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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Trial of Bendamustine in Combination With Rituximab in Older Patients With Previously Untreated Diffuse Large B-cell Lymphoma

Conditions
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Diffuse Large B-Cell Lymphoma, Lymphoma, Diffuse Large-Cell, Diffuse Large-Cell Lymphoma, Lymphoma

Intervention / Treatment
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* Drug: Bendamustine
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bendamustine, Rituximab<br>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<br>* 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<br>* Other names: (NDA) 022249;Drug: Rituximab<br>* Dosage form: Intravenous Dosage: 375 mg/m2 Frequency: Day 1 of every 3 weeks of a 21 day Cycle Duration: 3-6 Cycles<br>* Other names: (BLA) 103705;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate as Defined by The International Harmonization Project for Response Criteria | 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. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | 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 years | 
| Partial Response Rate | 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. | 2 years | 
| Estimate of Progression-Free Survival | 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. | 2 years with the median follow-up of 29 months | 
| Overall Survival | 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. | 2 years with the median follow-up of 29 months | 
| Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | 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. | Adverse events were collected while patients were on active treatment. The median treatment time was 18 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diffuse Large B-Cell Lymphoma, Elderly, Newly Diagnosed, Lineberger Comprehensive Cancer Center, University of North Carolina, Bendamustine, Rituximab, Rituxan, Treanda, Phase 2, Geriatric, Lymphoma