Combination Chemotherapy With or Without Rituximab in Non-Hodgkin's Lymphoma (IDEC-C2B8)

Randomized Intergroup Trial of First Line Treatment for Patients With Diffuse Large B-Cell Non-Hodgkin's Lymphoma With a CHOP-Like Chemotherapy Regimen With or Without the Anti-CD20 Antibody Rituximab

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy is more effective with or without rituximab in treating patients with non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying four different combination chemotherapy regimens and rituximab to see how well they work compared to four different combination chemotherapy regimens alone in treating patients with non-Hodgkin's lymphoma.

Study Overview

• Status: Completed
• Conditions: Lymphoma
• Intervention / Treatment: Drug: CHOP regimen; Biological: rituximab

Detailed Description

OBJECTIVES:

• Compare the time to treatment failure in patients with CD20-positive diffuse large B-cell non-Hodgkin's lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy with vs without rituximab.
• Compare the tumor control, progression rate, and complete remission rate in patients treated with these regimens.
• Compare the disease-free and overall survival rate of patients treated with these regimens.
• Compare the toxicity of these regimens in these patients.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to participating center, bulky disease (no vs yes), International Prognostic Index score (0 vs 1), and chemotherapy (CHOP vs CHOEP vs PMitCEBO vs MACOP-B). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive 1 of the following chemotherapy regimens according to participating country:

  • CHOP: Patients receive cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1 and oral prednisone or prednisolone on days 1-5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  • CHOEP-21: Patients receive cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1; etoposide IV on days 1-3; and oral prednisone on days 1-5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  • PMitCEBO: Patients receive mitoxantrone IV, cyclophosphamide IV, and etoposide IV on day 1; vincristine IV and bleomycin IV on day 8; and oral prednisolone daily during weeks 1-4 and every other day during week 5. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  • MACOP-B: Patients receive cyclophosphamide IV and doxorubicin IV on days 1, 15, 29, 43, 57, and 71; methotrexate IV and vincristine IV on days 8, 36, and 64; bleomycin IV and vincristine IV on days 22, 50, and 78; and oral or intramuscular prednisone on days 1-84. Treatment continues in the absence of disease progression or unacceptable toxicity.

• Arm II: Patients receive arm I regimens (according to participating country) and rituximab as follows:

  • CHOP and rituximab: Patients receive CHOP as in arm I and rituximab IV on day 1.
  • CHOEP-21 and rituximab: Patients receive CHOEP-21 as in arm I and rituximab IV on day 1.
  • PMitCEBO and rituximab: Patients receive PMitCEBO as in arm I and rituximab IV on day 1 during courses 1 and 4; on day 8 during courses 2 and 5; and on day 1 at 1 and 4 weeks after completion of the last course of PMitCEBO chemotherapy.
  • MACOP-B and rituximab: Patients receive MACOP-B as in arm I and rituximab IV on days 1, 22, 43, 64, 85, and 106.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 820 patients will be accrued for this study within approximately 2 years.

• Study Type: Interventional
• Enrollment (Actual): 824
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1C 6Z8
      • The Moncton Hospital
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, AIB 3V6
      • Dr. H. Bliss Murphy Cancer Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • QEII Health Sciences Center
  • Ontario
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario at Kingston
    • Kitchener, Ontario, Canada, N2G 1G3
      • Grand River Regional Cancer Centre
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Health Research Institute - General Division
    • St. Catharines, Ontario, Canada, L2R 7C6
      • Niagara Health System
    • Toronto, Ontario, Canada, M4N 3M5
      • Odette Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Univ. Health Network-Princess Margaret Hospital
    • Toronto, Ontario, Canada, M9C 1A5
      • Trillium Health Centre - West Toronto
    • Toronto, Ontario, Canada, M5G 2C4
      • Univ. Health Network-The Toronto General Hospital
  • Prince Edward Island
    • Charlottetown, Prince Edward Island, Canada, C1A 8T5
      • PEI Cancer Treatment Centre,Queen Elizabeth Hospital
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
      • Hopital Charles LeMoyne
    • Montreal, Quebec, Canada, H4J 1C5
      • Hopital Du Sacre-Coeur De Montreal
    • Montreal, Quebec, Canada, H2L 4M1
      • CHUM - Hopital Notre-Dame
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill University - Dept. Oncology
    • Montreal, Quebec, Canada, H1T 2M4
      • Hopital Maisonneuve-Rosemont
    • Quebec City, Quebec, Canada, G1S 4L8
      • CHA-Hopital Du St-Sacrement
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre hospitalier universitaire de Sherbrooke
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed diffuse large B-cell non-Hodgkin's lymphoma according to REAL classification

