Bendamustine + Rituximab in Older Patients With Previously Untreated Diffuse Large B-cell Lymphoma

• Sponsor: UNC Lineberger Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01234467
• Collaborator: Cephalon (Industry)
• Enrollment: 23
• Locations: 7
• Arm: 1
• Actual Duration (Months): 65.1
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this research study is to learn about the safety of the treatment with a combination of bendamustine and rituximab and to find out what effects, both good and bad this treatment has on DLBCL. In addition to learning about the combination of bendamustine and rituximab, the researchers are interested in learning about how this cancer treatment affects daily activities. Subjects will be asked to complete a Geriatric Assessment (GA). GAs are designed to gather information on memory, nutritional status, mental health, and level of social support. GAs are also designed to help the health care team understand how well subjects can carry out their day to day activities and to briefly describe what other medical conditions subjects may have. This assessment will help the health care team understand a subject's "functional age" (the age a subject functions at) as compared to a subject's actual age.

The researchers also want to learn how chemotherapy affects the aging process in our bodies. This is done by measuring the amount of p16 in blood. Researchers want to understand if chemotherapy changes the levels of p16 in blood.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B-Cell Lymphoma; Lymphoma, Diffuse Large-Cell; Diffuse Large-Cell Lymphoma; Lymphoma	Drug: Bendamustine; Drug: Rituximab	Phase 2

Detailed Description

This multicenter Phase II clinical study will investigate the complete response (CR) rate after therapy with bendamustine combined with rituximab in older (≥65 years old) patients with previously untreated stage II-IV DLBCL deemed poor candidates for cyclophosphamide, doxorubicin hydrochloride, vincristine (Oncovin®), prednisone, rituximab (CHOP-R); n=37. The hypothesis being tested is that this regimen will be safe and effective as frontline therapy in older DLBCL patients deemed poor candidates for CHOP-R. After 3 cycles of therapy, patients with less than a partial response (PR) will come off study, and be managed at the discretion of their treating physician. Patients who achieve a PR after 3 cycles will continue for a total of 8 cycles of therapy, while patients who achieve a CR will continue for a total of 6 cycles of therapy. Secondary objectives include overall response rates (ORR), disease-free, progression-free and overall survival, and an evaluation of the toxicity and tolerability of the regimen.

This trial also includes an exploratory analysis designed to evaluate a potential correlation between expression of the senescence marker p16INK4a and the toxicity associated with this regimen.

In addition, patients will be asked to participate in a Geriatric Assessment (GA) tool during the trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Bendamustine in Combination With Rituximab in Older Patients With Previously Untreated Diffuse Large B-cell Lymphoma
• Actual Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Aug 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Bendamustine, Rituximab This is a single arm intervention where patients will receive bendamustine at a dose of 120 mg/m^2 infused over 60 minutes in days 1 and 2 of each 21 day cycle along with rituximab 375 mg/m^2 after bendamustine on day 1 of each cycle. Patients with Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 3 at baseline were allowed to receive bendamustine at a dose of 90 mg/m^2 daily with a dose increase to 120 mg/m^2 daily if their ECOG improved.

Drug: Bendamustine; Dosage Form: Intravenous (60 minute infusion) Dosage: 120mg/m2 (ECOG = 0-2) or 90mg/m2 (ECOG = 3) Frequency: Day 1 and Day 2; Every 3 weeks of a 21 day cycle. Duration: 3-6 Cycles; Other Names: TREANDA BENDAMUSTINE HYDROCHLORIDE (NDA) 022249 ; Drug: Rituximab; Dosage form: Intravenous Dosage: 375 mg/m2 Frequency: Day 1 of every 3 weeks of a 21 day Cycle Duration: 3-6 Cycles; Other Names: Rituxan (BLA) 103705

Outcome Measures

Primary Outcome Measures

1. Complete Response (CR) Rate as Defined by The International Harmonization Project for Response Criteria [2 years]

   Complete response (CR) is defined as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. The complete response rate is the percentage of participants achieving a CR.

Secondary Outcome Measures

1. Overall Response Rate (ORR) [2 years]

   The ORR consists of the complete response rate + the partial response rate (percentage of participants achieving a complete or partial response). Complete response is defined by The International Harmonization Project for Response Criteria as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Partial response is defined as regression of measurable disease and no new sites.

