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

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]

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00278408

Enrollment

700

Registered

2006-01-18

Start date

2006-01-02

Completion date

2018-02-28

Last updated

2025-08-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

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

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.

Interventions

BIOLOGICALfilgrastim

BIOLOGICALrituximab

DRUGcyclophosphamide

DRUGdoxorubicin hydrochloride

DRUGprednisone

DRUGvincristine sulfate

RADIATIONradiation therapy

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 60 Years

Healthy volunteers

Inclusion 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

Design outcomes

Primary

Measure	Time frame	Description
3 Years Event-free Survival	Each patient will be observed for 3 years starting from completion of treatment.	Event-free survival was the primary endpoint, which was defined as the time from randomization until one of the following events had occurred: progression during therapy, partial response, no change, unknown status at the end of study therapy, relapse after complete response or unconfirmed complete response, death from any cause; or additional treatment, whichever came first.

Secondary

Measure	Time frame	Description
3 Years Overall Survival	Each patient will be observed for 3 years starting from completion of treatment.	Overall survival was defined as the time from randomization to death of any cause.
Rate of Complete Remissions and Progressive Disease	Each patient will be observed for 3 years starting from completion of treatment.	—
Number of Patients With a Relapse After a CR/CRu	Each patient will be observed for 3 years starting from completion of treatment.	Relapse is defined as, recurrence of disease symptoms, development of new lymphatic or extralymphatic lesions or a marked increase in lymphoma manifestation size by more thyn 25% after at least 2 months CR or CRu from the time point of the final restaging examination
Safety (Adverse Events, Serious Adverse Events, Rate of Secondary Neoplasia, Selected Laboratory Parameters, Including Leucocytes, Thrombocytes, and Haemoglobin)	Each patient will be observed for 3 years starting from completion of treatment.	—
3 Years Progression-free Survival	Each patient will be observed for 3 years starting from completion of treatment.	Progression of disease is defined as: recurrence of disease symptoms, development of new lymphatic or extralymphatic lesions or marked increase in lymphoma manifestation size by more than 25% in comparison with baseline.
Health-economic Aspects - Number of Patients Who Received Antibiotic Intervention and/or Red Blood Cell and Platelet Transfusion	Each patient will be observed for 3 years starting from completion of treatment.	—
Adherence to Protocol - Total Duration of Chemotherapy in Days (Median)	Each patient will be observed for 3 years starting from completion of treatment.	—
Adherence to Protocol - Absolute Dose Cyclophosphamide, Doxorubicin and Rituximab in mg/m² (Median)	Each patient will be observed for 3 years starting from completion of treatment.	—
Adherence to Protocol - Absolute Dose Vincristine and Prednisone in mg (Median)	Each patient will be observed for 3 years starting from completion of treatment.	—

Countries

Denmark, Germany, Israel, Italy

Participant flow

Recruitment details

From 02nd January 2006, to 16th November 2015, 700 patients were enrolled at 148 sites including hospitals and private practitioners.

Participants by arm

Arm	Count
Interventional: 6 R-CHOP-21 for Patients With Radiotherapy Indication 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. rituximab cyclophosphamide doxorubicin hydrochloride prednisone vincristine sulfate	81
Interventional: 6 R-CHOP-14 for Patients With Radiotherapy Indication Arm II (R-CHOP-14): 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 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. rituximab cyclophosphamide doxorubicin hydrochloride prednisone vincristine sulfate filgrastim	81
Interventional: 6 R-CHOP-21 + Radiotherapy for Patients With Radiotherapy Indication Arm III (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 followed by consolidating radiotherapy with 39.6 Gy. rituximab cyclophosphamide doxorubicin hydrochloride prednisone vincristine sulfate	155
Interventional: 6 R-CHOP-14 + Radiotherapy for Patients With Radiotherapy Indication Arm IV (R-CHOP-14): 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 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity followed by consolidating radiotherapy with 39.6 Gy. rituximab cyclophosphamide doxorubicin hydrochloride prednisone vincristine sulfate filgrastim	150
Interventional: 6 R-CHOP-21 for Patients Without Radiotherapy Indication Arm V (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. rituximab cyclophosphamide doxorubicin hydrochloride prednisone vincristine sulfate	114
Interventional: 6 R-CHOP-14 for Patients Without Radiotherapy Indication Arm VI (R-CHOP-14): 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 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. rituximab cyclophosphamide doxorubicin hydrochloride prednisone vincristine sulfate filgrastim	114
Total	695

Baseline characteristics

Characteristic	Interventional: 6 R-CHOP-14 for Patients With Radiotherapy Indication	Interventional: 6 R-CHOP-21 + Radiotherapy for Patients With Radiotherapy Indication	Interventional: 6 R-CHOP-14 + Radiotherapy for Patients With Radiotherapy Indication	Interventional: 6 R-CHOP-21 for Patients Without Radiotherapy Indication	Interventional: 6 R-CHOP-14 for Patients Without Radiotherapy Indication	Interventional: 6 R-CHOP-21 for Patients With Radiotherapy Indication	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	81 Participants	155 Participants	150 Participants	114 Participants	114 Participants	81 Participants	695 Participants
Age, Continuous	45 years	46 years	44 years	50 years	49 years	43 years	47 years
Race and Ethnicity Not Collected	—	—	—	—	—	—	0 Participants
Sex: Female, Male Female	38 Participants	69 Participants	67 Participants	43 Participants	43 Participants	32 Participants	292 Participants
Sex: Female, Male Male	43 Participants	86 Participants	83 Participants	71 Participants	71 Participants	49 Participants	403 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	7 / 81	7 / 81	15 / 155	11 / 150	10 / 114	11 / 114
other Total, other adverse events	49 / 81	58 / 81	98 / 155	82 / 150	41 / 114	65 / 114
serious Total, serious adverse events	17 / 81	17 / 81	43 / 155	41 / 150	30 / 114	27 / 114

Outcome results

Primary

3 Years Event-free Survival

Event-free survival was the primary endpoint, which was defined as the time from randomization until one of the following events had occurred: progression during therapy, partial response, no change, unknown status at the end of study therapy, relapse after complete response or unconfirmed complete response, death from any cause; or additional treatment, whichever came first.