Clinical trial NCT00278408: Rituximab and Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With B-Cell Non-Hodgkin's Lymphoma
Official title: 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]
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lymphoma
Keywords: contiguous stage II grade 3 follicular lymphoma
noncontiguous stage II grade 3 follicular lymphoma
stage I grade 3 follicular lymphoma
stage III grade 3 follicular lymphoma
stage IV grade 3 follicular lymphoma
contiguous stage II adult diffuse large cell lymphoma
contiguous stage II adult diffuse mixed cell lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
stage I adult diffuse large cell lymphoma
stage I adult diffuse mixed cell lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
nodal marginal zone B-cell lymphoma
anaplastic large cell lymphoma
contiguous stage II adult immunoblastic large cell lymphoma
noncontiguous stage II adult immunoblastic large cell lymphoma
stage I adult immunoblastic large cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage IV adult immunoblastic large cell lymphoma
contiguous stage II adult Burkitt lymphoma
contiguous stage II mantle cell lymphoma
noncontiguous stage II adult Burkitt lymphoma
noncontiguous stage II mantle cell lymphoma
stage I adult Burkitt lymphoma
stage I mantle cell lymphoma
stage III adult Burkitt lymphoma
stage III mantle cell lymphoma
stage IV adult Burkitt lymphoma
stage IV mantle cell lymphoma
contiguous stage II marginal zone lymphoma
noncontiguous stage II marginal zone lymphoma
stage I marginal zone lymphoma
stage III marginal zone lymphoma
stage IV marginal zone lymphoma
Lead sponsor: German High-Grade Non-Hodgkin's Lymphoma Study Group
Sponsor class: OTHER
First posted: 2006-01-18
Enrollment: 700
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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.

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.

Eligibility 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 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

