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

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ClinicalTrials.gov Identifier: NCT00891839
Recruitment Status : Completed
First Posted : May 1, 2009
Results First Posted : October 22, 2014
Last Update Posted : November 4, 2014
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Cephalon )

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Mantle Cell Lymphoma
Interventions Drug: Bendamustine
Drug: Rituximab
Enrollment 45
Recruitment Details  
Pre-assignment Details Forty-five patients were screened and all were enrolled.
Arm/Group Title Bendamustine+Rituximab
Hide 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 [1]
Not Completed 7
Reason Not Completed
Adverse Event             2
Withdrawal by Subject             2
Disease progression             3
[1]
completed treatment
Arm/Group Title Bendamustine+Rituximab
Hide 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 Number of Baseline Participants 45
Hide Baseline Analysis Population Description
Safety
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 45 participants
69.5  (8.02)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 45 participants
Female
13
  28.9%
Male
32
  71.1%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 45 participants
Hispanic or Latino
2
   4.4%
Not Hispanic or Latino
43
  95.6%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 45 participants
American Indian or Alaska Native
0
   0.0%
Asian
1
   2.2%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
3
   6.7%
White
39
  86.7%
More than one race
0
   0.0%
Unknown or Not Reported
2
   4.4%
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 45 participants
80.3  (13.59)
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 45 participants
172.7  (9.87)
Body Surface Area (BSA)  
Mean (Standard Deviation)
Unit of measure:  M^2
Number Analyzed 45 participants
1.9  (0.20)
Ann Arbor Staging System of Lymphoma   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 45 participants
Stage I 0
Stage II 4
Stage III 4
Stage IV 37
[1]
Measure Description:
  • Stage I indicates that the cancer is located in a single region.
  • Stage II indicates that the cancer is located in two separate regions, and that both affected areas are confined to one side of the diaphragm.
  • Stage III indicates that the cancer has spread to both sides of the diaphragm, including one organ or area near the lymph nodes or the spleen.
  • Stage IV indicates diffuse or disseminated involvement of one or more extralymphatic organs, including any involvement of the liver, bone marrow, or nodular involvement of the lungs
B-Symptoms   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 45 participants
Present 9
Absent 36
[1]
Measure Description:

The presence of B symptoms is a marker for more advanced disease with systemic, rather than merely local, involvement.

B symptoms include:

  • Fever greater than 38 °C. Pel-Ebstein fever, the classic intermittent fever associated with Hodgkin disease, occurs at variable intervals of days to weeks and lasts for 1–2 weeks before resolving. However, fever associated with lymphoma can follow virtually any pattern.
  • Drenching sweats, especially at night.
  • Unintentional weight loss of >10% of normal body weight over a period of 6 months or less.
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
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population consisting of all participants treated with at least 1 dose of bendamustine HCL.
Arm/Group Title Bendamustine+Rituximab
Hide 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 Number of Participants Analyzed 45
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
end of Cycle 3
71
(55.7 to 83.6)
end of Cycle 6
82
(68.0 to 92.0)
2.Secondary Outcome
Title Kaplan-Meier Estimate for Duration of Response
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population of participants who had a response.
Arm/Group Title Bendamustine+Rituximab
Hide 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 Number of Participants Analyzed 37
Median (95% Confidence Interval)
Unit of Measure: months
18.9
(13.3 to 35.3)
3.Secondary Outcome
Title Kaplan-Meier Estimate for Progression-Free Survival
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population
Arm/Group Title Bendamustine+Rituximab
Hide 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 Number of Participants Analyzed 45
Median (95% Confidence Interval)
Unit of Measure: months
17.2
(13.2 to 24.0)
4.Secondary Outcome
Title Kaplan-Meier Estimate for Overall Survival
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population
Arm/Group Title Bendamustine+Rituximab
Hide 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 Number of Participants Analyzed 45
Median (95% Confidence Interval)
Unit of Measure: months
38.4 [1] 
(23.4 to NA)
[1]
Upper range not estimable as not enough participants died
5.Secondary Outcome
Title Shifts in Baseline to Post-Treatment in Positron Emission Tomography (PET)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population of participants with PET data
Arm/Group Title Bendamustine+Rituximab
Hide 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 Number of Participants Analyzed 38
Measure Type: Number
Unit of Measure: participants
Baseline Negative - Study Negative 0
Baseline Positive - Study Negative 0
Baseline Negative - Study Positive 23
Baseline Positive - Study Positive 15
6.Secondary Outcome
Title Shifts in Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population. One participant dropped out prior to obtaining a post-treatment ECOG evaluation.
Arm/Group Title Bendamustine+Rituximab
Hide 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 Number of Participants Analyzed 44
Measure Type: Number
Unit of Measure: participants
Improved 8
Stayed the same 32
Deteriorated 4
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
Hide 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 (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Bendamustine+Rituximab
Affected / at Risk (%) # Events
Total   18/45 (40.00%)    
Blood and lymphatic system disorders   
Febrile neutropenia * 1  1/45 (2.22%)  1
Neutropenia * 1  1/45 (2.22%)  1
Cardiac disorders   
Cardiac failure congestive * 1  1/45 (2.22%)  1
Myocardial infarction * 1  1/45 (2.22%)  1
Endocrine disorders   
Inappropriate antidiuretic hormone secretion * 1  1/45 (2.22%)  1
Gastrointestinal disorders   
Diarrhoea * 1  1/45 (2.22%)  1
Haematochezia * 1  1/45 (2.22%)  1
General disorders   
Infusion related reaction * 1  1/45 (2.22%)  1
Pyrexia * 1  1/45 (2.22%)  1
Infections and infestations   
Bronchitis * 1  1/45 (2.22%)  1
Device related infection * 1  1/45 (2.22%)  1
Pneumonia * 1  3/45 (6.67%)  3
Toxoplasmosis * 1  1/45 (2.22%)  1
Upper respiratory tract infection * 1  1/45 (2.22%)  1
Urinary tract infection * 1  1/45 (2.22%)  1
Urosepsis * 1  1/45 (2.22%)  1
Metabolism and nutrition disorders   
Dehydration * 1  1/45 (2.22%)  1
Musculoskeletal and connective tissue disorders   
Back pain * 1  1/45 (2.22%)  1
Groin pain * 1  1/45 (2.22%)  1
Muscular weakness * 1  1/45 (2.22%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Burkitt's lymphoma * 1  1/45 (2.22%)  1