2. Partial Response Rate [2 years]

   The percentage of participants achieving a partial response (PR). PR is defined by The International Harmonization Project for Response Criteria as regression of measurable disease and no new sites.

3. Estimate of Progression-Free Survival [2 years with the median follow-up of 29 months]

   Progression-free survival (PFS) will be summarized using the Kaplan-Meier method. PFS was defined as the time from the start of treatment until lymphoma progression or death as a result of any cause. Progression was defined by The International Harmonization Project for Response Criteria as any new lesion or increase by ≥50% of previously involved sites from nadir.

4. Overall Survival [2 years with the median follow-up of 29 months]

   This represents the Kaplan-Meier estimates of median overall survival defined as the time from start of treatment until death as a result of any cause.

5. Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab [Adverse events were collected while patients were on active treatment. The median treatment time was 18 weeks.]

   The major grade 3 or higher adverse events were haematological toxicities. The results below include common haematological and non-haematological toxicities of grade 3 or higher. A complete record of all adverse events are reported in the adverse events section. National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0 were used to assess toxicity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with previously untreated , histologically confirmed, diffuse large B-cell lymphoma (DLBCL), immunophenotyped for CD20

• Age greater than or equal to 65 years

• Stage II-IV

• Measurable disease including lesions that can be accurately measured in 2 dimensions by CT and have a greatest transverse diameter of 1cm or greater, and/or by bone marrow histopathology.

• ECOG performance status of 0-3

• Deemed poor candidate for CHOP-R due to ejection fraction less than or equal to 45%, ECOG performance status of 2, or in the opinion of the treating physician, patient would not tolerate administration of CHOP-R chemotherapy for other reasons,

• Life expectancy of at least 3 months;

• Documented negative serologic testing for HIV, Hepatitis B (unless positive due to prior vaccination), and hepatitis C within the year prior to enrollment

• Adequate bone marrow function (without transfusion support within one week of screening) function:

• Hemoglobin > 8 g/dL

• Absolute neutrophil count (ANC) >1000 cells/mm3

• Platelet count > 75,000/mm3

• Adequate hepatic and renal function as demonstrated by:

• Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN)

• Total serum bilirubin < 2.5 x ULN

• Serum creatinine < 1.5 x ULN

• If sexually active male of reproductive capability, has agreed to use a medically accepted form of contraception from time of enrollment to completion of all follow-up study visits

• Signed an institutional review board (IRB) approved informed consent document

Exclusion Criteria:

• Central nervous system involvement by lymphoma

• History of previous allergic reactions to compounds of similar biological or chemical composition as rituximab or bendamustine

• Medical or other condition that would represent an inappropriate risk to the patient or would likely compromise achievement of the primary study objective.

• Other active malignancies (except: non-melanoma skin cancer, cervical carcinoma in situ without evidence of disease, prostatic intraepithelial neoplasia without evidence of prostate cancer)

• Patients on strong inhibitors of CYP1A2.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Seby B. Jones Cancer Center	Boone	North Carolina	United States	28607
2	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
3	Northeast Medical Center	Concord	North Carolina	United States	28025
4	Moses Cone Regional Cancer Center	Greensboro	North Carolina	United States	27403
5	Leo Jenkins Cancer Center, East Carolina University Medical Center	Greenville	North Carolina	United States	27834
6	Rex Healthcare	Raleigh	North Carolina	United States	27607
7	Marion L. Shepard Cancer Center	Washington	North Carolina	United States	27889

Sponsors and Collaborators

• UNC Lineberger Comprehensive Cancer Center
• Cephalon

Investigators

• Principal Investigator: Steven Park, MD, University of North Carolina, Chapel Hill

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Lineberger Comprehensive Cancer Center website

Publications

None provided.

• Responsible Party: UNC Lineberger Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT01234467
• Other Study ID Numbers: LCCC 1011; 10-1405
• First Posted: Nov 4, 2010
• Last Update Posted: May 24, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by UNC Lineberger Comprehensive Cancer Center: Diffuse Large B-Cell Lymphoma; Elderly; Newly Diagnosed; Lineberger Comprehensive Cancer Center; University of North Carolina; Bendamustine; Rituximab; Rituxan; Treanda; Phase 2; Geriatric; Lymphoma
• Additional relevant MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Rituximab; Bendamustine Hydrochloride

Study Results

Participant Flow

Recruitment Details	23 patients were enrolled between March 2011 and May 2013.
Pre-assignment Detail	28 patients were assessed for eligibility; 4 patients were excluded for not meeting the inclusion criteria and 1 patient eventually declined to participate. Leaving 23 patients enrolled.

