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

Sponsor

German High-Grade Non-Hodgkin's Lymphoma Study Group (Other)

Overall Status

Completed

CT.gov ID

NCT00278408

Collaborator

(none)

700

Enrollment

Locations

Arms

147

Duration (Months)

8.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: filgrastim Biological: rituximab Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: prednisone Drug: vincristine sulfate Radiation: radiation therapy	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

700 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Nov 1, 2005

Actual Primary Completion Date :

Feb 1, 2018

Actual Study Completion Date :

Feb 1, 2018

Arms and Interventions

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.	Biological: rituximab Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: prednisone Drug: vincristine sulfate
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.	Biological: rituximab Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: prednisone Drug: vincristine sulfate Radiation: radiation therapy
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.	Biological: filgrastim Biological: rituximab Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: prednisone Drug: vincristine sulfate
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.	Biological: filgrastim Biological: rituximab Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: prednisone Drug: vincristine sulfate Radiation: radiation therapy

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Klinikum St. Marien	Amberg	Germany	D-92224
2	Klinikum Augsburg	Augsburg	Germany	DOH-86156
3	Kreiskrankenhaus Aurich	Aurich	Germany	26603
4	Klinikum Bayreuth	Bayreuth	Germany	D-95445
5	Charite - Campus Charite Mitte	Berlin	Germany	D-10117
6	Charite University Hospital - Campus Virchow Klinikum	Berlin	Germany	D-13353
7	Franziskus Hospital	Bielefeld	Germany	D-33615
8	Augusta-Kranken-Anstalt gGmbH	Bochum	Germany	D-44791
9	Staedtisches Klinikum Braunschweig	Braunschweig	Germany	D-38114
10	Klinikum Bremen-Mitte	Bremen	Germany	D-28205
11	Onkologische Schwerpunktpraxis Celle	Celle	Germany	D-29221
12	Hospital Kuchwald Chemnitz	Chemnitz	Germany	09113
13	Praxis Fuer Haematologie Internistische Onkologie	Cologne	Germany	D-50677
14	Medizinische Universitaetsklinik I at the University of Cologne	Cologne	Germany	D-50924
15	Carl - Thiem - Klinkum Cottbus	Cottbus	Germany	D-03048
16	Klinikum Dortmund	Dortmund	Germany	D-44137
17	Virngrund-Klinik Ellwangen	Ellwangen	Germany	73479
18	Hans - Susemihl - Krankenhaus	Emden	Germany	26721
19	St. Antonius Hospital	Eschweiler	Germany	DOH-52249
20	Universitaetsklinikum Essen	Essen	Germany	D-45122
21	Klinikum Frankfurt (Oder) GmbH	Frankfurt (Oder)	Germany	D-15236
22	Krankenhaus Nordwest	Frankfurt	Germany	D-60488
23	Klinikum der J.W. Goethe Universitaet	Frankfurt	Germany	D-60590
24	Universitaetsklinikum Freiburg	Freiburg	Germany	D-79106
25	Klinikum Garmisch - Partenkirchen GmbH	Garmisch-Partenkirchen	Germany	D-82467
26	Saint Josef Hospital	Gelsenkirchen	Germany	D-45899
27	Wilhelm-Anton-Hospital gGmbH, Goch	Goch	Germany	D-47574
28	Universitaetsklinikum Goettingen	Goettingen	Germany	D-37075
29	Klinik Fuer Innere Medizin, Hematology/Oncology, Ernst Moritz Armdt Universitaet	Greifswald	Germany	D-17475
30	St. Marien Hospital - Katholisches Krankenhaus Hagen gGmbH	Hagen	Germany	D-58095
