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

Lymphoma Clinical Trial

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]

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00278408
• Other study ID #: CDR0000459796
• Secondary ID: DSHNHL-2004-3EUD
• Status: Completed
• Phase: Phase 3
• Start date: November 2005
• Est. completion date: February 2018

Study information

• Verified date: November 2015
• Source: German High-Grade Non-Hodgkin's Lymphoma Study Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 700
• Est. completion date: February 2018
• Est. primary completion date: February 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Lymphoma

Intervention

Biological:
• filgrastim

• rituximab

Drug:
• cyclophosphamide

• doxorubicin hydrochloride

• prednisone

• vincristine sulfate

Radiation:
• radiation therapy

Locations

Country	Name	City	State
Germany	Klinikum St. Marien	Amberg
Germany	Klinikum Augsburg	Augsburg
Germany	Kreiskrankenhaus Aurich	Aurich
Germany	Klinikum Bayreuth	Bayreuth
Germany	Charite - Campus Charite Mitte	Berlin
Germany	Charite University Hospital - Campus Virchow Klinikum	Berlin
Germany	Franziskus Hospital	Bielefeld
Germany	Augusta-Kranken-Anstalt gGmbH	Bochum
Germany	Staedtisches Klinikum Braunschweig	Braunschweig
Germany	Klinikum Bremen-Mitte	Bremen
Germany	Onkologische Schwerpunktpraxis Celle	Celle
Germany	Hospital Kuchwald Chemnitz	Chemnitz
Germany	Medizinische Universitaetsklinik I at the University of Cologne	Cologne
Germany	Praxis Fuer Haematologie Internistische Onkologie	Cologne
Germany	Carl - Thiem - Klinkum Cottbus	Cottbus
Germany	Klinikum Dortmund	Dortmund
Germany	Virngrund-Klinik Ellwangen	Ellwangen
Germany	Hans - Susemihl - Krankenhaus	Emden
Germany	St. Antonius Hospital	Eschweiler
Germany	Universitaetsklinikum Essen	Essen
Germany	Klinikum der J.W. Goethe Universitaet	Frankfurt
Germany	Krankenhaus Nordwest	Frankfurt
Germany	Klinikum Frankfurt (Oder) GmbH	Frankfurt (Oder)
Germany	Universitaetsklinikum Freiburg	Freiburg
Germany	Klinikum Garmisch - Partenkirchen GmbH	Garmisch-Partenkirchen
Germany	Saint Josef Hospital	Gelsenkirchen
Germany	Wilhelm-Anton-Hospital gGmbH, Goch	Goch
Germany	Universitaetsklinikum Goettingen	Goettingen
Germany	Klinik Fuer Innere Medizin, Hematology/Oncology, Ernst Moritz Armdt Universitaet	Greifswald
Germany	St. Marien Hospital - Katholisches Krankenhaus Hagen gGmbH	Hagen
Germany	Krankenhaus Martha-Maria Halle-Doelau gGmbH	Halle
Germany	Asklepios Klinik St. Georg	Hamburg
Germany	University Medical Center Hamburg - Eppendorf	Hamburg
Germany	Klinikum Stadt Hanau	Hanau
Germany	Krankenhaus Siloah - Medizinische Klinik II	Hannover
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Medizinische Universitaetsklinik und Poliklinik	Heidelberg
Germany	Privatklinik Dr. R. Schindlbeck GmbH & Co. KG	Herrsching
Germany	St. Bernward Krankenhaus	Hildesheim
Germany	Haematologie und Internistische Onkologie Praxis	Homberg
Germany	Universitaetsklinikum des Saarlandes	Homburg
Germany	Clinic for Bone Marrow Transplantation and Hematology and Oncology	Idar-Oberstein
Germany	Staedtisches Klinikum Karlsruhe gGmbH	Karlsruhe
Germany	Internistische Gemeinschaftspraxis - Kassel	Kassel
Germany	Klinikum Kempten Oberallgaeu	Kempten
Germany	Staedtisches Krankenhaus Kiel	Kiel
Germany	University Hospital Schleswig-Holstein - Kiel Campus	Kiel
Germany	Internistische Praxis - Landshut	Landshut
Germany	Klinikum der Stadt Ludwigshafen am Rhein	Ludwigshafen am Rhein
Germany	Kreiskrankenhaus Luedenscheid	Luedenscheid
Germany	Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg	Magdeburg
Germany	III Medizinische Klinik Mannheim	Mannheim
Germany	Klinikum Minden	Minden
Germany	Krankenhaus Maria Hilf GmbH	Moenchengladbach
Germany	Haematologisch - Onkologische Gemeinschaftspraxis - Muenster	Muenster
Germany	Medizinische Klinik und Poliklinik A - Universitaetsklinikum Muenster	Muenster
Germany	Klinikum der Universitaet Muenchen - Grosshadern Campus	Munich
Germany	Klinikum Rechts Der Isar - Technische Universitaet Muenchen	Munich
Germany	Onkologische Schwerwpunktpraxis Dr. Ladda	Neumarkt
Germany	Klinikum Oldenburg	Oldenburg
Germany	Bruederkrankenhaus St. Josef Paderborn	Paderborn
Germany	Klinikum der Universitaet Regensburg	Regensburg
Germany	Klinikum Suedstadt Rostock	Rostock
Germany	Leopoldina - Krankenhaus	Schwienfurt
Germany	St. Marien - Krankenhaus Siegen GMBH	Siegen
Germany	Onkologische Schwerpunktpraxis - Straubing	Straubing
Germany	Diakonie Klinikum Stuttgart	Stuttgart
Germany	Klinik fuer Onkologie - Katharinenhospital Stuttgart	Stuttgart
Germany	Krankenanstalt Mutterhaus der Borromaerinnen	Trier
Germany	Krankenhaus Der Barmherzigen Brueder	Trier
Germany	Praxis Fuer Internistische Haematologie / Onkologie	Troisdorf
Germany	Praxis fuer Haematologie und Onkologie	Twistringen
Germany	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm	Ulm
Germany	St. Marienhospital - Vechta	Vechta
Germany	Regional Hospital Waldbrol	Waldbrol
Germany	Dr. Horst-Schmidt-Kliniken	Wiesbaden
Germany	Kliniken St. Antonius	Wuppertal 2
Germany	Heinrich-Braun-Krankenhaus Zwickau	Zwickau
Israel	Rabin Medical Center - Beilinson Campus	Petah-Tikva

Sponsors (1)

Lead Sponsor	Collaborator
German High-Grade Non-Hodgkin's Lymphoma Study Group

Countries where clinical trial is conducted

Germany,  Israel, 

Outcome

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