Bendamustine Hydrochloride in Combination With Rituximab in Patients With Relapsed Refractory Mantle Cell Lymphoma

• Sponsor: Cephalon (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00891839
• Collaborator: (none)
• Enrollment: 45
• Locations: 13
• Arm: 1
• Duration (Months): 59
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the efficacy and safety of the combination of bendamustine and rituximab in patients with relapsed/refractory mantle cell lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Mantle Cell Lymphoma	Drug: Bendamustine; Drug: Rituximab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Study of Bendamustine Hydrochloride in Combination With Rituximab in the Treatment of Patients With Relapsed/Refractory Mantle Cell Lymphoma
• Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Bendamustine+Rituximab Patients receive bendamustine at 90 mg/m^2 intravenously (iv) on days 1 and 2, and 375 mg/m^2 of rituximab by iv on day 1 of each 28-day cycle. Six 28-day cycles were planned and up to 8 cycles permitted for patients who do not have progressive disease and who have not achieved a complete response (CR).

Drug: Bendamustine; Bendamustine at 90 mg/m^2 intravenously (iv) on days 1 and 2 of each 28-day cycle. Dosage calculations for bendamustine are based on the patient's body surface area (BSA) at baseline, using actual weight for calculations. If there is a 10% change in a patient's weight during treatment, the most recent weight is used to recalculate the BSA. The new BSA is used in determining the doses to be administered in any subsequent cycles.; Other Names: bendamustine HCl TREANDA® CEP-18083 ; Drug: Rituximab; Patients receive 375 mg/m^2 of rituximab, administered by iv infusion on day 1 of every 28-day cycle of treatment. Dosage calculations for rituximab are based on the patient's BSA at baseline, using actual weight for calculations. If there is a 10% change in a patient's weight during treatment, the most recent weight is used to recalculate the BSA. The new BSA is used in determining the doses to be administered in any subsequent cycles.; Other Names: Rituxan

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (Complete Response + Partial Response) at the End of Cycles 3 and 6 Using the 2007 International Working Group Criteria [Month 3 (end of cycle 3), Month 6 (end of cycle 6)]

   The International Working Group (IWG) criteria (Cheson et al 2007) for a complete response is a complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. A partial response is at least a 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase should be observed in the size of other nodes, liver or spleen, and no new sites of disease should be observed. 95% CIs are calculated using binomial exact method.

Secondary Outcome Measures

1. Kaplan-Meier Estimate for Duration of Response [Day 1 up to Month 43]

   Duration of response is defined as the time between the date of the first response to date of progression or death. Response is determined on the basis of the 2007 IWG criteria. A complete response is a complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. A partial response is at least a 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase should be observed in the size of other nodes, liver or spleen, and no new sites of disease should be observed.

2. Kaplan-Meier Estimate for Progression-Free Survival [Day 1 up to Month 45]

   Progression-free survival is defined as the time from first exposure to study medication to disease progression or relapse, or death due to any cause. Progression is defined using the 2007 International Working Group criteria, as any new lesion or increase by at least 50% of previously involved sites from nadir.

3. Kaplan-Meier Estimate for Overall Survival [Day 1 up to Month 57]

   Overall survival is defined as the time from first exposure to study medication to death, or to last date from adverse events, concomitant medications, vital signs, lost to follow-up, or last known alive, for overall survival censoring date.

4. Shifts in Baseline to Post-Treatment in Positron Emission Tomography (PET) [Baseline (Days -30 to 0), post treatment (up to Month 9, 30 days following completion of therapy)]

   Participants had a whole-body PET at baseline and at the end of cycle 6 or the end-of-treatment visit. Negative PET refers to PET results showing no abnormal lymph nodes; conversely, positive PET refers to PET results showing abnormal lymph nodes.

5. Shifts in Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status [Day 0 (baseline) up to Month 8]

   The ECOG scale is: Grade 0: Fully active, able to carry on all pre-disease activities without restriction; Grade 1: Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; Grade 2: Ambulatory and capable of all self-care but unable to work. Up and about more than 50% of waking hours; Grade 3: Capable of only limited self-care, confined to bed or chair > 50% of waking hours; Grade 4: Completely disabled. Cannot carry on any self-care. Confined to bed or Chair. The shift table compares baseline ECOG scores to the ECOG scores as of the last treatment visit.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• histopathologically confirmed diagnosis of typical or atypical mantle cell lymphoma, except for blastoid type.

• documented relapsed/refractory mantle cell lymphoma.

