Rituximab and Combination Chemotherapy in Treating Patients With Non-Hodgkin's Lymphoma

NCT ID: NCT00278421

Last Updated: 2021-03-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 592 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-11-30
• Study Completion Date: 2018-08-31

Brief Summary

RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving rituximab together with combination chemotherapy may kill more cancer cells. It is not yet known which schedule of rituximab and combination chemotherapy is more effective in treating non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying two different schedules of rituximab and combination chemotherapy to compare how well they work in treating patients with aggressive B-cell non-Hodgkin's lymphoma.

Detailed Description

OBJECTIVES:

Primary

• Compare the efficacy of 2 different schedules of immunochemotherapy comprising rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone in patients with previously untreated, low-risk, aggressive B-cell non-Hodgkin's lymphoma.
• Compare acute and chronic side effects in patients treated with these regimens.
• Compare time to treatment failure in patients treated with these regimens.

Secondary

• Compare the time to progression in patients treated with these regimens.
• Compare the overall and disease-free/relapse-free survival of patients treated with these regimens.
• Compare the complete response rate in patients treated with these regimens.
• Compare the tumor control in patients treated with these regimens.
• Compare the safety of these regimens in these patients.
• Compare the pharmacoeconomics of these regimens.
• Compare patient adherence to these regimens.

OUTLINE: This is an open-label, randomized, multicenter study. Patients are stratified according to participating center. Patients are randomized to 1 of 2 treatment arms.

All patients are given the option of receiving a 1-week course of pretreatment therapy comprising vincristine IV once on day -6 and oral prednisone once daily on days -6 to 0.

• Arm I: Patients receive R-CHOP immunochemotherapy comprising rituximab IV, cyclophosphamide IV over 15 minutes, doxorubicin hydrochloride IV, and vincristine IV on day 1 and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo restaging of their disease. Patients with disease progression proceed to salvage therapy off study. All other patients receive 3 more courses of R-CHOP.
• Arm II: Patients receive R-CHOP as in arm I. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo restaging of their disease. Patients with disease progression proceed to salvage therapy off study. All other patients receive 1 more course of R-CHOP followed by 2 courses of rituximab alone.

All patients undergo final restaging after 6 courses of rituximab. Patients with disease progression, stable disease, or partial response proceed to salvage therapy off study.

After completion of study treatment, patients are followed periodically for 5 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 622 patients will be accrued for this study.

Conditions

Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Interventional: 6 R-CHOP-21

Arm I: Patients receive R-CHOP immunochemotherapy comprising rituximab IV, cyclophosphamide IV over 15 minutes, doxorubicin hydrochloride IV, and vincristine IV on day 1 and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo restaging of their disease. Patients with disease progression proceed to salvage therapy off study. All other patients receive 3 more courses of R-CHOP.

Group Type: ACTIVE_COMPARATOR

rituximab

Intervention Type: BIOLOGICAL

cyclophosphamide

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

prednisone

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

Interventional: 4 R-CHOP-21 + 2 x R

Arm II: Patients receive R-CHOP as in arm I. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo restaging of their disease. Patients with disease progression proceed to salvage therapy off study. All other patients receive 1 more course of R-CHOP followed by 2 courses of rituximab alone.

Group Type: ACTIVE_COMPARATOR

rituximab

Intervention Type: BIOLOGICAL

cyclophosphamide

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

prednisone

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

Interventions

rituximab

Intervention Type: BIOLOGICAL

cyclophosphamide

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

prednisone

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed aggressive B-cell non-Hodgkin's lymphoma, including the following subtypes:

• Grade 3 follicular lymphoma
• Diffuse B-cell lymphoma, including diffuse large cell lymphoma with any of the following variants:

• Centroblastic
• Immunoblastic
• Plasmablastic
• Anaplastic large cell
• T-cell-rich B-cell lymphoma
• Primary effusion lymphoma
• Intravascular B-cell lymphoma
• Primary mediastinal B-cell lymphoma
• Burkitt's or Burkitt-like lymphoma
• Mantle cell lymphoma (blastoid)
• Aggressive marginal zone lymphoma (monocytoid)
• Previously untreated disease
• CD20-positive disease
• International Prognostic Index (IPI) score 0
• No bulky disease