Arm/Group Title	Bendamustine, Rituximab
Arm/Group Description	This is a single arm intervention where patients will receive bendamustine at a dose of 120 mg/m^2 infused over 60 minutes in days 1 and 2 of each 21 day cycle along with rituximab 375 mg/m^2 after bendamustine on day 1 of each cycle. Patients with Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 3 at baseline were allowed to receive bendamustine at a dose of 90 mg/m^2 daily with a dose increase to 120 mg/m^2 daily if their ECOG improved. Bendamustine: Dosage Form: Intravenous (60 minute infusion) Dosage: 120mg/m2 (ECOG = 0-2) or 90mg/m2 (ECOG = 3) Frequency: Day 1 and Day 2; Every 3 weeks of a 21 day cycle. Duration: 3-6 Cycles Rituximab: Dosage form: Intravenous Dosage: 375 mg/m2 Frequency: Day 1 of every 3 weeks of a 21 day Cycle Duration: 3-6 Cycles
Period Title: Overall Study
STARTED	23
COMPLETED	11
NOT COMPLETED	12

Baseline Characteristics

Arm/Group Title	Bendamustine, Rituximab
Arm/Group Description	This is a single arm intervention where patients will receive bendamustine at a dose of 120 mg/m^2 infused over 60 minutes in days 1 and 2 of each 21 day cycle along with rituximab 375 mg/m^2 after bendamustine on day 1 of each cycle. Patients with Eastern Cooperative Oncology Group (ECOG) PS of 3 at baseline were allowed to receive bendamustine at a dose of 90 mg/m^2 daily with a dose increase to 120 mg/m^2 daily if their ECOG improved. Bendamustine: Dosage Form: Intravenous (60 minute infusion) Dosage: 120mg/m2 (ECOG = 0-2) or 90mg/m2 (ECOG = 3) Frequency: Day 1 and Day 2; Every 3 weeks of a 21 day cycle. Duration: 3-6 Cycles Rituximab: Dosage form: Intravenous Dosage: 375 mg/m2 Frequency: Day 1 of every 3 weeks of a 21 day Cycle Duration: 3-6 Cycles
Overall Participants	23
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	80
Sex: Female, Male (Count of Participants)
Female	11 47.8%
Male	12 52.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 8.7%
White	21 91.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	23 100%
Stage (Count of Participants)
II	4 17.4%
III	7 30.4%
IV	12 52.2%
ECOG Performance Status (Count of Participants)
0	2 8.7%
1	9 39.1%
2	6 26.1%
3	6 26.1%
International Prognostic Index (IPI) (Count of Participants)
2	5 21.7%
3	5 21.7%
4	8 34.8%
5	5 21.7%
Lactate Dehydrogenase (LDH) (Count of Participants)
Normal	8 34.8%
Elevated	15 65.2%
Pathology Subtype (Count of Participants)
Non-Germinal Center	12 52.2%
Germinal Center	7 30.4%
Not Classified	4 17.4%

Outcome Measures

1. Primary Outcome

Title	Complete Response (CR) Rate as Defined by The International Harmonization Project for Response Criteria
Description	Complete response (CR) is defined as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. The complete response rate is the percentage of participants achieving a CR.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

This represents the data after inclusion of the first 23 patients at the planned interim analysis. The data analysis was performed prior to the previously determined 3-year follow-up period because the study did not reach the initially planned sample size to determine the survival rates in a statistically significant manner as secondary objectives.