Primary outcomes:
measure: 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
timeFrame: 3 years
Secondary outcomes:
measure: Complete response (CR) rate until first relapse
timeFrame: through study completion
measure: Progression rate during treatment
timeFrame: 3 years
measure: Survival
timeFrame: through study completion
measure: Tumor control measured from day 1 of course 1 of CHOP therapy (non-tumor related events are censored)
timeFrame: 3 years
measure: Disease-free survival measured from day 1 of course 1 of CHOP therapy
timeFrame: life-long
measure: Relapse-free survival of patients with complete response (CR) or unconfirmed complete response (CRu) following complete immunochemotherapy
timeFrame: through study completion
measure: Safety (adverse events, serious adverse events) assessed at 3 months after completion of study treatment
timeFrame: 3 years
measure: Consolidating radiotherapy
timeFrame: 3 years
Other outcomes:
Locations:
city: Amberg
country: Germany
facility: Klinikum St. Marien
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Aurich
country: Germany
facility: Kreiskrankenhaus Aurich
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth
city: Berlin
country: Germany
facility: Charite - Campus Charite Mitte
city: Berlin
country: Germany
facility: Charite University Hospital - Campus Virchow Klinikum
city: Bielefeld
country: Germany
facility: Franziskus Hospital
city: Bochum
country: Germany
facility: Augusta-Kranken-Anstalt gGmbH
city: Braunschweig
country: Germany
facility: Staedtisches Klinikum Braunschweig
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte
city: Celle
country: Germany
facility: Onkologische Schwerpunktpraxis Celle
city: Chemnitz
country: Germany
facility: Hospital Kuchwald Chemnitz
city: Cologne
country: Germany
facility: Praxis Fuer Haematologie Internistische Onkologie
city: Cologne
country: Germany
facility: Medizinische Universitaetsklinik I at the University of Cologne
city: Cottbus
country: Germany
facility: Carl - Thiem - Klinkum Cottbus
city: Dortmund
country: Germany
facility: Klinikum Dortmund
city: Ellwangen
country: Germany
facility: Virngrund-Klinik Ellwangen
city: Emden
country: Germany
facility: Hans - Susemihl - Krankenhaus
city: Eschweiler
country: Germany
facility: St. Antonius Hospital
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Frankfurt (Oder)
country: Germany
facility: Klinikum Frankfurt (Oder) GmbH
city: Frankfurt
country: Germany
facility: Krankenhaus Nordwest
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe Universitaet
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Garmisch-Partenkirchen
country: Germany
facility: Klinikum Garmisch - Partenkirchen GmbH
city: Gelsenkirchen
country: Germany
facility: Saint Josef Hospital
city: Goch
country: Germany
facility: Wilhelm-Anton-Hospital gGmbH, Goch
city: Goettingen
country: Germany
facility: Universitaetsklinikum Goettingen
city: Greifswald
country: Germany
facility: Klinik Fuer Innere Medizin, Hematology/Oncology, Ernst Moritz Armdt Universitaet
city: Hagen
country: Germany
facility: St. Marien Hospital - Katholisches Krankenhaus Hagen gGmbH
city: Halle
country: Germany
facility: Krankenhaus Martha-Maria Halle-Doelau gGmbH
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg
city: Hamburg
country: Germany
facility: University Medical Center Hamburg - Eppendorf
city: Hanau
country: Germany
facility: Klinikum Stadt Hanau
city: Hannover
country: Germany
facility: Krankenhaus Siloah - Medizinische Klinik II
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Medizinische Universitaetsklinik und Poliklinik
city: Herrsching
country: Germany
facility: Privatklinik Dr. R. Schindlbeck GmbH & Co. KG
city: Hildesheim
country: Germany
facility: St. Bernward Krankenhaus
city: Homberg
country: Germany
facility: Haematologie und Internistische Onkologie Praxis
city: Homburg
country: Germany
facility: Universitaetsklinikum des Saarlandes
city: Idar-Oberstein
country: Germany
facility: Clinic for Bone Marrow Transplantation and Hematology and Oncology
city: Karlsruhe
country: Germany
facility: Staedtisches Klinikum Karlsruhe gGmbH
city: Kassel
country: Germany
facility: Internistische Gemeinschaftspraxis - Kassel
city: Kempten
country: Germany
facility: Klinikum Kempten Oberallgaeu
city: Kiel
country: Germany
facility: Staedtisches Krankenhaus Kiel
city: Kiel
country: Germany
facility: University Hospital Schleswig-Holstein - Kiel Campus
city: Landshut
country: Germany
facility: Internistische Praxis - Landshut
city: Ludwigshafen am Rhein
country: Germany
facility: Klinikum der Stadt Ludwigshafen am Rhein
city: Luedenscheid
country: Germany
facility: Kreiskrankenhaus Luedenscheid
city: Magdeburg
country: Germany
facility: Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg
city: Mannheim
country: Germany
facility: III Medizinische Klinik Mannheim
city: Minden
country: Germany
facility: Klinikum Minden
city: Moenchengladbach
country: Germany
facility: Krankenhaus Maria Hilf GmbH
city: Muenster
country: Germany
facility: Haematologisch - Onkologische Gemeinschaftspraxis - Muenster
city: Muenster
country: Germany
facility: Medizinische Klinik und Poliklinik A - Universitaetsklinikum Muenster
city: Munich
country: Germany
facility: Klinikum der Universitaet Muenchen - Grosshadern Campus
city: Munich
country: Germany
facility: Klinikum Rechts Der Isar - Technische Universitaet Muenchen
city: Neumarkt
country: Germany
facility: Onkologische Schwerwpunktpraxis Dr. Ladda
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Paderborn
country: Germany
facility: Bruederkrankenhaus St. Josef Paderborn
city: Regensburg
country: Germany
facility: Klinikum der Universitaet Regensburg
city: Rostock
country: Germany
facility: Klinikum Suedstadt Rostock
city: Schwienfurt
country: Germany
facility: Leopoldina - Krankenhaus
city: Siegen
country: Germany
facility: St. Marien - Krankenhaus Siegen GMBH
city: Straubing
country: Germany
facility: Onkologische Schwerpunktpraxis - Straubing
city: Stuttgart
country: Germany
facility: Klinik fuer Onkologie - Katharinenhospital Stuttgart
city: Stuttgart
country: Germany
facility: Diakonie Klinikum Stuttgart
city: Trier
country: Germany
facility: Krankenanstalt Mutterhaus der Borromaerinnen
city: Trier
country: Germany
facility: Krankenhaus Der Barmherzigen Brueder
city: Troisdorf
country: Germany
facility: Praxis Fuer Internistische Haematologie / Onkologie
city: Twistringen
country: Germany
facility: Praxis fuer Haematologie und Onkologie
city: Ulm
country: Germany
facility: Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
city: Vechta
country: Germany
facility: St. Marienhospital - Vechta
city: Waldbrol
country: Germany
facility: Regional Hospital Waldbrol
city: Wiesbaden
country: Germany
facility: Dr. Horst-Schmidt-Kliniken
city: Wuppertal 2
country: Germany
facility: Kliniken St. Antonius
city: Zwickau
country: Germany
facility: Heinrich-Braun-Krankenhaus Zwickau
city: Petah-Tikva
country: Israel
facility: Rabin Medical Center - Beilinson Campus
Study officials:
affiliation: Universitaetsklinikum des Saarlandes
name: Michael G.M. Pfreundschuh, MD †
role: STUDY_CHAIR
affiliation: Study Office Homburg
name: Viola Poeschel, MD
role: STUDY_DIRECTOR
References: