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

Non-Hodgkin's Lymphoma Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00877006
• Other study ID #: C18083/3064/NL/MN
• Status: Completed
• Phase: Phase 3
• First received: April 3, 2009
• Last updated: January 8, 2018
• Start date: April 30, 2009
• Est. completion date: March 31, 2012

Study information

• Verified date: January 2018
• Source: Teva Pharmaceutical Industries
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 447
• Est. completion date: March 31, 2012
• Est. primary completion date: March 31, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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:

1. fever (>38ºC) of unclear etiology

2. night sweats

3. 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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Mantle-Cell
• Lymphoma, Non-Hodgkin
• Mantle Cell Lymphoma
• Non-Hodgkin's Lymphoma

Intervention

Drug:
• bendamustine

• rituximab

• vincristine

• prednisone

• cyclophosphamide

• doxorubicin

Locations

Country	Name	City	State
Australia	Teva Investigational Site 305	Concord
Australia	Teva Investigational Site 317	Douglas
Australia	Teva Investigational Site 308	East Melbourne
Australia	Teva Investigational Site 310	Fitzroy
Australia	Teva Investigational Site 311	Fitzroy
Australia	Teva Investigational Site 301	Garran
Australia	Teva Investigational Site 316	Geelong
Australia	Teva Investigational Site 304	Hobart
Australia	Teva Investigational Site 312	Kurralta Park
Australia	Teva Investigational Site 307	Melbourne
Australia	Teva Investigational Site 318	Parkville
Australia	Teva Investigational Site 315	Perth	Western Australia
Australia	Teva Investigational Site 300	South Brisbane
Australia	Teva Investigational Site 303	Westmead
Australia	Teva Investigational Site 314	Wodonga
Australia	Teva Investigational Site 313	Woodville
Australia	Teva Investigational Site 309	Woolloongabba
Brazil	Teva Investigational Site 503	Barretos
Brazil	Teva Investigational Site 504	Brasilia
Brazil	Teva Investigational Site 506	Curitiba
Brazil	Teva Investigational Site 505	Goiânia
Brazil	Teva Investigational Site 502	Jau
Brazil	Teva Investigational Site 509	Lajeado
Brazil	Teva Investigational Site 507	Porto Alegre
Brazil	Teva Investigational Site 508	Porto Alegre
Brazil	Teva Investigational Site 511	Rio De Janeiro
Brazil	Teva Investigational Site 500	Santo Andre
Brazil	Teva Investigational Site 501	Sao Paulo
Canada	Teva Investigational Site 202	Barrie
Canada	Teva Investigational Site 206	Calgary
Canada	Teva Investigational Site 200	Halifax
Canada	Teva Investigational Site 201	Ottawa
Canada	Teva Investigational Site 203	Vancouver
Canada	Teva Investigational Site 204	Winnipeg
Mexico	Teva Investigational Site 602	Aguascalientes
Mexico	Teva Investigational Site 603	Hermosillo
Mexico	Teva Investigational Site 600	Monterrey
Mexico	Teva Investigational Site 601	Monterrey
New Zealand	Teva Investigational Site 401	Auckland
New Zealand	Teva Investigational Site 405	Auckland
New Zealand	Teva Investigational Site 400	Christchurch
New Zealand	Teva Investigational Site 402	Newtown
New Zealand	Teva Investigational Site 404	Palmerston North
New Zealand	Teva Investigational Site 403	Takapuna
Peru	Teva Investigational Site 700	Lima
Peru	Teva Investigational Site 701	Lima
Peru	Teva Investigational Site 704	Lima
Peru	Teva Investigational Site 702	Miraflores
Peru	Teva Investigational Site 703	Miraflores
United States	Teva Investigational Site 18	Abingdon	Virginia
United States	Teva Investigational Site 46	Albuquerque	New Mexico
United States	Teva Investigational Site 154	Arlington	Texas
United States	Teva Investigational Site 158	Arlington	Texas
United States	Teva Investigational Site 43	Augusta	Maine
United States	Teva Investigational Site 72	Augusta	Georgia
United States	Teva Investigational Site 15	Aurora	Colorado
United States	Teva Investigational Site 24	Beech Grove	Indiana
United States	Teva Investigational Site 59	Bethlehem	Pennsylvania
United States	Teva Investigational Site 49	Centralia	Illinois
United States	Teva Investigational Site 25	Charleston	South Carolina
United States	Teva Investigational Site 17	Charlotte	North Carolina
United States	Teva Investigational Site 35	Charlottesville	Virginia
United States	Teva Investigational Site 56	Chattanooga	Tennessee
United States	Teva Investigational Site 48	Chicago	Illinois
United States	Teva Investigational Site 9	Chicago	Illinois
United States	Teva Investigational Site 34	Cincinnati	Ohio
United States	Teva Investigational Site 60	Cincinnati	Ohio
United States	Teva Investigational Site 28	Cleveland	Ohio
United States	Teva Investigational Site 162	Columbia	Missouri