Arm/Group Title	Bendamustine, Rituximab
Arm/Group Description	This is a single arm intervention where patients will receive bendamustine at a dose of 120 mg/m^2 infused over 60 minutes in days 1 and 2 of each 21 day cycle along with rituximab 375 mg/m^2 after bendamustine on day 1 of each cycle. Patients with Eastern Cooperative Oncology Group (ECOG) PS of 3 at baseline were allowed to receive bendamustine at a dose of 90 mg/m^2 daily with a dose increase to 120 mg/m^2 daily if their ECOG improved. Bendamustine: Dosage Form: Intravenous (60 minute infusion) Dosage: 120mg/m2 (ECOG = 0-2) or 90mg/m2 (ECOG = 3) Frequency: Day 1 and Day 2; Every 3 weeks of a 21 day cycle. Duration: 3-6 Cycles Rituximab: Dosage form: Intravenous Dosage: 375 mg/m2 Frequency: Day 1 of every 3 weeks of a 21 day Cycle Duration: 3-6 Cycles
Measure Participants	23
Number (95% Confidence Interval) [percentage of participants]	52 226.1%

2. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	The ORR consists of the complete response rate + the partial response rate (percentage of participants achieving a complete or partial response). Complete response is defined by The International Harmonization Project for Response Criteria as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Partial response is defined as regression of measurable disease and no new sites.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

This represents the data after inclusion of the first 23 patients at the planned interim analysis. The data analysis was performed prior to the previously determined 3-year follow-up period because the study did not reach the initially planned sample size to determine the survival rates in a statistically significant manner as secondary objectives.

Arm/Group Title	Bendamustine, Rituximab
Arm/Group Description	This is a single arm intervention where patients will receive bendamustine at a dose of 120 mg/m^2 infused over 60 minutes in days 1 and 2 of each 21 day cycle along with rituximab 375 mg/m^2 after bendamustine on day 1 of each cycle. Patients with Eastern Cooperative Oncology Group (ECOG) PS of 3 at baseline were allowed to receive bendamustine at a dose of 90 mg/m^2 daily with a dose increase to 120 mg/m^2 daily if their ECOG improved. Bendamustine: Dosage Form: Intravenous (60 minute infusion) Dosage: 120mg/m2 (ECOG = 0-2) or 90mg/m2 (ECOG = 3) Frequency: Day 1 and Day 2; Every 3 weeks of a 21 day cycle. Duration: 3-6 Cycles Rituximab: Dosage form: Intravenous Dosage: 375 mg/m2 Frequency: Day 1 of every 3 weeks of a 21 day Cycle Duration: 3-6 Cycles
Measure Participants	23
Number [percentage of participants]	78 339.1%

3. Secondary Outcome

Title	Partial Response Rate
Description	The percentage of participants achieving a partial response (PR). PR is defined by The International Harmonization Project for Response Criteria as regression of measurable disease and no new sites.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

This represents the data after inclusion of the first 23 patients at the planned interim analysis. The data analysis was performed prior to the previously determined 3-year follow-up period because the study did not reach the initially planned sample size to determine the survival rates in a statistically significant manner as secondary objectives.

Arm/Group Title	Bendamustine, Rituximab
Arm/Group Description	This is a single arm intervention where patients will receive bendamustine at a dose of 120 mg/m^2 infused over 60 minutes in days 1 and 2 of each 21 day cycle along with rituximab 375 mg/m^2 after bendamustine on day 1 of each cycle. Patients with Eastern Cooperative Oncology Group (ECOG) PS of 3 at baseline were allowed to receive bendamustine at a dose of 90 mg/m^2 daily with a dose increase to 120 mg/m^2 daily if their ECOG improved. Bendamustine: Dosage Form: Intravenous (60 minute infusion) Dosage: 120mg/m2 (ECOG = 0-2) or 90mg/m2 (ECOG = 3) Frequency: Day 1 and Day 2; Every 3 weeks of a 21 day cycle. Duration: 3-6 Cycles Rituximab: Dosage form: Intravenous Dosage: 375 mg/m2 Frequency: Day 1 of every 3 weeks of a 21 day Cycle Duration: 3-6 Cycles
Measure Participants	23
Number (95% Confidence Interval) [percentage of participants]	26 113%

4. Secondary Outcome

Title	Estimate of Progression-Free Survival
Description	Progression-free survival (PFS) will be summarized using the Kaplan-Meier method. PFS was defined as the time from the start of treatment until lymphoma progression or death as a result of any cause. Progression was defined by The International Harmonization Project for Response Criteria as any new lesion or increase by ≥50% of previously involved sites from nadir.
Time Frame	2 years with the median follow-up of 29 months

Outcome Measure Data

Analysis Population Description

This represents the data after inclusion of the first 23 patients at the planned interim analysis. The data analysis was performed prior to the previously determined 3-year follow-up period because the study did not reach the initially planned sample size to determine the survival rates in a statistically significant manner as secondary objectives.

