Rituximab and Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With B-Cell Non-Hodgkin's Lymphoma

March 9, 2021 updated by: German High-Grade Non-Hodgkin's Lymphoma Study Group

Randomized Study Comparing an Immuno-Chemotherapy With 6 Cycles of the Monoclonal Anti-CD20 Antibody Rituximab in Combination With 6 Cycles of Chemotherapy With CHOP ( Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) at 21-day Intervals or 14-day Intervals, Both With or Without Consolidating Radiotherapy or Large Tumour Masses (≥7.5 cm) and/or Extranodal Involvement in Patients With Aggressive CD20 B-Cell Lymphoma Aged 18 to 60 Years With Age-Adjusted IPI=1 (All) or IPI=0 With a Large Tumour Mass (≥7.5 cm) [UNFOLDER 21/14 Study]

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 hydrochloride, 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. Radiation therapy uses high-energy x-rays to kill cancer cells. Giving rituximab and combination chemotherapy together with radiation therapy may kill more cancer cells. It is not yet known which schedule of rituximab and combination chemotherapy is more effective when given with or without radiation therapy in treating non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying two different schedules of rituximab and combination chemotherapy with or without radiation therapy to compare how well they work in treating patients with aggressive B-cell non-Hodgkin's lymphoma.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

Primary

  • Compare the time to treatment failure in patients with previously untreated, low-risk, aggressive, B-cell non-Hodgkin's lymphoma treated with 2 different schedules of immunochemotherapy comprising rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone with vs without radiotherapy.

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 study center, serum lactic dehydrogenase level (≤ upper limit of normal [ULN] vs > ULN), disease stage (I or II vs III or IV), ECOG performance status (0-1 vs 2-3), bulky disease, and extranodal involvement. Patients with initial bulky disease and/or qualifying extranodal involvement are randomized to 1 of 4 treatment arms. Patients with non-bulky disease are randomized to treatment arms I or III.

All patients will be 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 (R-CHOP-21): Patients receive R-CHOP immunochemotherapy comprising rituximab IV, cyclophosphamide IV over 15 minutes, doxorubicin IV, and vincristine IV on day 1 and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
  • Arm II (R-CHOP-21 and radiotherapy): Patients receive R-CHOP as in arm I. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning 2-6 weeks after the last course of R-CHOP, patients who achieve a complete remission (CR) undergo radiotherapy 5 days a week for approximately 5½ weeks.
  • Arm III (R-CHOP-14): Patients receive R-CHOP as in arm I. Patients also receive filgrastim (G-CSF) subcutaneously once daily on days 4-13 or until blood counts recover. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
  • Arm IV (R-CHOP-14 and radiotherapy): Patients receive R-CHOP as in arm I. Patients also receive G-CSF an in arm III. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning 2-6 weeks after the last course of R-CHOP, patients who achieve CR undergo radiotherapy as in arm II.

Patients in all arms undergo restaging of their disease after courses 3 and 6 of R-CHOP. Patients with stable disease after 6 courses or disease progression after courses 3 or 6 proceed to salvage chemotherapy off study. Patients achieving a partial remission or an unconfirmed CR after 6 courses undergo additional restaging 4 weeks later. Patients with disease progression proceed to salvage chemotherapy off study. Patients who achieve CR after 6 courses of R-CHOP or have a confirmed CR after the additional restaging undergo radiotherapy according to randomization (as above).

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

PROJECTED ACCRUAL: A total of 1,072 patients will be accrued for this study.