• Largest single or conglomerate tumor < 7.5 cm in diameter
• No mucosa-associated lymphoid tissue (MALT) lymphoma
• No CNS involvement of lymphoma (intracerebral, meningeal, or intraspinal)

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1
• Platelet count ≥ 100,000/mm^3
• WBC ≥ 2,500/mm^3
• Lactate dehydrogenase normal
• Not pregnant or lactating
• Fertile patients must use effective contraception during and for 1 year after study participation
• Negative pregnancy test
• No known hypersensitivity to the study medications
• No known HIV-positivity
• No active hepatitis infection
• No impaired left ventricular function
• No severe cardiac arrhythmias
• No other impaired organ function
• No other serious disorder
• No other malignancy within the past 5 years except carcinoma in situ or basal cell skin cancer

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy or radiotherapy
• No prior immunosuppressive treatment with cytostatics
• No planned radiotherapy to extranodal involvement
• No concurrent participation in other treatment studies

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

German High-Grade Non-Hodgkin's Lymphoma Study Group

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael G.M. Pfreundschuh, MD †

Role: STUDY_CHAIR

Universitaetsklinikum des Saarlandes

Viola Poeschel, MD

Role: STUDY_DIRECTOR

Study Office Homburg

Locations

Haematologisch Onkologische Praxis

Aachen, , Germany

Klinikum Augsburg

Augsburg, , Germany

Klinikum Bayreuth

Bayreuth, , Germany

Haematologisch-Onkologische Schwerpunktpraxis - Weilheim

Berlin, , Germany

Charite - Universitaetsmedizin Berlin - Campus Benjamin Franklin

Berlin, , Germany

Franziskus Hospital

Bielefeld, , Germany

Augusta-Kranken-Anstalt gGmbH

Bochum, , Germany

Staedtisches Klinikum Braunschweig

Braunschweig, , Germany

DIAKO Ev. Diakonie Krankenhaus gGmbH

Bremen, , Germany

Hospital Kuchwald Chemnitz

Chemnitz, , Germany

Praxis Fuer Haematologie Internistische Onkologie

Cologne, , Germany

Medizinische Universitaetsklinik I at the University of Cologne

Cologne, , Germany

Carl - Thiem - Klinkum Cottbus

Cottbus, , Germany

Praxis Dr. Rheinhold Siegmund - Dr. Matthias Penke

Damme, , Germany

Klinikum Dortmund

Dortmund, , Germany

Hans - Susemihl - Krankenhaus

Emden, , Germany

St. Antonius Hospital

Eschweiler, , Germany

Universitaetsklinikum Essen

Essen, , Germany

Klinikum Frankfurt (Oder) GmbH

Frankfurt (Oder), , Germany

Universitaetsklinikum Freiburg

Freiburg im Breisgau, , Germany

Klinikum Fulda

Fulda, , Germany

Saint Josef Hospital

Gelsenkirchen, , Germany

Universitaetsklinikum Goettingen

Göttingen, , Germany

Klinik Fuer Innere Medizin, Hematology/Oncology, Ernst Moritz Armdt Universitaet

Greifswald, , Germany

Kreiskrankenhaus Gummersbach GMBH

Gummersbach, , Germany

St. Marien Hospital - Katholisches Krankenhaus Hagen gGmbH

Hagen, , Germany

St. Sixtus Hospital

Haltern, , Germany

Asklepios Klinik St. Georg

Hamburg, , Germany

University Medical Center Hamburg - Eppendorf

Hamburg, , Germany

Haematologisch-Onkologische Praxis Altona

Hamburg, , Germany

St. Marien-Hospital Hamm - Klinik Knappenstrasse

Hamm, , Germany

Evangelische Krankenhaus Hamm

Hamm, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Ruprecht - Karls - Universitaet Heidelberg

Heidelberg, , Germany

St. Bernward Krankenhaus

Hildesheim, , Germany

Universitaetsklinikum des Saarlandes

Homburg, , Germany

Clinic for Bone Marrow Transplantation and Hematology and Oncology

Idar-Oberstein, , Germany

Staedtisches Klinikum Karlsruhe gGmbH

Karlsruhe, , Germany

St. Vincentius - Kliniken

Karlsruhe, , Germany

Klinikum Kempten Oberallgaeu

Kempten, , Germany

University Hospital Schleswig-Holstein - Kiel Campus

Kiel, , Germany

Caritas - Krakenhaus Lebach

Lebach, , Germany

Klinikum Lippe - Lemgo

Lemgo, , Germany

St. Vincenz Hospital Limburg

Limburg, , Germany

Klinikum der Stadt Ludwigshafen am Rhein

Ludwigshafen am Rhein, , Germany

Kreiskrankenhaus Luedenscheid

Lüdenscheid, , Germany

Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg

Magdeburg, , Germany

III Medizinische Klinik Mannheim

Mannheim, , Germany

Universitaetsklinikum Giessen und Marburg GmbH - Marburg

Marburg, , Germany

Krankenhaus Ludmillenstift

Meppen, , Germany

Krankenhaus Maria Hilf GmbH

Mönchengladbach, , Germany

Klinikum der Universitaet Muenchen - Grosshadern Campus

Munich, , Germany

Klinikum Rechts Der Isar - Technische Universitaet Muenchen

Munich, , Germany

Klinikum Schwaebisch Gmuend Stauferklinik

Mutlangen, , Germany

Haematologisch - Onkologische Gemeinschaftspraxis - Muenster

Münster, , Germany

Medizinische Klinik und Poliklinik A - Universitaetsklinikum Muenster

Münster, , Germany

Onkologische Schwerwpunktpraxis Dr. Ladda

Neumarkt, , Germany

Lukaskrankenhaus Neuss

Neuss, , Germany

Schlossbergkliniken Oberstaufen

Oberstaufen, , Germany

Klinikum Oldenburg

Oldenburg, , Germany

Pforzheim, , Germany

Klinikum Ernst Von Bergmann

Potsdam, , Germany

Prosper-Hospital Recklinghausen

Recklinghausen, , Germany

Rostock, , Germany

St. Marien - Krankenhaus Siegen GMBH

Siegen, , Germany

Diakonie Klinikum Stuttgart

Stuttgart, , Germany

Krankenanstalt Mutterhaus der Borromaerinnen

Trier, , Germany

Southwest German Cancer Center at Eberhard-Karls-University

Tübingen, , Germany

Universitaetsklinikum Tuebingen

Tübingen, , Germany

Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm

Ulm, , Germany

St. Marienhospital - Vechta

Vechta, , Germany

Onkologische Schwerpunktpraxis

Wendlingen, , Germany

Dr. Horst-Schmidt-Kliniken

Wiesbaden, , Germany

Helios Kliniken Wuppertal University Hospital

Wuppertal, , Germany

Rabin Medical Center - Beilinson Campus

Petah Tikva, , Israel

Ospedale Civile - Piacenza

Piacenza, , Italy

Arcispedale S. Maria Nuova

Reggio Emilia, , Italy

Cellulari ed Ematologia Sapienza

Roma, , Italy

Countries

Germany; Israel; Italy

References

Poeschel V, Held G, Ziepert M, Witzens-Harig M, Holte H, Thurner L, Borchmann P, Viardot A, Soekler M, Keller U, Schmidt C, Truemper L, Mahlberg R, Marks R, Hoeffkes HG, Metzner B, Dierlamm J, Frickhofen N, Haenel M, Neubauer A, Kneba M, Merli F, Tucci A, de Nully Brown P, Federico M, Lengfelder E, di Rocco A, Trappe R, Rosenwald A, Berdel C, Maisenhoelder M, Shpilberg O, Amam J, Christofyllakis K, Hartmann F, Murawski N, Stilgenbauer S, Nickelsen M, Wulf G, Glass B, Schmitz N, Altmann B, Loeffler M, Pfreundschuh M; FLYER Trial Investigators; German Lymphoma Alliance. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet. 2019 Dec 21;394(10216):2271-2281. doi: 10.1016/S0140-6736(19)33008-9.

Reference Type: DERIVED

PMID: 31868632 (View on PubMed)

Other Identifiers

DSHNHL-2004-2

Identifier Type: -

Identifier Source: secondary_id

EU-205110

Identifier Type: -

Identifier Source: secondary_id

EUDRACT-2005-00521738

Identifier Type: -

Identifier Source: secondary_id

DSHNHL-FLYER-6664

Identifier Type: -

Identifier Source: secondary_id

CDR0000459685

Identifier Type: -

Identifier Source: org_study_id