Arm/Group Title	Bendamustine, Rituximab
Arm/Group Description	This is a single arm intervention where patients will receive bendamustine at a dose of 120 mg/m^2 infused over 60 minutes in days 1 and 2 of each 21 day cycle along with rituximab 375 mg/m^2 after bendamustine on day 1 of each cycle. Patients with Eastern Cooperative Oncology Group (ECOG) PS of 3 at baseline were allowed to receive bendamustine at a dose of 90 mg/m^2 daily with a dose increase to 120 mg/m^2 daily if their ECOG improved. Bendamustine: Dosage Form: Intravenous (60 minute infusion) Dosage: 120mg/m2 (ECOG = 0-2) or 90mg/m2 (ECOG = 3) Frequency: Day 1 and Day 2; Every 3 weeks of a 21 day cycle. Duration: 3-6 Cycles Rituximab: Dosage form: Intravenous Dosage: 375 mg/m2 Frequency: Day 1 of every 3 weeks of a 21 day Cycle Duration: 3-6 Cycles
Measure Participants	23
Median (95% Confidence Interval) [Months]	5.4

5. Secondary Outcome

Title	Overall Survival
Description	This represents the Kaplan-Meier estimates of median overall survival defined as the time from start of treatment until death as a result of any cause.
Time Frame	2 years with the median follow-up of 29 months

Outcome Measure Data

Analysis Population Description

This represents the data after inclusion of the first 23 patients at the planned interim analysis. The data analysis was performed prior to the previously determined 3-year follow-up period because the study did not reach the initially planned sample size to determine the survival rates in a statistically significant manner as secondary objectives.

Arm/Group Title	Bendamustine, Rituximab
Arm/Group Description	This is a single arm intervention where patients will receive bendamustine at a dose of 120 mg/m^2 infused over 60 minutes in days 1 and 2 of each 21 day cycle along with rituximab 375 mg/m^2 after bendamustine on day 1 of each cycle. Patients with Eastern Cooperative Oncology Group (ECOG) PS of 3 at baseline were allowed to receive bendamustine at a dose of 90 mg/m^2 daily with a dose increase to 120 mg/m^2 daily if their ECOG improved. Bendamustine: Dosage Form: Intravenous (60 minute infusion) Dosage: 120mg/m2 (ECOG = 0-2) or 90mg/m2 (ECOG = 3) Frequency: Day 1 and Day 2; Every 3 weeks of a 21 day cycle. Duration: 3-6 Cycles Rituximab: Dosage form: Intravenous Dosage: 375 mg/m2 Frequency: Day 1 of every 3 weeks of a 21 day Cycle Duration: 3-6 Cycles
Measure Participants	23
Median (95% Confidence Interval) [Months]	10.2

6. Secondary Outcome

Title	Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab
Description	The major grade 3 or higher adverse events were haematological toxicities. The results below include common haematological and non-haematological toxicities of grade 3 or higher. A complete record of all adverse events are reported in the adverse events section. National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0 were used to assess toxicity.
Time Frame	Adverse events were collected while patients were on active treatment. The median treatment time was 18 weeks.

Outcome Measure Data

Analysis Population Description

This represents the data after inclusion of the first 23 patients at the planned interim analysis. The data analysis was performed prior to the previously determined 3-year follow-up period because the study did not reach the initially planned sample size to determine the survival rates in a statistically significant manner as secondary objectives.