United States	Teva Investigational Site 71	Columbia	South Carolina
United States	Teva Investigational Site 50	Columbus	Georgia
United States	Teva Investigational Site 11	Corona	California
United States	Teva Investigational Site 44	Danville	Pennsylvania
United States	Teva Investigational Site 155	Denver	Colorado
United States	Teva Investigational Site 22	Duluth	Minnesota
United States	Teva Investigational Site 151	Durham	North Carolina
United States	Teva Investigational Site 6	El Paso	Texas
United States	Teva Investigational Site 39	Fargo	North Dakota
United States	Teva Investigational Site 5	Fort Collins	Colorado
United States	Teva Investigational Site 58	Fort Myers	Florida
United States	Teva Investigational Site 161	Fort Worth	Texas
United States	Teva Investigational Site 21	Fountain Valley	California
United States	Teva Investigational Site 52	Fountain Valley	California
United States	Teva Investigational Site 64	Fullerton	California
United States	Teva Investigational Site 38	Hollywood	Florida
United States	Teva Investigational Site 152	Indianapolis	Indiana
United States	Teva Investigational Site 31	Iowa City	Iowa
United States	Teva Investigational Site 23	Jacksonville	Florida
United States	Teva Investigational Site 157	Kansas City	Missouri
United States	Teva Investigational Site 65	Lake Worth	Florida
United States	Teva Investigational Site 33	Lexington	Kentucky
United States	Teva Investigational Site 167	Little Rock	Arkansas
United States	Teva Investigational Site 40	Los Angeles	California
United States	Teva Investigational Site 53	Los Angeles	California
United States	Teva Investigational Site 74	Lowell	Massachusetts
United States	Teva Investigational Site 73	Macon	Georgia
United States	Teva Investigational Site 41	Madison	Wisconsin
United States	Teva Investigational Site 156	Miami	Florida
United States	Teva Investigational Site 66	Morgantown	West Virginia
United States	Teva Investigational Site 29	Morristown	New Jersey
United States	Teva Investigational Site 30	Nashville	Tennessee
United States	Teva Investigational Site 70	New Britain	Connecticut
United States	Teva Investigational Site 164	Norfolk	Virginia
United States	Teva Investigational Site 14	Normal	Illinois
United States	Teva Investigational Site 37	Norwalk	Connecticut
United States	Teva Investigational Site 160	Orlando	Florida
United States	Teva Investigational Site 68	Orlando	Florida
United States	Teva Investigational Site 3	Philadelphia	Pennsylvania
United States	Teva Investigational Site 13	Pittsburgh	Pennsylvania
United States	Teva Investigational Site 7	Pottstown	Pennsylvania
United States	Teva Investigational Site 54	Richmond	Virginia
United States	Teva Investigational Site 8	Rochester	New York
United States	Teva Investigational Site 4	Saint Louis Park	Minnesota
United States	Teva Investigational Site 2	Salt Lake City	Utah
United States	Teva Investigational Site 159	San Antonio	Texas
United States	Teva Investigational Site 57	San Diego	California
United States	Teva Investigational Site 42	Seattle	Washington
United States	Teva Investigational Site 19	Shreveport	Louisiana
United States	Teva Investigational Site 67	Southington	Connecticut
United States	Teva Investigational Site 150	Spokane	Washington
United States	Teva Investigational Site 153	Springfield	Oregon
United States	Teva Investigational Site 166	Sugar Land	Texas
United States	Teva Investigational Site 10	Syracuse	New York
United States	Teva Investigational Site 165	Tucson	Arizona
United States	Teva Investigational Site 163	Vancouver	Washington
United States	Teva Investigational Site 63	Waterloo	Iowa
United States	Teva Investigational Site 62	Wausau	Wisconsin
United States	Teva Investigational Site 47	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Teva Branded Pharmaceutical Products, R&D Inc.

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  Mexico,  New Zealand,  Peru, 

References & Publications (1)

Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-lin — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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
Secondary	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)
Secondary	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)
Secondary	Clinically Significant Abnormal Vital Signs		32 weeks (conducted at screening, Day 1 of each cycle, and end-of-treatment visit)
Secondary	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
Secondary	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
Secondary	Therapeutic Classification of Prior Medications		prior to start of treatment
Secondary	Therapeutic Classification of Concomitant Medications		32 weeks
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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