium ≥ LLN, and not higher than CTCAE grade 1 in case of elevated value

Note: Potassium, calcium, magnesium, and/or phosphorus supplements may be given to correct values that are < LLN:

• AST/SGOT and ALT/SGPT ≤ 2.5 x ULN

• Serum total bilirubin ≤ 1.5 ULN (or ≤ 3.0 x ULN if patient has Gilbert syndrome)

• Serum creatinine levels ≤ 2.5 x ULN, or calculated creatinine clearance ≥ 40 ml/min

1. Patient has provided written informed consent prior to any screening procedures

2. Patient is able to swallow capsules

3. Patient must be able to adhere to the study visit schedule and other protocol requirements

4. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at within 7 days prior to start of study treatment

Exclusion Criteria:

1. Primary refractory disease (patients that never reached at least an MR for over 60 days under any prior therapy)

2. Patients who have a history of prior MM treatment with a DAC inhibitor including panobinostat

3. Patients who have had prior allogeneic stem cell transplantation and show evidence of active graft-versus-host disease that requires immunosuppressive therapy

4. Peripheral neuropathy ≥ CTCAE grade 2

5. Patients who will need valproic acid for any medical condition during the study or within 5 days prior to the first administration of study drug / treatment or who cannot be switch to safely to alternative anti-epileptic medication

6. Patients who have impaired cardiac function including any of the following:

• Congenital long QT syndrome, complete left bundle branch block or use of a permanent cardiac pacemaker, history or presence of ventricular tachyarrhythmias, clinically significant resting bradycardia (< 50 beats per minute). Right bundle branch block + left anterior hemiblock (bifascicular block)

• QTcF > 450 msec on screening ECG

• Presence of unstable atrial fibrillation. Patients with stable atrial fibrillation are allowed in the study provided they do not meet other cardiac or prohibited drug exclusion criteria

• Previous history of angina pectoris or acute MI within 6 months

• Congestive heart failure (New York Heart Association functional classification III-IV)

• Patient has any other clinically significant cardiovascular disease (e.g. uncontrolled hypertension)

1. Patient has an impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat (e.g., ulcerative disease, uncontrolled nausea, vomiting, malabsorption syndrome, obstruction, or significant small bowel resection)

2. Patient has unresolved diarrhea ≥ CTCAE grade 2

3. Patients who have any other concurrent severe and/or uncontrolled medical condition(s) including, but not limited to: uncontrolled diabetes mellitus, active or uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease (e.g. dyspnea at rest from any cause), symptomatic thyroid dysfunction, significant bleeding tendency, that could cause unacceptable safety risks or compromise compliance with the protocol

4. Patients who are using medications that have a known relative risk of prolonging the QT interval or of inducing Torsade de Pointes, where such treatment cannot be discontinued or switched to a different medication prior to starting study drug

5. Women who are pregnant or breast feeding

6. Patients with evidence of another malignancy not in remission or history of such a malignancy within the last 5 years (except for treated basal or squamous cell carcinoma, or in situ cancer of the cervix)

7. Patients who have received prior to starting study treatment either radiation therapy to > 30% of marrow-bearing bone within 4 weeks; myelotoxic chemotherapy within 4 weeks; or immunotherapy within 8 weeks; or who have not yet recovered from side effects of such therapies

8. Patients with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff

9. Use of chemo-, biologic or immunologic therapy and/or other investigational agents while the patient is on study treatment.

10. Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted only if commenced prior to the start of screening period)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California at Los Angeles	Los Angeles	California	United States	90095
2	Stanford University Medical Center Division of Hematology	Stanford	California	United States	94305-5826
3	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida	United States	33612
4	Emory University School of Medicine/Winship Cancer Institute Dept. of Winship Cancer Inst.	Atlanta	Georgia	United States	30322
5	Georgia Regents University MedCollege of GA Cancer Ctr 2	Augusta	Georgia	United States	30912
6	Hematology/Oncology of the North Shore Orchard Healthcare Res. Inc.	Skokie	Illinois	United States	60076
7	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
8	Somerset Hematology Oncology Associates Somerset Hema Oncol Assoc (2)	Somerset	New Jersey	United States	08873
9	Montefiore Medical Center	Bronx	New York	United States	10467
10	Duke University Medical Center Dept. of DUMC (4)	Durham	North Carolina	United States	27710
11	Vanderbilt University Medical Center, Clinical Trials Center Vanderbilt UMC	Nashville	Tennessee	United States	37212
12	MD Anderson Cancer Center/University of Texas MD Anderson CC	Houston	Texas	United States	77030
13	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
• Principal Investigator: Steven Young, M.D., Somerset Hematology Oncology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01083602
• Other Study ID Numbers: CLBH589DUS71
• First Posted: Mar 10, 2010
• Last Update Posted: Dec 21, 2017
• Last Verified: Nov 1, 2017

• Keywords provided by Novartis Pharmaceuticals: Multiple Myeloma; Relapsed Multiple Myeloma; Refractory Multiple Myeloma
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Bortezomib; Panobinostat

Study Results

Participant Flow

Arm/Group Title	Panobinostat + Bortezomib & Dexamethasone
Arm/Group Description	panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma
Period Title: Overall Study
STARTED	55
COMPLETED	0
NOT COMPLETED	55

Baseline Characteristics

Arm/Group Title	Panobinostat + Bortezomib & Dexamethasone
Arm/Group Description	panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma
Overall Participants	55
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.9 (10.54)
Sex: Female, Male (Count of Participants)
Female	26 47.3%
Male	29 52.7%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (PR+nCR+CR)
Description	Overall response rate=(PR+nCR+CR) CR= < 5% plasma cells in bone marrow. No confirmation on bone marrow plasma cell (additional assessment) is needed to document CR except patients with non-secretory myeloma where the bone marrow examination must be repeated after an interval of at least 6 weeks, Absence of M-protein in serum and urine by immunofixation,nCR same as CR without out Absence of M-protein in serum and urine by immunofixation,PR+ 50% reduction of serum M-protein and sofft tissue Plasmacytomas all for more than 6 weeks.
Time Frame	after eight cycyles of treatment (24 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Panobinostat + Bortezomib & Dexamethasone
Arm/Group Description	panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma
Measure Participants	55
Number (95% Confidence Interval) [percentage of participants]	34.5 62.7%

2. Secondary Outcome

Title	Responders to Treatment
Description	The primary endpoint for this phase II study of patients with bortezomib-refractory MM is response after a maximum of 8 cycles of therapy as defined by the modified EBMT criteria.
Time Frame	after eight cycyles of treatment (24 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Panobinostat + Bortezomib & Dexamethasone
Arm/Group Description	panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma
Measure Participants	55
Complete Response (CR)	0 0%
near Complete Response(nCR)	1 1.8%
Partial Response (PR)	18 32.7%
Minimal Response (MR)	10 18.2%
No Change	20 36.4%
Pregressive Disease (PD)	3 5.5%
Unknown	3 5.5%

3. Secondary Outcome

Title	Time to Response (Greater Than or Equal to PR) Based on Investigator Assessment
Description	Time to response is defined as the time from the date of first administration of study treatment to the date of first documented evidence of CR or nCR or PR (whichever status is recorded first). Patients who do not have a response of PR or better by the data cut-off date are censored.
Time Frame	after eight cycyles of treatment (24 weeks)

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Panobinostat + Bortezomib & Dexamethasone
Arm/Group Description	panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma
Measure Participants	55
Mean (Standard Deviation) [Days]	51.8 (30.92)

4. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival (PFS) was defined as the time from the date of first study treatment to first occurrence of documented progressive disease /relapse or death. Time from randomization until disease progression or death by Kaplan-Meier estimates
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS)

Arm/Group Title	Panobinostat + Bortezomib & Dexamethasone
Arm/Group Description	panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma
Measure Participants	55
Median (95% Confidence Interval) [days]	164.0

5. Secondary Outcome

Title	Time to Progression
Description	Time from randomization until objective tumor progression; does not include deaths-- Kaplan-Meier estimates
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Panobinostat + Bortezomib & Dexamethasone
Arm/Group Description	panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma
Measure Participants	55
Median (95% Confidence Interval) [Days]	164.0

6. Secondary Outcome

Title	Over All Survival
Description	Kaplan Meier estimates- median time to event
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Panobinostat + Bortezomib & Dexamethasone
Arm/Group Description	panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma
Measure Participants	55
Median (95% Confidence Interval) [Days]	559.0

Adverse Events

Arm/Group Title	PAN + BTZ + Dex
Arm/Group Description	PAN + BTZ + Dex
All Cause Mortality
	PAN + BTZ + Dex
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	PAN + BTZ + Dex
	Affected / at Risk (%)	# Events
Total	39/55 (70.9%)
Blood and lymphatic system disorders
Anaemia	4/55 (7.3%)
Febrile neutropenia	1/55 (1.8%)
Neutropenia	1/55 (1.8%)
Pancytopenia	1/55 (1.8%)
Thrombocytopenia	15/55 (27.3%)
Cardiac disorders
Atrial fibrillation	1/55 (1.8%)
Gastrointestinal disorders
Abdominal pain	1/55 (1.8%)
Diarrhoea	3/55 (5.5%)
Diverticulum	1/55 (1.8%)
Gastritis	1/55 (1.8%)
Haemorrhoids	1/55 (1.8%)
Nausea	1/55 (1.8%)
Oesophagitis	1/55 (1.8%)
Pancreatitis	1/55 (1.8%)
General disorders
Asthenia	2/55 (3.6%)
Pyrexia	5/55 (9.1%)
Hepatobiliary disorders
Cholecystitis	1/55 (1.8%)
Hepatic function abnormal	1/55 (1.8%)
Hepatic ischaemia	1/55 (1.8%)
Infections and infestations
Arthritis bacterial	1/55 (1.8%)
Cellulitis	2/55 (3.6%)
Clostridium difficile colitis	1/55 (1.8%)
Clostridium difficile infection	1/55 (1.8%)
Influenza	2/55 (3.6%)
Parainfluenzae virus infection	1/55 (1.8%)
Pneumonia	8/55 (14.5%)
Postoperative wound infection	1/55 (1.8%)
Sepsis	4/55 (7.3%)
Septic shock	3/55 (5.5%)
Sinusitis	1/55 (1.8%)
Skin infection	1/55 (1.8%)
Staphylococcal sepsis	1/55 (1.8%)
Urinary tract infection	1/55 (1.8%)
Injury, poisoning and procedural complications
Alcohol poisoning	1/55 (1.8%)
Investigations
Neutrophil count decreased	1/55 (1.8%)
Platelet count decreased	1/55 (1.8%)
White blood cell count decreased	1/55 (1.8%)
Metabolism and nutrition disorders
Dehydration	3/55 (5.5%)
Hypercalcaemia	2/55 (3.6%)
Hyperkalaemia	1/55 (1.8%)
Hyponatraemia	1/55 (1.8%)
Hypophagia	1/55 (1.8%)
Musculoskeletal and connective tissue disorders
Back pain	3/55 (5.5%)
Bone pain	1/55 (1.8%)
Nervous system disorders
Lethargy	1/55 (1.8%)
Peroneal nerve palsy	1/55 (1.8%)
Psychiatric disorders
Alcoholism	1/55 (1.8%)
Confusional state	1/55 (1.8%)
Depression	1/55 (1.8%)
Mental status changes	1/55 (1.8%)
Renal and urinary disorders
Renal failure acute	4/55 (7.3%)
Renal impairment	2/55 (3.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/55 (3.6%)
Dyspnoea exertional	1/55 (1.8%)
Hypoxia	1/55 (1.8%)
Pneumonitis	1/55 (1.8%)
Pulmonary embolism	1/55 (1.8%)
Vascular disorders
Hypotension	3/55 (5.5%)
Orthostatic hypotension	1/55 (1.8%)
Other (Not Including Serious) Adverse Events
	PAN + BTZ + Dex
	Affected / at Risk (%)	# Events
Total	53/55 (96.4%)
Blood and lymphatic system disorders
Anaemia	23/55 (41.8%)
Neutropenia	11/55 (20%)
Thrombocytopenia	23/55 (41.8%)
Eye disorders
Lacrimation increased	5/55 (9.1%)
Vision blurred	10/55 (18.2%)
Gastrointestinal disorders
Abdominal discomfort	5/55 (9.1%)
Abdominal distension	11/55 (20%)
Abdominal pain	8/55 (14.5%)
Abdominal pain upper	7/55 (12.7%)
Constipation	19/55 (34.5%)
Diarrhoea	39/55 (70.9%)
Dyspepsia	6/55 (10.9%)
Flatulence	7/55 (12.7%)
Nausea	33/55 (60%)
Stomatitis	7/55 (12.7%)
Vomiting	16/55 (29.1%)
General disorders
Asthenia	10/55 (18.2%)
Chest pain	3/55 (5.5%)
Chills	4/55 (7.3%)
Fatigue	37/55 (67.3%)
Oedema	6/55 (10.9%)
Oedema peripheral	21/55 (38.2%)
Pyrexia	8/55 (14.5%)
Infections and infestations
Candida infection	3/55 (5.5%)
Oral candidiasis	3/55 (5.5%)
Rhinitis	3/55 (5.5%)
Sinusitis	3/55 (5.5%)
Tooth infection	3/55 (5.5%)
Upper respiratory tract infection	18/55 (32.7%)
Urinary tract infection	4/55 (7.3%)
Injury, poisoning and procedural complications
Contusion	6/55 (10.9%)
Fall	3/55 (5.5%)
Investigations
Blood creatinine increased	6/55 (10.9%)
Weight decreased	8/55 (14.5%)
Metabolism and nutrition disorders
Decreased appetite	23/55 (41.8%)
Dehydration	6/55 (10.9%)
Hyperglycaemia	5/55 (9.1%)
Hypocalcaemia	3/55 (5.5%)
Hypokalaemia	13/55 (23.6%)
Hypomagnesaemia	7/55 (12.7%)
Hyponatraemia	6/55 (10.9%)
Hypophosphataemia	4/55 (7.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/55 (7.3%)
Back pain	9/55 (16.4%)
Bone pain	4/55 (7.3%)
Muscle spasms	5/55 (9.1%)
Muscular weakness	9/55 (16.4%)
Musculoskeletal pain	4/55 (7.3%)
Myalgia	9/55 (16.4%)
Pain in extremity	4/55 (7.3%)
Nervous system disorders
Amnesia	3/55 (5.5%)
Dizziness	21/55 (38.2%)
Dysgeusia	13/55 (23.6%)
Headache	12/55 (21.8%)
Hypoaesthesia	6/55 (10.9%)
Neuropathy peripheral	15/55 (27.3%)
Paraesthesia	3/55 (5.5%)
Peripheral sensory neuropathy	3/55 (5.5%)
Syncope	5/55 (9.1%)
Tremor	4/55 (7.3%)
Psychiatric disorders
Confusional state	4/55 (7.3%)
Depression	3/55 (5.5%)
Insomnia	13/55 (23.6%)
Respiratory, thoracic and mediastinal disorders
Cough	9/55 (16.4%)
Dyspnoea	19/55 (34.5%)
Dyspnoea exertional	5/55 (9.1%)
Epistaxis	6/55 (10.9%)
Oropharyngeal pain	4/55 (7.3%)
Skin and subcutaneous tissue disorders
Dry skin	3/55 (5.5%)
Ecchymosis	3/55 (5.5%)
Hyperhidrosis	3/55 (5.5%)
Pruritus	8/55 (14.5%)
Rash	4/55 (7.3%)
Skin lesion	3/55 (5.5%)
Vascular disorders
Deep vein thrombosis	4/55 (7.3%)
Haematoma	3/55 (5.5%)
Hot flush	4/55 (7.3%)
Hypertension	3/55 (5.5%)
Hypotension	9/55 (16.4%)
Orthostatic hypotension	4/55 (7.3%)

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 (ie, data from all sites) in the clinical trial.