Study Type

Interventional

Enrollment (Actual)

700

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Amberg, Germany, D-92224
        • Klinikum St. Marien
      • Augsburg, Germany, DOH-86156
        • Klinikum Augsburg
      • Aurich, Germany, 26603
        • Kreiskrankenhaus Aurich
      • Bayreuth, Germany, D-95445
        • Klinikum Bayreuth
      • Berlin, Germany, D-13353
        • Charite University Hospital - Campus Virchow Klinikum
      • Berlin, Germany, D-10117
        • Charité - Campus Charité Mitte
      • Bielefeld, Germany, D-33615
        • Franziskus Hospital
      • Bochum, Germany, D-44791
        • Augusta-Kranken-Anstalt gGmbH
      • Braunschweig, Germany, D-38114
        • Staedtisches Klinikum Braunschweig
      • Bremen, Germany, D-28205
        • Klinikum Bremen-Mitte
      • Celle, Germany, D-29221
        • Onkologische Schwerpunktpraxis Celle
      • Chemnitz, Germany, 09113
        • Hospital Kuchwald Chemnitz
      • Cologne, Germany, D-50677
        • Praxis Fuer Haematologie Internistische Onkologie
      • Cologne, Germany, D-50924
        • Medizinische Universitaetsklinik I at the University of Cologne
      • Cottbus, Germany, D-03048
        • Carl - Thiem - Klinkum Cottbus
      • Dortmund, Germany, D-44137
        • Klinikum Dortmund
      • Ellwangen, Germany, 73479
        • Virngrund-Klinik Ellwangen
      • Emden, Germany, 26721
        • Hans - Susemihl - Krankenhaus
      • Eschweiler, Germany, DOH-52249
        • St. Antonius Hospital
      • Essen, Germany, D-45122
        • Universitaetsklinikum Essen
      • Frankfurt, Germany, D-60590
        • Klinikum der J.W. Goethe Universitaet
      • Frankfurt, Germany, D-60488
        • Krankenhaus Nordwest
      • Frankfurt (Oder), Germany, D-15236
        • Klinikum Frankfurt (Oder) GmbH
      • Freiburg, Germany, D-79106
        • Universitaetsklinikum Freiburg
      • Garmisch-Partenkirchen, Germany, D-82467
        • Klinikum Garmisch - Partenkirchen GmbH
      • Gelsenkirchen, Germany, D-45899
        • Saint Josef Hospital
      • Goch, Germany, D-47574
        • Wilhelm-Anton-Hospital gGmbH, Goch
      • Goettingen, Germany, D-37075
        • Universitaetsklinikum Goettingen
      • Greifswald, Germany, D-17475
        • Klinik Fuer Innere Medizin, Hematology/Oncology, Ernst Moritz Armdt Universitaet
      • Hagen, Germany, D-58095
        • St. Marien Hospital - Katholisches Krankenhaus Hagen gGmbH
      • Halle, Germany, D-06120
        • Krankenhaus Martha-Maria Halle-Doelau gGmbH
      • Hamburg, Germany, D-20246
        • University Medical Center Hamburg - Eppendorf
      • Hamburg, Germany, D-20099
        • Asklepios Klinik St. Georg
      • Hanau, Germany, 63450
        • Klinikum Stadt Hanau
      • Hannover, Germany, D-30625
        • Medizinische Hochschule Hannover
      • Hannover, Germany, D-30449
        • Krankenhaus Siloah - Medizinische Klinik II
      • Heidelberg, Germany, 69115
        • Medizinische Universitaetsklinik und Poliklinik
      • Herrsching, Germany, D-82211
        • Privatklinik Dr. R. Schindlbeck GmbH & Co. KG
      • Hildesheim, Germany, D-31134
        • St. Bernward Krankenhaus
      • Homberg, Germany, D-34576
        • Haematologie und Internistische Onkologie Praxis