Myelodysplastic syndrome * 1  1/45 (2.22%)  1
Tumour flare * 1  1/45 (2.22%)  1
Nervous system disorders   
Sedation * 1  1/45 (2.22%)  1
Psychiatric disorders   
Confusional state * 1  2/45 (4.44%)  2
Hallucination, auditory * 1  1/45 (2.22%)  1
Hallucination, visual * 1  1/45 (2.22%)  1
Mental status changes * 1  1/45 (2.22%)  1
Renal and urinary disorders   
Ureteric obstruction * 1  1/45 (2.22%)  1
Urinary tract obstruction * 1  1/45 (2.22%)  1
Respiratory, thoracic and mediastinal disorders   
Chronic obstructive pulmonary disease * 1  1/45 (2.22%)  1
Dyspnoea * 1  1/45 (2.22%)  1
Pleural effusion * 1  2/45 (4.44%)  2
Pneumothorax * 1  1/45 (2.22%)  1
Pulmonary embolism * 1  1/45 (2.22%)  1
Respiratory failure * 1  1/45 (2.22%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (15.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Bendamustine+Rituximab
Affected / at Risk (%) # Events
Total   45/45 (100.00%)    
Blood and lymphatic system disorders   
Anaemia * 1  10/45 (22.22%)  14
Leukopenia * 1  9/45 (20.00%)  12
Lymphopenia * 1  6/45 (13.33%)  9
Neutropenia * 1  21/45 (46.67%)  29
Thrombocytopenia * 1  12/45 (26.67%)  21
Cardiac disorders   
Tachycardia * 1  6/45 (13.33%)  6
Eye disorders   
Vision blurred * 1  3/45 (6.67%)  3
Gastrointestinal disorders   
Abdominal pain * 1  6/45 (13.33%)  6
Constipation * 1  17/45 (37.78%)  32
Diarrhoea * 1  16/45 (35.56%)  26
Dry mouth * 1  5/45 (11.11%)  7
Dyspepsia * 1  3/45 (6.67%)  4
Flatulence * 1  3/45 (6.67%)  3
Nausea * 1  31/45 (68.89%)  61
Stomatitis * 1  3/45 (6.67%)  3
Vomiting * 1  16/45 (35.56%)  27
General disorders   
Asthenia * 1  5/45 (11.11%)  7
Chest pain * 1  3/45 (6.67%)  6
Chills * 1  7/45 (15.56%)  15
Fatigue * 1  25/45 (55.56%)  36
Infusion related reaction * 1  4/45 (8.89%)  8
Mucosal inflammation * 1  4/45 (8.89%)  4
Oedema peripheral * 1  7/45 (15.56%)  12
Pyrexia * 1  13/45 (28.89%)  24
Immune system disorders   
Cytokine release syndrome * 1  5/45 (11.11%)  11
Infections and infestations   
Pneumonia * 1  3/45 (6.67%)  3
Sinusitis * 1  3/45 (6.67%)  3
Upper respiratory tract infection * 1  6/45 (13.33%)  6
Urinary tract infection * 1  4/45 (8.89%)  4
Injury, poisoning and procedural complications   
Arthropod bite * 1  3/45 (6.67%)  3
Contusion * 1  3/45 (6.67%)  4
Investigations   
Neutrophil count decreased * 1  3/45 (6.67%)  4
Weight decreased * 1  14/45 (31.11%)  15
Metabolism and nutrition disorders   
Decreased appetite * 1  19/45 (42.22%)  25
Dehydration * 1  4/45 (8.89%)  5
Hypokalaemia * 1  9/45 (20.00%)  14
Hypomagnesaemia * 1  4/45 (8.89%)  7
Hypophosphataemia * 1  3/45 (6.67%)  3
Musculoskeletal and connective tissue disorders   
Arthralgia * 1  4/45 (8.89%)  5
Back pain * 1  8/45 (17.78%)  10
Bone pain * 1  4/45 (8.89%)  7
Muscular weakness * 1  3/45 (6.67%)  3
Musculoskeletal pain * 1  3/45 (6.67%)  3
Myalgia * 1  4/45 (8.89%)  6
Pain in extremity * 1  3/45 (6.67%)  3
Nervous system disorders   
Dizziness * 1  11/45 (24.44%)  18
Dysgeusia * 1  4/45 (8.89%)  5
Headache * 1  8/45 (17.78%)  13
Psychiatric disorders   
Anxiety * 1  3/45 (6.67%)  5
Confusional state * 1  3/45 (6.67%)  3
Insomnia * 1  9/45 (20.00%)  11
Respiratory, thoracic and mediastinal disorders   
Cough * 1  12/45 (26.67%)  18
Dyspnoea * 1  13/45 (28.89%)  22
Dyspnoea exertional * 1  3/45 (6.67%)  4
Oropharyngeal pain * 1  5/45 (11.11%)  7
Pleural effusion * 1  3/45 (6.67%)  5
Skin and subcutaneous tissue disorders   
Dry skin * 1  3/45 (6.67%)  4
Ecchymosis * 1  3/45 (6.67%)  3
Pruritus * 1  6/45 (13.33%)  6
Rash * 1  6/45 (13.33%)  14
Vascular disorders   
Flushing * 1  4/45 (8.89%)  5
Hypertension * 1  3/45 (6.67%)  4
Hypotension * 1  9/45 (20.00%)  12
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (15.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Director, Clinical Research
Organization: Teva Branded Pharmaceutical Products, R&D Inc.
Phone: 215-591-3000
EMail: ustevatrials@tevapharm.com
Layout table for additonal information
Responsible Party: Teva Pharmaceutical Industries ( Cephalon )
ClinicalTrials.gov Identifier: NCT00891839     History of Changes
Other Study ID Numbers: C18083/2039/NL/US-CA
First Submitted: April 29, 2009
First Posted: May 1, 2009
Results First Submitted: October 17, 2014
Results First Posted: October 22, 2014
Last Update Posted: November 4, 2014