Study of Bendamustine Hydrochloride and Rituximab (BR) Compared With R-CVP or R-CHOP in the First-Line Treatment of Patients With Advanced Indolent Non-Hodgkin's Lymphoma (NHL) or Mantle Cell Lymphoma (MCL) - Referred to as the BRIGHT Study

Study Overview
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Brief Summary
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The primary objective of the study is to compare the complete response (CR) rate of bendamustine and rituximab (BR) with that of standard treatment regimens of either rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with advanced, indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL).

Official Title
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An Open-Label, Randomized, Parallel-Group Study of Bendamustine Hydrochloride and Rituximab (BR) Compared With Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in the First-Line Treatment of Patients With Advanced Indolent Non-Hodgkin's Lymphoma (NHL) or Mantle Cell Lymphoma (MCL)

Conditions
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Non-Hodgkin's Lymphoma, Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: bendamustine
* Drug: rituximab
* Drug: vincristine
* Drug: prednisone
* Drug: cyclophosphamide
* Drug: doxorubicin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histopathologic confirmation of one of the following cluster of differentiation antigen 20 positive (CD20+) B-cell non-Hodgkin's lymphomas (tissue diagnostic procedures must be performed within 6 months of study entry and with biopsy material available for review): follicular lymphoma (NCI CTCAE grade 1 or 2) immunoplasmacytoma/immunocytoma (Waldenstrom's macroglobulinemia) splenic marginal zone B-cell lymphoma extra-nodal marginal zone lymphoma of mucosa-associated lymphoid tumor (MALT) type nodal marginal zone B-cell lymphoma mantle cell lymphoma Meets one of the following need-for-treatment criteria (with the exception of mantle cell lymphoma for which treatment is indicated): presence of at least one of the following B-symptoms: fever (>38ºC) of unclear etiology night sweats weight loss of greater than 10% within the prior 6 months large tumor mass (bulky disease) presence of lymphoma-related complications, including narrowing of ureters or bile ducts, tumor-related compression of a vital organ, lymphoma-induced pain, cytopenias related to lymphoma/leukemia, splenomegaly, pleural effusions, or ascites hyperviscosity syndrome due to monoclonal gammopathy CD20+ B cells in lymph node biopsy or other lymphoma pathology specimen. No prior treatment (patients on watch and wait may enter the study if a recent biopsy [obtained within the last 6 months] is available) Adequate hematologic function (unless abnormalities related to lymphoma infiltration of the bone marrow or hypersplenism due to lymphoma) as follows: hemoglobin of >= 10.0 g/dL absolute neutrophil count (ANC) >=1.5*10^9/L platelet count >=100*10^9/L Bidimensionally measurable disease (field not previously radiated) Able to provide written informed consent Eastern Cooperative Oncology Group (ECOG) Performance Status <=2 Estimated life expectancy >=6 months Serum creatinine of <=2.0 mg/dL or creatinine clearance >=50 mL/min Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤2.5*upper limit of normal (ULN), and alkaline phosphatase and total bilirubin within normal limits Left ventricular ejection fraction (LVEF) >= 50% by multiple gated acquisition scan (MUGA) or cardiac echocardiogram (ECHO), prior for any patient to be treated with R-CHOP A medically accepted method of contraception to be used by women of childbearing potential (not surgically sterile or at least 12 months naturally postmenopausal) Men capable of producing offspring and not surgically sterile must practice abstinence or use a barrier method of birth control. Key Exclusion Criteria: Chronic lymphocytic leukemia, small lymphocytic lymphoma (SLL), or grade 3 follicular lymphoma Transformed disease (bone marrow blasts are permitted; however, transformed disease indicating leukemic involvement is not permitted) Central nervous system (CNS) lymphomatous involvement or leptomeningeal lymphoma Prior radiation for NHL, except for a single course of locally delimited radiation therapy with a radiation field not exceeding 2 adjacent lymph node regions Active malignancy, other than NHL, within the past 3 years except for localized prostate cancer treated with hormone therapy, cervical carcinoma in situ, breast cancer in situ, or non-melanoma skin cancer following definitive treatment New York Heart Association (NYHA) Class III or IV heart failure, arrhythmias or unstable angina, electrocardiograph (ECG) evidence of active ischemia or active conduction system abnormalities, or myocardial infarction within the last 6 months (prior to study entry, ECG abnormalities at screening must be documented by the investigator as not medically relevant) Known human immunodeficiency virus (HIV) positivity Active hepatitis B or hepatitis C infection (hepatitis B surface antigen testing required) Women who are pregnant or lactating Corticosteroids for treatment of lymphoma within 28 days of study entry Chronically administered low-dose corticosteroids (e.g., prednisone ≤20 mg/day) for indications other than lymphoma or lymphoma-related complications are permitted Any serious uncontrolled, medical or psychological disorder that would impair the ability of the patient to receive therapy Any condition which places the patient at unacceptable risk or confounds the ability of the investigators to interpret study data Any other investigational agent within 28 days of study entry Known hypersensitivity to bendamustine, mannitol, or other study-related drugs Ann Arbor stage I disease.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bendamustine and Rituximab (BR)<br>Participants received the investigational bendamustine and rituximab regimen for 6 to 8 28-day cycles: bendamustine 90 mg/m^2 intravenous (IV) on Days 1 and 2; rituximab 375 mg/m^2 IV on Day 1 | Drug: bendamustine<br> <br> * Other names: SDX-105;Drug: rituximab<br> <br> * Other names: Zytux;|
| Active Comparator: R-CHOP/R-CVP<br>Participants received the standard regimen (R-CHOP or R-CVP) for 6 to 8 21-days cycles. R-CHOP: rituximab 375 mg/m^2 IV on Day 1; vincristine 1.4 mg/m^2 (up to 2 mg/m^2 maximum dose) IV on Day 1; doxorubicin 50 mg/m^2 IV Day 1; cyclophosphamide 750 mg/m^2 IV Day 1; prednisone 100 mg oral on Days 1 to 5 R-CVP: rituximab 375 mg/m^2 IV on Day 1; cyclophosphamide 750 mg/m^2 IV on Day 1 or cyclophosphamide 1000 mg/m^2 IV on Day 1; vincristine 1.4 mg/m^2 (up to 2 mg/m^2 maximum dose) IV on Day 1; prednisone 100 mg oral on Days 1 to 5 | Drug: rituximab<br> <br> * Other names: Zytux;Drug: vincristine<br> <br> * Other names: Oncovin;Drug: prednisone<br> <br> Drug: cyclophosphamide<br> <br> * Other names: Revimmune;Drug: doxorubicin<br> <br> * Other names: Adriamycin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response (CR) at End of Treatment Period | CR=complete disappearance of all detectable clinical evidence of disease and disease-related symptoms, if present pretherapy; protocol-specified positron emission tomography (PET) scan assessment criteria; (if the spleen and/or liver were enlarged on the basis of physical examination and/or anatomic imaging before treatment) the liver and/or spleen were considered normal size on physical examination and by anatomic imaging after therapy, with disappearance of all nodules related to lymphoma; (if the bone marrow was involved by lymphoma before treatment) the infiltrate must have cleared on subsequent bone marrow biopsies. | 6 to 8 21 or 28-day cycles (18-32 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Response at End of Treatment Period | Overall Response=participants with Complete Remission (CR) + those with Partial Remission (PR). CR=see Outcome Measure 1 for details. PR= at least a 50% decrease in the sum of the product of the greatest diameters (SPD) of up to 6 of the largest dominant nodes/masses; at least a 50% decrease in the SPD of hepatic and splenic nodules in their greatest transverse diameter; no increase in the size of the liver, spleen, and other nodes; no measurable disease in organs other than the liver or spleen; no new sites of disease; protocol-specified PET scan and bone marrow criteria. | 6 to 8 21 or 28-day cycles (18-32 weeks) | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths and Discontinuations Due to AEs at End of Treatment Period | AE=any untoward medical occurrence that develops or worsens in severity after dispensation of the study drug and does not necessarily have a causal relationship to the study drug. An AE can, therefore, be any unfavorable and unintended physical sign, symptom, or laboratory parameter that develops or worsens in severity during the course of the study, or significant worsening of the disease under study (or any concurrent disease), whether or not considered related to the study drug. AEs were graded as 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). SAE=an adverse event occurring at any dose that results in: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity (a substantial disruption of one's ability to conduct normal life functions), a congenital anomaly/birth defect, or other important medical event. | 32 weeks | 
| Worst Overall Common Terminology Criteria for Adverse Events (CTCAE) Grades for Serum Chemistry Laboratory Test Results | Clinical laboratory data were graded according to National Cancer Institute's (NCI) CTCAE version 3, and graded as 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). The table presents the worst CTCAE grades for serum chemistry test results experienced by participants overall (i.e., the worst post-baseline grade value for each participant and laboratory test across all cycles). | 32 weeks (conducted at screening, Day 1 of each cycle, and end-of-treatment visit) | 