      • Homburg, Germany, D-66424
        • Universitaetsklinikum des Saarlandes
      • Idar-Oberstein, Germany, D-55743
        • Clinic for Bone Marrow Transplantation and Hematology and Oncology
      • Karlsruhe, Germany, 76133
        • Staedtisches Klinikum Karlsruhe gGmbH
      • Kassel, Germany, D-34117
        • Internistische Gemeinschaftspraxis - Kassel
      • Kempten, Germany, D-87439
        • Klinikum Kempten Oberallgaeu
      • Kiel, Germany, 23116
        • Staedtisches Krankenhaus Kiel
      • Kiel, Germany, D-24116
        • University Hospital Schleswig-Holstein - Kiel Campus
      • Landshut, Germany, 84028
        • Internistische Praxis - Landshut
      • Ludwigshafen am Rhein, Germany, D-67063
        • Klinikum der Stadt Ludwigshafen am Rhein
      • Luedenscheid, Germany, 58515
        • Kreiskrankenhaus Luedenscheid
      • Magdeburg, Germany, D-39120
        • Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg
      • Mannheim, Germany, D-68305
        • III Medizinische Klinik Mannheim
      • Minden, Germany, D-32423
        • Klinikum Minden
      • Moenchengladbach, Germany, D-41063
        • Krankenhaus Maria Hilf GmbH
      • Muenster, Germany, D-48149
        • Haematologisch - Onkologische Gemeinschaftspraxis - Muenster
      • Muenster, Germany, D-48149
        • Medizinische Klinik und Poliklinik A - Universitaetsklinikum Muenster
      • Munich, Germany, D-81377
        • Klinikum der Universitaet Muenchen - Grosshadern Campus
      • Munich, Germany, D-81675
        • Klinikum Rechts der Isar - Technische Universitaet Muenchen
      • Neumarkt, Germany, D-92318
        • Onkologische Schwerwpunktpraxis Dr. Ladda
      • Oldenburg, Germany, D-26133
        • Klinikum Oldenburg
      • Paderborn, Germany, D-33098
        • Bruederkrankenhaus St. Josef Paderborn
      • Regensburg, Germany, D-93053
        • Klinikum der Universitaet Regensburg
      • Rostock, Germany, D-18059
        • Klinikum Suedstadt Rostock
      • Schwienfurt, Germany, D-97422
        • Leopoldina - Krankenhaus
      • Siegen, Germany, D-57072
        • St. Marien - Krankenhaus Siegen GMBH
      • Straubing, Germany, 94315
        • Onkologische Schwerpunktpraxis - Straubing
      • Stuttgart, Germany, D-70174
        • Klinik fuer Onkologie - Katharinenhospital Stuttgart
      • Stuttgart, Germany, D-70176
        • Diakonie Klinikum Stuttgart
      • Trier, Germany, D-54219
        • Krankenanstalt Mutterhaus der Borromaerinnen
      • Trier, Germany, D-54292
        • Krankenhaus Der Barmherzigen Brueder
      • Troisdorf, Germany, 53840
        • Praxis Fuer Internistische Haematologie / Onkologie
      • Twistringen, Germany, D-27239
        • Praxis fuer Haematologie und Onkologie
      • Ulm, Germany, D-89081
        • Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
      • Vechta, Germany, D-49377
        • St. Marienhospital - Vechta
      • Waldbrol, Germany, D-51545
        • Regional Hospital Waldbrol
      • Wiesbaden, Germany, D-65199
        • Dr. Horst-Schmidt-Kliniken
      • Wuppertal 2, Germany, D-42283
        • Kliniken St. Antonius
      • Zwickau, Germany, 08060
        • Heinrich-Braun-Krankenhaus Zwickau
  • Israel
      • Petah-Tikva, Israel, 49100
        • Rabin Medical Center - Beilinson Campus

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 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 or 1 (age-adjusted)

    • Only patients with bulky disease, as defined by largest single or conglomerate tumor ≥ 7.5 cm in diameter, are allowed to have an IPI score of 0
  • No mucosa-associated lymphoid tissue (MALT) lymphoma
  • No CNS involvement of lymphoma (intracerebral, meningeal, or intraspinal)

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-2
  • Platelet count ≥ 100,000/mm³
  • WBC ≥ 2,500/mm³
  • No known hypersensitivity to the study medications
  • No known HIV-positivity
  • No active hepatitis infection
  • Not pregnant or lactating
  • Negative pregnancy test
  • No other malignancy within the past 5 years except carcinoma in situ or basal cell skin cancer
  • No impaired left ventricular function
  • No severe cardiac arrhythmias
  • No other impaired organ function
  • No other serious disorder

PRIOR CONCURRENT THERAPY:

  • No prior chemotherapy or radiotherapy
  • No prior immunosuppressive treatment with cytostatics
  • No concurrent participation in other treatment studies

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Interventional: 6 R-CHOP-21
Arm I (R-CHOP-21): Patients receive R-CHOP immunochemotherapy comprising rituximab IV, cyclophosphamide IV over 15 minutes, doxorubicin IV, and vincristine IV on day 1 and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: cyclophosphamide
Drug: prednisone
Drug: vincristine sulfate
Drug: doxorubicin hydrochloride
Biological: rituximab
Active Comparator: Interventional: 6 R-CHOP-21 + radiotherapy
Arm II (R-CHOP-21 and radiotherapy): Patients receive R-CHOP as in arm I. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning 2-6 weeks after the last course of R-CHOP, patients who achieve a complete remission (CR) undergo radiotherapy 5 days a week for approximately 5½ weeks.
Drug: cyclophosphamide
Radiation: radiation therapy
Drug: prednisone
Drug: vincristine sulfate
Drug: doxorubicin hydrochloride
Biological: rituximab
Active Comparator: Interventional: 6 R-CHOP-14
Arm III (R-CHOP-14): Patients receive R-CHOP as in arm I. Patients also receive filgrastim (G-CSF) subcutaneously once daily on days 4-13 or until blood counts recover. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: cyclophosphamide
Drug: prednisone
Drug: vincristine sulfate
Drug: doxorubicin hydrochloride
Biological: filgrastim
Biological: rituximab
Active Comparator: Interventional: 6 R-CHOP-14 and radiotherapy
Arm IV (R-CHOP-14 and radiotherapy): Patients receive R-CHOP as in arm I. Patients also receive G-CSF an in arm III. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning 2-6 weeks after the last course of R-CHOP, patients who achieve CR undergo radiotherapy as in arm II.
Drug: cyclophosphamide
Radiation: radiation therapy
Drug: prednisone
Drug: vincristine sulfate
Drug: doxorubicin hydrochloride
Biological: filgrastim
Biological: rituximab

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Time to treatment failure (TTF) measured from day 1 of course 1 of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy up to 3 years on study with life-long follow-up
Time Frame: 3 years
3 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Complete response (CR) rate until first relapse
Time Frame: through study completion
through study completion
Progression rate during treatment
Time Frame: 3 years
3 years
Survival
Time Frame: through study completion
through study completion
Tumor control measured from day 1 of course 1 of CHOP therapy (non-tumor related events are censored)
Time Frame: 3 years
3 years
Disease-free survival measured from day 1 of course 1 of CHOP therapy
Time Frame: life-long
life-long
Relapse-free survival of patients with complete response (CR) or unconfirmed complete response (CRu) following complete immunochemotherapy
Time Frame: through study completion
through study completion
Safety (adverse events, serious adverse events) assessed at 3 months after completion of study treatment
Time Frame: 3 years
3 years
Consolidating radiotherapy
Time Frame: 3 years
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

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

Investigators

  • Study Chair: Michael G.M. Pfreundschuh, MD †, Universitaetsklinikum des Saarlandes
  • Study Director: Viola Poeschel, MD, Study Office Homburg

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2005

Primary Completion (Actual)

February 1, 2018

Study Completion (Actual)

February 1, 2018

Study Registration Dates

First Submitted

January 16, 2006

First Submitted That Met QC Criteria

January 16, 2006

First Posted (Estimate)

January 18, 2006

Study Record Updates

Last Update Posted (Actual)

March 10, 2021

Last Update Submitted That Met QC Criteria

March 9, 2021

Last Verified

November 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000459796
  • DSHNHL-2004-3
  • EUDRACT-2005-005218-19
  • EU-205111

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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