Arm/Group Title	Bendamustine, Rituximab
Arm/Group Description	This is a single arm intervention where patients will receive bendamustine at a dose of 120 mg/m^2 infused over 60 minutes in days 1 and 2 of each 21 day cycle along with rituximab 375 mg/m^2 after bendamustine on day 1 of each cycle. Patients with Eastern Cooperative Oncology Group (ECOG) PS of 3 at baseline were allowed to receive bendamustine at a dose of 90 mg/m^2 daily with a dose increase to 120 mg/m^2 daily if their ECOG improved. Bendamustine: Dosage Form: Intravenous (60 minute infusion) Dosage: 120mg/m2 (ECOG = 0-2) or 90mg/m2 (ECOG = 3) Frequency: Day 1 and Day 2; Every 3 weeks of a 21 day cycle. Duration: 3-6 Cycles Rituximab: Dosage form: Intravenous Dosage: 375 mg/m2 Frequency: Day 1 of every 3 weeks of a 21 day Cycle Duration: 3-6 Cycles
Measure Participants	23
Lymphopenia	70
Anemia	26
Neutropenia	17
Thrombocytopenia	17
Lymphocytosis	4
Fatigue	13
Anorexia	9
Hyperglycemia	9
Urinary Tract Infection	9
Arthralgia	4
Atrial Fibrillation	4
Cognitive Disturbance	4
Generalized Muscle Weakness	4
Heart Failure	4
Hypoalbuminemia	4
Hyponatremia	4
Infusion Related Reaction	4
Myalgia	4
Nausea	4
Pleural Effusion	4
Maculopapular Rash	4
Sepsis	4
Skin Infection	4