| Worst Overall CTCAE Grade for Hematology Laboratory Test Results | Hematology test data were graded according to National Cancer Institute's (NCI) CTCAE version 3, and graded as 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). The table presents the worst CTCAE grades for hematology test results experienced by participants overall (i.e., the worst post-baseline grade value for each participant and hematology test across all cycles). | 32 weeks (conducted at screening, Day 1 of each cycle, weekly during treatment, and at the end-of-treatment visit) | 
| Clinically Significant Abnormal Vital Signs |  | 32 weeks (conducted at screening, Day 1 of each cycle, and end-of-treatment visit) | 
| Potentially Clinically Significant Abnormal Weight | Participants were weighed at Baseline and at Endpoint (Week 32); those participants with an increase or decrease of >=10% were considered potentially clinically significant. | Baseline, Week 32 | 
| Eastern Cooperative Oncology Group (ECOG) Performance Status at the End of Treatment Period | Participants' ECOG Performance Status was evaluated at the end of treatment as improved, stayed the same, or worsened from baseline (see Baseline Characteristics for ECOG Performance Status). | Week 32 | 
| Therapeutic Classification of Prior Medications |  | prior to start of treatment | 
| Therapeutic Classification of Concomitant Medications |  | 32 weeks | 
| Change From Baseline to End of Treatment in the Global Health Status Score of the European Organization for Research and Treatment of Cancer (EORTC) 30-item Core Quality of Life Questionnaire (QLQ-C30) | EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnoea, appetite loss, insomnia, constipation/diarrhea, and financial difficulties). This outcome reports the global health status on a scale of 0-100 with a high score for the global health status/QOL represents a high quality of life. | Day 1 (prior to treatment), 32 weeks | 
| Participants With Disease Progression, Relapse or Death At the End of the Treatment Period or the Long-Term Follow-up Period | Relapsed disease (after CR) and progressive disease (PD) (after PR or SD): Lymph nodes were considered abnormal if the long axis was greater than 1.5 cm. Lymph nodes with a long axis of 1.1 to 1.5 cm were considered abnormal if its short axis was greater than 1.0 cm. In patients with no prior history of pulmonary lymphoma, new lung nodules identified by CT require histologic confirmation. >= 50% increase from nadir in sum of the products of the greatest diameters (SPD) of any previously involved nodes, or in a single involved node, or the size of other lesions (eg, splenic or hepatic nodules). To be considered progressive disease, a lymph node with a diameter of the short axis of less than 1.0 cm must have increased by 2: 50% and to a size of 1.5 cm by 1.5 cm, or more than 1.5 cm in the long axis other conditions as specified in the protocol | Treatment Period: 18-32 weeks Long-Term Follow-up Period: up to 5 years after the Treatment Period | 
| Kaplan-Meier Estimate for Progression-free Survival (PFS) | PFS was defined as the time from randomization to disease progression or relapse, or death from any cause, whichever occurred first. | Day 1 up to 5.6 years (Treatment Period + Long-Term Follow-up Period) | 
| Kaplan-Meier Estimate for Event-free Survival (EFS) | EFS was defined as the time from randomization to treatment failure, disease progression or relapse, other malignancies, or death from any cause, whichever occurred first. Treatment failure was defined as failure to achieve a CR or PR after 6 cycles of treatment. If a patient failed to achieve CR or PR by the time of data analysis or early withdrawal, the treatment failure date was set at 126 days (6 cycles of treatment) after randomization or the new anticancer treatment date, whichever is earlier. | Day 1 up to 5.6 years (Treatment Period + Long-Term Follow-up Period) | 
| Kaplan-Meier Estimate for Duration of Response (DOR) | DOR was defined as the time from first response (CR or PR) to disease progression or relapse, or death due to any cause. | Day 1 up to 5.6 years (Treatment Period + Long-Term Follow-up Period) | 
| Overall Survival (OS) | OS was defined as the time from randomization to death from any cause. | Day 1 up to 5.6 years (Treatment Period + Long-Term Follow-up Period) | 
| Participants Who Died At the End of the Treatment Period or the Long-Term Follow-up Period | Death is due to any cause. Data are broken out by patients who died within 30 days of the last dose of study medications, and those who died greater than 30 days of the last dose of study medications. | Treatment Period: 18-32 weeks Long-Term Follow-up Period: up to 5 years after the Treatment Period |