• CD20 positive B cells in the lymph node biopsy or other lymphoma pathology specimen.

• adequate hematologic function according to specific trial parameters.

• bidimensionally measurable disease with at least 1 lesion measuring 2.0 cm or more in a single dimension, or the patient is in the leukemic phase of the disease.

• patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or

• patient has an estimated life expectancy of at least 3 months.

• women of childbearing potential (not surgically sterile or 2 years postmenopausal) must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 30 days after participation in the study.

• men not surgically sterile or who are capable of producing offspring must practice abstinence or use a barrier method of birth control, and must agree to continue use of this method for the duration of study drug treatment and for 30 days after participation in the treatment period.

Exclusion Criteria:

• has received more than 3 previous standard chemotherapy regimens.

• has the blastoid subtype of mantle cell lymphoma.

• documented history of central nervous system (CNS) lymphomatous involvement.

• a history of previous high-dose chemotherapy with allogeneic stem cell transplantation (history of autologous stem cell transplantation is allowed).

• previous treatment with bendamustine.

• has an active malignancy other than MCL, or has had a malignancy other than MCL within the past 3 years, except for controlled prostate cancer without evidence of bone metastases, localized bladder cancer, cervical carcinoma in situ, breast cancer in situ, or non-melanoma skin cancer.

• has New York Heart Association (NYHA) Class III or IV heart failure, arrhythmias or unstable angina, electrocardiographic evidence of active ischemia or active conduction system abnormalities, or myocardial infarction within the last 6 months.

• has serum creatinine of more than 2.0 mg/dL or creatinine clearance of less than 30 mL/min based on the Cockcroft-Gault method or from a 24-hour urine collection.

• does not have adequate hepatic organ function as evidenced by specific trial parameters.

• has known human immunodeficiency virus (HIV) infection.

• has active hepatitis B infection. Hepatitis B surface antigen must be tested.

• a pregnant or lactating woman. (Any women becoming pregnant during the study will be withdrawn from the study.)

• has received corticosteroids within 28 days of study entry unless chronically administered (prednisone ≤20 mg/day) for indications other than lymphoma or lymphoma-related complications.

• any serious uncontrolled, medical or psychological disorder that would impair the ability of the patient to participate in or complete this study.

• any condition which places the patient at unacceptable risk or confounds the ability of the investigators to interpret study data.

• patient has received other investigational agent(s) within 28 days of study entry.

• patient has received chemotherapy within the prior 28 days.

• patient has a known hypersensitivity to bendamustine, mannitol, or rituximab.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 11	Fountain Valley	California	United States
2	Teva Investigational Site 2	Los Angeles	California	United States
3	Teva Investigational Site 35	Orlando	Florida	United States
4	Teva Investigational Site 30	Lafayette	Indiana	United States
5	Teva Investigational Site 20	Bethesda	Maryland	United States
6	Teva Investigational Site 4	Hackensack	New Jersey	United States
7	Teva Investigational Site 3	Buffalo	New York	United States
8	Teva Investigational Site 43	Gettysburg	Pennsylvania	United States
9	Teva Investigational Site 33	Bryan	Texas	United States
10	Teva Investigational Site 41	Grapevine	Texas	United States
11	Teva Investigational Site 23	Lynchburg	Virginia	United States
12	Teva Investigational Site 6	Ottawa		Canada
13	Teva Investigational Site 7	Toronto		Canada

Sponsors and Collaborators

• Cephalon

Investigators

• Study Director: Sponsor's Medical Expert, Cephalon

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Cephalon
• ClinicalTrials.gov Identifier: NCT00891839
• Other Study ID Numbers: C18083/2039/NL/US-CA
• First Posted: May 1, 2009
• Last Update Posted: Nov 4, 2014
• Last Verified: Oct 1, 2014

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell; Rituximab; Bendamustine Hydrochloride

Study Results

Participant Flow

Pre-assignment Detail	Forty-five patients were screened and all were enrolled.

Arm/Group Title	Bendamustine+Rituximab
Arm/Group Description	Participants receive bendamustine at 90 mg/m^2 intravenously (iv) on days 1 and 2, and 375 mg/m^2 of rituximab by iv on day 1 of each 28-day cycle. Six 28-day cycles were planned and up to 8 cycles permitted for patients who do not have progressive disease and who have not achieved a complete response (CR).
Period Title: Overall Study
STARTED	45
COMPLETED	38
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Bendamustine+Rituximab
Arm/Group Description	Participants receive bendamustine at 90 mg/m^2 intravenously (iv) on days 1 and 2, and 375 mg/m^2 of rituximab by iv on day 1 of each 28-day cycle. Six 28-day cycles were planned and up to 8 cycles permitted for patients who do not have progressive disease and who have not achieved a complete response (CR).
Overall Participants	45
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.5 (8.02)
Sex: Female, Male (Count of Participants)
Female	13 28.9%
Male	32 71.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 4.4%
Not Hispanic or Latino	43 95.6%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 2.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 6.7%
White	39 86.7%
More than one race	0 0%
Unknown or Not Reported	2 4.4%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	80.3 (13.59)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	172.7 (9.87)
Body Surface Area (BSA) (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.9 (0.20)
Ann Arbor Staging System of Lymphoma (participants) [Number]
Stage I	0 0%
Stage II	4 8.9%
Stage III	4 8.9%
Stage IV	37 82.2%
B-Symptoms (participants) [Number]
Present	9 20%
Absent	36 80%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (Complete Response + Partial Response) at the End of Cycles 3 and 6 Using the 2007 International Working Group Criteria
Description	The International Working Group (IWG) criteria (Cheson et al 2007) for a complete response is a complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. A partial response is at least a 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase should be observed in the size of other nodes, liver or spleen, and no new sites of disease should be observed. 95% CIs are calculated using binomial exact method.
Time Frame	Month 3 (end of cycle 3), Month 6 (end of cycle 6)

Outcome Measure Data

Analysis Population Description

Safety population consisting of all participants treated with at least 1 dose of bendamustine HCL.

Arm/Group Title	Bendamustine+Rituximab
Arm/Group Description	Participants receive bendamustine at 90 mg/m^2 intravenously (iv) on days 1 and 2, and 375 mg/m^2 of rituximab by iv on day 1 of each 28-day cycle. Six 28-day cycles were planned and up to 8 cycles permitted for patients who do not have progressive disease and who have not achieved a complete response (CR).
Measure Participants	45
end of Cycle 3	71 157.8%
end of Cycle 6	82 182.2%

2. Secondary Outcome

Title	Kaplan-Meier Estimate for Duration of Response
Description	Duration of response is defined as the time between the date of the first response to date of progression or death. Response is determined on the basis of the 2007 IWG criteria. A complete response is a complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. A partial response is at least a 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase should be observed in the size of other nodes, liver or spleen, and no new sites of disease should be observed.
Time Frame	Day 1 up to Month 43

Outcome Measure Data

Analysis Population Description

Safety population of participants who had a response.

Arm/Group Title	Bendamustine+Rituximab
Arm/Group Description	Participants receive bendamustine at 90 mg/m^2 intravenously (iv) on days 1 and 2, and 375 mg/m^2 of rituximab by iv on day 1 of each 28-day cycle. Six 28-day cycles were planned and up to 8 cycles permitted for patients who do not have progressive disease and who have not achieved a complete response (CR).
Measure Participants	37
Median (95% Confidence Interval) [months]	18.9

3. Secondary Outcome

Title	Kaplan-Meier Estimate for Progression-Free Survival
Description	Progression-free survival is defined as the time from first exposure to study medication to disease progression or relapse, or death due to any cause. Progression is defined using the 2007 International Working Group criteria, as any new lesion or increase by at least 50% of previously involved sites from nadir.
Time Frame	Day 1 up to Month 45

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Bendamustine+Rituximab
Arm/Group Description	Participants receive bendamustine at 90 mg/m^2 intravenously (iv) on days 1 and 2, and 375 mg/m^2 of rituximab by iv on day 1 of each 28-day cycle. Six 28-day cycles were planned and up to 8 cycles permitted for patients who do not have progressive disease and who have not achieved a complete response (CR).
Measure Participants	45
Median (95% Confidence Interval) [months]	17.2

4. Secondary Outcome

Title	Kaplan-Meier Estimate for Overall Survival
Description	Overall survival is defined as the time from first exposure to study medication to death, or to last date from adverse events, concomitant medications, vital signs, lost to follow-up, or last known alive, for overall survival censoring date.
Time Frame	Day 1 up to Month 57

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Bendamustine+Rituximab
Arm/Group Description	Participants receive bendamustine at 90 mg/m^2 intravenously (iv) on days 1 and 2, and 375 mg/m^2 of rituximab by iv on day 1 of each 28-day cycle. Six 28-day cycles were planned and up to 8 cycles permitted for patients who do not have progressive disease and who have not achieved a complete response (CR).
Measure Participants	45
Median (95% Confidence Interval) [months]	38.4

5. Secondary Outcome

Title	Shifts in Baseline to Post-Treatment in Positron Emission Tomography (PET)
Description	Participants had a whole-body PET at baseline and at the end of cycle 6 or the end-of-treatment visit. Negative PET refers to PET results showing no abnormal lymph nodes; conversely, positive PET refers to PET results showing abnormal lymph nodes.
Time Frame	Baseline (Days -30 to 0), post treatment (up to Month 9, 30 days following completion of therapy)

Outcome Measure Data

Analysis Population Description

Safety population of participants with PET data

Arm/Group Title	Bendamustine+Rituximab
Arm/Group Description	Participants receive bendamustine at 90 mg/m^2 intravenously (iv) on days 1 and 2, and 375 mg/m^2 of rituximab by iv on day 1 of each 28-day cycle. Six 28-day cycles were planned and up to 8 cycles permitted for patients who do not have progressive disease and who have not achieved a complete response (CR).
Measure Participants	38
Baseline Negative - Study Negative	0 0%
Baseline Positive - Study Negative	0 0%
Baseline Negative - Study Positive	23 51.1%
Baseline Positive - Study Positive	15 33.3%

6. Secondary Outcome

Title	Shifts in Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status
Description	The ECOG scale is: Grade 0: Fully active, able to carry on all pre-disease activities without restriction; Grade 1: Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; Grade 2: Ambulatory and capable of all self-care but unable to work. Up and about more than 50% of waking hours; Grade 3: Capable of only limited self-care, confined to bed or chair > 50% of waking hours; Grade 4: Completely disabled. Cannot carry on any self-care. Confined to bed or Chair. The shift table compares baseline ECOG scores to the ECOG scores as of the last treatment visit.
Time Frame	Day 0 (baseline) up to Month 8

Outcome Measure Data

Analysis Population Description

Safety population. One participant dropped out prior to obtaining a post-treatment ECOG evaluation.

Arm/Group Title	Bendamustine+Rituximab
Arm/Group Description	Participants receive bendamustine at 90 mg/m^2 intravenously (iv) on days 1 and 2, and 375 mg/m^2 of rituximab by iv on day 1 of each 28-day cycle. Six 28-day cycles were planned and up to 8 cycles permitted for patients who do not have progressive disease and who have not achieved a complete response (CR).
Measure Participants	44
Improved	8 17.8%
Stayed the same	32 71.1%
Deteriorated	4 8.9%

Adverse Events

Time Frame	Day 1 up to Month 8
Adverse Event Reporting Description	Participants are counted only once in each preferred term category, and only once in each system organ class category and high-level term.
Arm/Group Title	Bendamustine+Rituximab
Arm/Group Description	Participants receive bendamustine at 90 mg/m^2 intravenously (iv) on days 1 and 2, and 375 mg/m^2 of rituximab by iv on day 1 of each 28-day cycle. Six 28-day cycles were planned and up to 8 cycles permitted for patients who do not have progressive disease and who have not achieved a complete response (CR).
All Cause Mortality
	Bendamustine+Rituximab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bendamustine+Rituximab
	Affected / at Risk (%)	# Events
Total	18/45 (40%)
Blood and lymphatic system disorders
Febrile neutropenia	1/45 (2.2%)	1
Neutropenia	1/45 (2.2%)	1
Cardiac disorders
Cardiac failure congestive	1/45 (2.2%)	1
Myocardial infarction	1/45 (2.2%)	1
Endocrine disorders
Inappropriate antidiuretic hormone secretion	1/45 (2.2%)	1
Gastrointestinal disorders
Diarrhoea	1/45 (2.2%)	1
Haematochezia	1/45 (2.2%)	1
General disorders
Infusion related reaction	1/45 (2.2%)	1
Pyrexia	1/45 (2.2%)	1
Infections and infestations
Bronchitis	1/45 (2.2%)	1
Device related infection	1/45 (2.2%)	1
Pneumonia	3/45 (6.7%)	3
Toxoplasmosis	1/45 (2.2%)	1
Upper respiratory tract infection	1/45 (2.2%)	1
Urinary tract infection	1/45 (2.2%)	1
Urosepsis	1/45 (2.2%)	1
Metabolism and nutrition disorders
Dehydration	1/45 (2.2%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/45 (2.2%)	1
Groin pain	1/45 (2.2%)	1
Muscular weakness	1/45 (2.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Burkitt's lymphoma	1/45 (2.2%)	1
Myelodysplastic syndrome	1/45 (2.2%)	1
Tumour flare	1/45 (2.2%)	1
Nervous system disorders
Sedation	1/45 (2.2%)	1
Psychiatric disorders
Confusional state	2/45 (4.4%)	2
Hallucination, auditory	1/45 (2.2%)	1
Hallucination, visual	1/45 (2.2%)	1
Mental status changes	1/45 (2.2%)	1
Renal and urinary disorders
Ureteric obstruction	1/45 (2.2%)	1
Urinary tract obstruction	1/45 (2.2%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/45 (2.2%)	1
Dyspnoea	1/45 (2.2%)	1
Pleural effusion	2/45 (4.4%)	2
Pneumothorax	1/45 (2.2%)	1
Pulmonary embolism	1/45 (2.2%)	1
Respiratory failure	1/45 (2.2%)	1
Other (Not Including Serious) Adverse Events
	Bendamustine+Rituximab
	Affected / at Risk (%)	# Events
Total	45/45 (100%)
Blood and lymphatic system disorders
Anaemia	10/45 (22.2%)	14
Leukopenia	9/45 (20%)	12
Lymphopenia	6/45 (13.3%)	9
Neutropenia	21/45 (46.7%)	29
Thrombocytopenia	12/45 (26.7%)	21
Cardiac disorders
Tachycardia	6/45 (13.3%)	6
Eye disorders
Vision blurred	3/45 (6.7%)	3
Gastrointestinal disorders
Abdominal pain	6/45 (13.3%)	6
Constipation	17/45 (37.8%)	32
Diarrhoea	16/45 (35.6%)	26
Dry mouth	5/45 (11.1%)	7
Dyspepsia	3/45 (6.7%)	4
Flatulence	3/45 (6.7%)	3
Nausea	31/45 (68.9%)	61
Stomatitis	3/45 (6.7%)	3
Vomiting	16/45 (35.6%)	27
General disorders
Asthenia	5/45 (11.1%)	7
Chest pain	3/45 (6.7%)	6
Chills	7/45 (15.6%)	15
Fatigue	25/45 (55.6%)	36
Infusion related reaction	4/45 (8.9%)	8
Mucosal inflammation	4/45 (8.9%)	4
Oedema peripheral	7/45 (15.6%)	12
Pyrexia	13/45 (28.9%)	24
Immune system disorders
Cytokine release syndrome	5/45 (11.1%)	11
Infections and infestations
Pneumonia	3/45 (6.7%)	3
Sinusitis	3/45 (6.7%)	3
Upper respiratory tract infection	6/45 (13.3%)	6
Urinary tract infection	4/45 (8.9%)	4
Injury, poisoning and procedural complications
Arthropod bite	3/45 (6.7%)	3
Contusion	3/45 (6.7%)	4
Investigations
Neutrophil count decreased	3/45 (6.7%)	4
Weight decreased	14/45 (31.1%)	15
Metabolism and nutrition disorders
Decreased appetite	19/45 (42.2%)	25
Dehydration	4/45 (8.9%)	5
Hypokalaemia	9/45 (20%)	14
Hypomagnesaemia	4/45 (8.9%)	7
Hypophosphataemia	3/45 (6.7%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	4/45 (8.9%)	5
Back pain	8/45 (17.8%)	10
Bone pain	4/45 (8.9%)	7
Muscular weakness	3/45 (6.7%)	3
Musculoskeletal pain	3/45 (6.7%)	3
Myalgia	4/45 (8.9%)	6
Pain in extremity	3/45 (6.7%)	3
Nervous system disorders
Dizziness	11/45 (24.4%)	18
Dysgeusia	4/45 (8.9%)	5
Headache	8/45 (17.8%)	13
Psychiatric disorders
Anxiety	3/45 (6.7%)	5
Confusional state	3/45 (6.7%)	3
Insomnia	9/45 (20%)	11
Respiratory, thoracic and mediastinal disorders
Cough	12/45 (26.7%)	18
Dyspnoea	13/45 (28.9%)	22
Dyspnoea exertional	3/45 (6.7%)	4
Oropharyngeal pain	5/45 (11.1%)	7
Pleural effusion	3/45 (6.7%)	5
Skin and subcutaneous tissue disorders
Dry skin	3/45 (6.7%)	4
Ecchymosis	3/45 (6.7%)	3
Pruritus	6/45 (13.3%)	6
Rash	6/45 (13.3%)	14
Vascular disorders
Flushing	4/45 (8.9%)	5
Hypertension	3/45 (6.7%)	4
Hypotension	9/45 (20%)	12

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.