Adverse Events

Time Frame	Adverse events were collected while patients were on active treatment. The median treatment time was 18 weeks.
Arm/Group Title	Bendamustine, Rituximab
Arm/Group Description	This is a single arm intervention where patients will receive bendamustine at a dose of 120 mg/m^2 infused over 60 minutes in days 1 and 2 of each 21 day cycle along with rituximab 375 mg/m^2 after bendamustine on day 1 of each cycle. Patients with Eastern Cooperative Oncology Group (ECOG) PS of 3 at baseline were allowed to receive bendamustine at a dose of 90 mg/m^2 daily with a dose increase to 120 mg/m^2 daily if their ECOG improved. Bendamustine: Dosage Form: Intravenous (60 minute infusion) Dosage: 120mg/m2 (ECOG = 0-2) or 90mg/m2 (ECOG = 3) Frequency: Day 1 and Day 2; Every 3 weeks of a 21 day cycle. Duration: 3-6 Cycles Rituximab: Dosage form: Intravenous Dosage: 375 mg/m2 Frequency: Day 1 of every 3 weeks of a 21 day Cycle Duration: 3-6 Cycles
All Cause Mortality
	Bendamustine, Rituximab
	Affected / at Risk (%)	# Events
Total	17/23 (73.9%)
Serious Adverse Events
	Bendamustine, Rituximab
	Affected / at Risk (%)	# Events
Total	15/23 (65.2%)
Blood and lymphatic system disorders
Anemia	1/23 (4.3%)
Febrile neutropenia	1/23 (4.3%)
Cardiac disorders
Heart failure	1/23 (4.3%)
Gastrointestinal disorders
Duodenal hemorrhage	1/23 (4.3%)
Gastric hemorrhage	1/23 (4.3%)
General disorders
Death NOS	1/23 (4.3%)
Fever	2/23 (8.7%)
Non-cardiac chest pain	1/23 (4.3%)
Infections and infestations
Lung infection	1/23 (4.3%)
Sepsis	2/23 (8.7%)
Skin infection	1/23 (4.3%)
Urinary tract infection	3/23 (13%)
Investigations
Neutrophil count decreased	2/23 (8.7%)
Platelet count decreased	2/23 (8.7%)
Creatinine increased	1/23 (4.3%)
Metabolism and nutrition disorders
Anorexia	2/23 (8.7%)
Hyponatremia	1/23 (4.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/23 (4.3%)
Nervous system disorders
Cognitive Disturbance	1/23 (4.3%)
Stroke	1/23 (4.3%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/23 (4.3%)
Dyspnea	2/23 (8.7%)
Productive cough	1/23 (4.3%)
Vascular disorders
Thromboembolic event	1/23 (4.3%)
Other (Not Including Serious) Adverse Events
	Bendamustine, Rituximab
	Affected / at Risk (%)	# Events
Total	23/23 (100%)
Blood and lymphatic system disorders
Anemia	20/23 (87%)
Cardiac disorders
Atrial fibrillation	2/23 (8.7%)
Chest pain - cardiac	1/23 (4.3%)
Gastrointestinal disorders
Abdominal pain	2/23 (8.7%)
Colitis	2/23 (8.7%)
Constipation	7/23 (30.4%)
Diarrhea	8/23 (34.8%)
Dyspepsia	3/23 (13%)
Gastroesophageal reflux disease	1/23 (4.3%)
Mucositis oral	1/23 (4.3%)
Nausea	11/23 (47.8%)
Oral pain	1/23 (4.3%)
Vomiting	6/23 (26.1%)
General disorders
Edema face	1/23 (4.3%)
Edema limbs	4/23 (17.4%)
Fatigue	20/23 (87%)
Fever	3/23 (13%)
Infusion related reaction	4/23 (17.4%)
Localized edema	1/23 (4.3%)
Pain	2/23 (8.7%)
Infections and infestations
Infections and infestations - Other, specify	1/23 (4.3%)
Lip infection	1/23 (4.3%)
Mucosal infection	2/23 (8.7%)
Urinary tract infection	6/23 (26.1%)
Injury, poisoning and procedural complications
Fall	4/23 (17.4%)
Investigations
Activated partial thromboplastin time prolonged	1/23 (4.3%)
Alanine aminotransferase increased	5/23 (21.7%)
Alkaline phosphatase increased	13/23 (56.5%)
Aspartate aminotransferase increased	14/23 (60.9%)
Blood bilirubin increased	3/23 (13%)
Cardiac troponin I increased	1/23 (4.3%)
Creatinine increased	10/23 (43.5%)
Ejection fraction decreased	1/23 (4.3%)
INR increased	1/23 (4.3%)
Lymphocyte count decreased	17/23 (73.9%)
Neutrophil count decreased	10/23 (43.5%)
Platelet count decreased	15/23 (65.2%)
Weight loss	7/23 (30.4%)
White blood cell decreased	14/23 (60.9%)
Lymphocyte count increased	1/23 (4.3%)
Metabolism and nutrition disorders
Alkalosis	1/23 (4.3%)
Anorexia	14/23 (60.9%)
Dehydration	4/23 (17.4%)
Hypercalcemia	3/23 (13%)
Hyperglycemia	10/23 (43.5%)
Hyperkalemia	6/23 (26.1%)
Hypermagnesemia	6/23 (26.1%)
Hypernatremia	2/23 (8.7%)
Hyperuricemia	1/23 (4.3%)
Hypoalbuminemia	19/23 (82.6%)
Hypocalcemia	10/23 (43.5%)
Hypokalemia	10/23 (43.5%)
Hypomagnesemia	9/23 (39.1%)
Hyponatremia	10/23 (43.5%)
Hypophosphatemia	6/23 (26.1%)
Metabolism and nutrition disorders - Other, specify	1/23 (4.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/23 (4.3%)
Back pain	2/23 (8.7%)
Generalized muscle weakness	2/23 (8.7%)
Muscle weakness lower limb	1/23 (4.3%)
Myalgia	2/23 (8.7%)
Pain in extremity	4/23 (17.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/23 (4.3%)
Tumor pain	1/23 (4.3%)
Nervous system disorders
Dizziness	4/23 (17.4%)
Dysgeusia	2/23 (8.7%)
Headache	1/23 (4.3%)
Hypersomnia	1/23 (4.3%)
Lethargy	1/23 (4.3%)
Nervous system disorders - Other, specify	1/23 (4.3%)
Paresthesia	1/23 (4.3%)
Psychiatric disorders
Confusion	2/23 (8.7%)
Depression	1/23 (4.3%)
Insomnia	2/23 (8.7%)
Restlessness	1/23 (4.3%)
Renal and urinary disorders
Hemoglobinuria	1/23 (4.3%)
Proteinuria	3/23 (13%)
Urinary frequency	2/23 (8.7%)
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction	1/23 (4.3%)
Cough	2/23 (8.7%)
Dyspnea	6/23 (26.1%)
Pleural effusion	3/23 (13%)
Voice alteration	1/23 (4.3%)
Skin and subcutaneous tissue disorders
Dry skin	1/23 (4.3%)
Pain of skin	1/23 (4.3%)
Rash acneiform	3/23 (13%)
Rash maculo-papular	2/23 (8.7%)
Skin ulceration	1/23 (4.3%)
Vascular disorders
Flushing	1/23 (4.3%)
Hypertension	3/23 (13%)
Hypotension	2/23 (8.7%)

Limitations/Caveats

The planned interim analysis was designed for futility (if ORR is less than 13/23 patients). It passed the futility criteria, but based on the survival rate at the time of interim analysis, the investigators decided to terminate the trial.

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.