Clinical trial NCT00278421: Rituximab and Combination Chemotherapy in Treating Patients With Non-Hodgkin's Lymphoma
Official title: Randomized Study Comparing 4 and 6 Cycles of Chemotherapy With CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) at 21-day Intervals, Both With 6 Cycles of Immunotherapy With the Monoclonal Anti-CD20-Positive B-Cell Lymphoma Aged 18-60 Years Having no Risk Factor (Age-Adjusted IPI=0) and No Large Tumor Mass (Diameter <7,5cm) [FLYER 6-6-6-4 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
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
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
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
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
stage III adult Burkitt lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage IV adult Burkitt lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
Lead sponsor: German High-Grade Non-Hodgkin's Lymphoma Study Group
Sponsor class: OTHER
First posted: 2006-01-18
Enrollment: 592
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, 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.

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 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

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: through study completion
Secondary outcomes:
measure: Complete response (CR) rate duration until first relapse
timeFrame: through study completion
measure: Progression rate during treatment
timeFrame: through study completion
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: through study completion
measure: Disease-free survival measured from day 1 of course 1 of CHOP therapy
timeFrame: through study completion
measure: Safety (adverse events, serious adverse events) assessed at 3 months after treatment
timeFrame: through study completion
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Haematologisch Onkologische Praxis
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth
city: Berlin
country: Germany
facility: Haematologisch-Onkologische Schwerpunktpraxis - Weilheim
city: Berlin
country: Germany
facility: Charite - Universitaetsmedizin Berlin - Campus Benjamin Franklin
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: DIAKO Ev. Diakonie Krankenhaus gGmbH
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: Damme
country: Germany
facility: Praxis Dr. Rheinhold Siegmund - Dr. Matthias Penke
city: Dortmund
country: Germany
facility: Klinikum Dortmund
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: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Fulda
country: Germany
facility: Klinikum Fulda
city: Gelsenkirchen
country: Germany
facility: Saint Josef Hospital
city: Goettingen
country: Germany
facility: Universitaetsklinikum Goettingen
city: Greifswald
country: Germany
facility: Klinik Fuer Innere Medizin, Hematology/Oncology, Ernst Moritz Armdt Universitaet
city: Gummersbach
country: Germany
facility: Kreiskrankenhaus Gummersbach GMBH
city: Hagen
country: Germany
facility: St. Marien Hospital - Katholisches Krankenhaus Hagen gGmbH
city: Haltern
country: Germany
facility: St. Sixtus Hospital
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg
city: Hamburg
country: Germany
facility: University Medical Center Hamburg - Eppendorf
city: Hamburg
country: Germany
facility: Haematologisch-Onkologische Praxis Altona
city: Hamm
country: Germany
facility: St. Marien-Hospital Hamm - Klinik Knappenstrasse
city: Hamm
country: Germany
facility: Evangelische Krankenhaus Hamm
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Ruprecht - Karls - Universitaet Heidelberg
city: Hildesheim
country: Germany
facility: St. Bernward Krankenhaus
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: Karlsruhe
country: Germany
facility: St. Vincentius - Kliniken
city: Kempten
country: Germany
facility: Klinikum Kempten Oberallgaeu
city: Kiel
country: Germany
facility: University Hospital Schleswig-Holstein - Kiel Campus
city: Lebach
country: Germany
facility: Caritas - Krakenhaus Lebach
city: Lemgo
country: Germany
facility: Klinikum Lippe - Lemgo
city: Limburg
country: Germany
facility: St. Vincenz Hospital Limburg
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: Marburg
country: Germany
facility: Universitaetsklinikum Giessen und Marburg GmbH - Marburg
city: Meppen
country: Germany
facility: Krankenhaus Ludmillenstift
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: Mutlangen
country: Germany
facility: Klinikum Schwaebisch Gmuend Stauferklinik
city: Neumarkt
country: Germany
facility: Onkologische Schwerwpunktpraxis Dr. Ladda
city: Neuss
country: Germany
facility: Lukaskrankenhaus Neuss
city: Oberstaufen
country: Germany
facility: Schlossbergkliniken Oberstaufen
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Pforzheim
country: Germany
city: Potsdam
country: Germany
facility: Klinikum Ernst Von Bergmann
city: Recklinghausen
country: Germany
facility: Prosper-Hospital Recklinghausen
city: Rostock
country: Germany
city: Siegen
country: Germany
facility: St. Marien - Krankenhaus Siegen GMBH
city: Stuttgart
country: Germany
facility: Diakonie Klinikum Stuttgart
city: Trier
country: Germany
facility: Krankenanstalt Mutterhaus der Borromaerinnen
city: Tuebingen
country: Germany
facility: Southwest German Cancer Center at Eberhard-Karls-University
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Ulm
country: Germany
facility: Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
city: Vechta
country: Germany
facility: St. Marienhospital - Vechta
city: Wendlingen
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Wiesbaden
country: Germany
facility: Dr. Horst-Schmidt-Kliniken
city: Wuppertal
country: Germany
facility: Helios Kliniken Wuppertal University Hospital
city: Petah-Tikva
country: Israel
facility: Rabin Medical Center - Beilinson Campus
city: Piacenza
country: Italy
facility: Ospedale Civile - Piacenza
city: Reggio Emilia
country: Italy
facility: Arcispedale S. Maria Nuova
city: Roma
country: Italy
facility: Cellulari ed Ematologia Sapienza
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:
citation: 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.