31	Krankenhaus Martha-Maria Halle-Doelau gGmbH	Halle	Germany	D-06120
32	Asklepios Klinik St. Georg	Hamburg	Germany	D-20099
33	University Medical Center Hamburg - Eppendorf	Hamburg	Germany	D-20246
34	Klinikum Stadt Hanau	Hanau	Germany	63450
35	Krankenhaus Siloah - Medizinische Klinik II	Hannover	Germany	D-30449
36	Medizinische Hochschule Hannover	Hannover	Germany	D-30625
37	Medizinische Universitaetsklinik und Poliklinik	Heidelberg	Germany	69115
38	Privatklinik Dr. R. Schindlbeck GmbH & Co. KG	Herrsching	Germany	D-82211
39	St. Bernward Krankenhaus	Hildesheim	Germany	D-31134
40	Haematologie und Internistische Onkologie Praxis	Homberg	Germany	D-34576
41	Universitaetsklinikum des Saarlandes	Homburg	Germany	D-66424
42	Clinic for Bone Marrow Transplantation and Hematology and Oncology	Idar-Oberstein	Germany	D-55743
43	Staedtisches Klinikum Karlsruhe gGmbH	Karlsruhe	Germany	76133
44	Internistische Gemeinschaftspraxis - Kassel	Kassel	Germany	D-34117
45	Klinikum Kempten Oberallgaeu	Kempten	Germany	D-87439
46	Staedtisches Krankenhaus Kiel	Kiel	Germany	23116
47	University Hospital Schleswig-Holstein - Kiel Campus	Kiel	Germany	D-24116
48	Internistische Praxis - Landshut	Landshut	Germany	84028
49	Klinikum der Stadt Ludwigshafen am Rhein	Ludwigshafen am Rhein	Germany	D-67063
50	Kreiskrankenhaus Luedenscheid	Luedenscheid	Germany	58515
51	Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg	Magdeburg	Germany	D-39120
52	III Medizinische Klinik Mannheim	Mannheim	Germany	D-68305
53	Klinikum Minden	Minden	Germany	D-32423
54	Krankenhaus Maria Hilf GmbH	Moenchengladbach	Germany	D-41063
55	Haematologisch - Onkologische Gemeinschaftspraxis - Muenster	Muenster	Germany	D-48149
56	Medizinische Klinik und Poliklinik A - Universitaetsklinikum Muenster	Muenster	Germany	D-48149
57	Klinikum der Universitaet Muenchen - Grosshadern Campus	Munich	Germany	D-81377
58	Klinikum Rechts Der Isar - Technische Universitaet Muenchen	Munich	Germany	D-81675
59	Onkologische Schwerwpunktpraxis Dr. Ladda	Neumarkt	Germany	D-92318
60	Klinikum Oldenburg	Oldenburg	Germany	D-26133
61	Bruederkrankenhaus St. Josef Paderborn	Paderborn	Germany	D-33098
62	Klinikum der Universitaet Regensburg	Regensburg	Germany	D-93053
63	Klinikum Suedstadt Rostock	Rostock	Germany	D-18059
64	Leopoldina - Krankenhaus	Schwienfurt	Germany	D-97422
65	St. Marien - Krankenhaus Siegen GMBH	Siegen	Germany	D-57072
66	Onkologische Schwerpunktpraxis - Straubing	Straubing	Germany	94315
67	Klinik fuer Onkologie - Katharinenhospital Stuttgart	Stuttgart	Germany	D-70174
68	Diakonie Klinikum Stuttgart	Stuttgart	Germany	D-70176
69	Krankenanstalt Mutterhaus der Borromaerinnen	Trier	Germany	D-54219
70	Krankenhaus Der Barmherzigen Brueder	Trier	Germany	D-54292
71	Praxis Fuer Internistische Haematologie / Onkologie	Troisdorf	Germany	53840
72	Praxis fuer Haematologie und Onkologie	Twistringen	Germany	D-27239
73	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm	Ulm	Germany	D-89081
74	St. Marienhospital - Vechta	Vechta	Germany	D-49377
75	Regional Hospital Waldbrol	Waldbrol	Germany	D-51545
76	Dr. Horst-Schmidt-Kliniken	Wiesbaden	Germany	D-65199
77	Kliniken St. Antonius	Wuppertal 2	Germany	D-42283
78	Heinrich-Braun-Krankenhaus Zwickau	Zwickau	Germany	08060
79	Rabin Medical Center - Beilinson Campus	Petah-Tikva	Israel	49100