  • Diagnosed within the past 6 weeks
  • CD20+ disease
  • Ann Arbor stage II, III, or IV disease or stage I bulky disease

• International Prognostic Index (IPI) score of 0 or 1

  • Score 0 defined by all of the following:

    • Stage I or II disease
    • ECOG performance status of 0 or 1
    • Lactic dehydrogenase (LDH) no greater than upper limit of normal (ULN)

  • Score 1 defined by 1 of the following:

    • Stage I or II disease; ECOG performance status of 0 or 1; and LDH greater than ULN
    • Stage I or II disease; ECOG performance status 2 or 3; and LDH no greater than ULN
    • Stage III or IV disease; ECOG performance status 0 or 1; and LDH no greater than ULN
• Previously untreated disease
• Mediastinal B-cell lymphoma allowed
• No secondary lymphoma after prior chemotherapy or radiotherapy for other malignancies
• No transformed lymphoma
• No primary CNS lymphoma
• No primary gastrointestinal (MALT) lymphoma
• No post-transplant lymphoproliferative disorder

PATIENT CHARACTERISTICS:

Age

• 18 to 60

Performance status

• See Disease Characteristics
• ECOG 0-3

Life expectancy

• At least 3 months

Hematopoietic

• Not specified

Hepatic

• Bilirubin no greater than 2.0 mg/dL*
• Transaminases no greater than 3 times normal*
• No active chronic hepatitis B or C infection NOTE: *Unless related to lymphoma

Renal

• Creatinine no greater than 2 times normal* NOTE: *Unless related to lymphoma

Cardiovascular

• No myocardial infarction within the past 6 months
• No uncompensated heart failure
• No dilatative cardiomyopathy
• No coronary heart disease with ST segment depression on ECG
• No severe uncompensated hypertension

Pulmonary

• No chronic lung disease with hypoxemia

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No known allergic reactions against foreign proteins
• No other prior malignancy except basal cell skin cancer or carcinoma in situ of the cervix
• No concurrent disease that would preclude study treatment
• No active infections requiring systemic antibiotics or antiviral medications
• No severe uncompensated diabetes mellitus
• No clinical signs of cerebral dysfunction
• No severe psychiatric disease

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior murine antibodies

Chemotherapy

• No other concurrent anticancer chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No concurrent response-adapted (slow response or unconfirmed complete response) radiotherapy

Surgery

• Not specified

Other

• No prior lymphoma-specific treatment
• More than 12 weeks since prior participation in another clinical trial
• No prior participation in this study
• No other concurrent study medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Arm A: CHOP-21; Cyclophosphamide 750 mg/m² i.v. day 1 Doxorubicin 50 mg/m² i.v. day 1 Vincristine 2 mg (abs.) i.v. day 1 Prednisone 100 mg/d p.o. days 1 to 5 Recycle: day 22 Total number of cycles 6	Drug: CHOP regimen; Cyclophosphamide 750 mg/m² i.v. day 1 Doxorubicin 50 mg/m² i.v. day 1 Vincristine 2 mg (abs.) i.v. day 1 Prednisone 100 mg/d p.o. days 1 to 5 Recycle day 22 Total number of cycles: 6
ACTIVE_COMPARATOR: Arm B: CHOP-21 + Rituximab; Rituximab 375 mg/m² i.v. day 1* Cyclophosphamide 750 mg/m² i.v. day 1 Doxorubicin 50 mg/m² i.v. day 1 Vincristine 2 mg (abs.) i.v. day 1 Prednisone 100 mg/d p.o. days 1 to 5 Recycle day 22 Total number of cycles: 6	Drug: CHOP regimen; Cyclophosphamide 750 mg/m² i.v. day 1 Doxorubicin 50 mg/m² i.v. day 1 Vincristine 2 mg (abs.) i.v. day 1 Prednisone 100 mg/d p.o. days 1 to 5 Recycle day 22 Total number of cycles: 6; Biological: rituximab; Rituximab 375 mg/m² i.v. day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to treatment failure (TTF) at 3 years	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival at 3 years	3 years
Complete remission rate after completion of treatment	3 years
Tumor control measured by TTF with non-tumor events censored at 3 years	3 years
Disease-free survival (DFS) measured by TTF after an event during and directly after treatment at 3 years	3 years
Progression rate determined by dividing the number of patients with disease progression by number of patients with evaluable outcome at 3 years	3 years
Time to progression measured at 3 years	3 years
Toxicity assessed by NCI CTC v2.0 after completion of treatment	3 years

Collaborators and Investigators

• Sponsor: NCIC Clinical Trials Group
• Investigators: Study Chair: Kevin Imrie, MD, Toronto Sunnybrook Regional Cancer Centre

Publications and helpful links

General Publications

• Pfreundschuh M, Ho AD, Cavallin-Stahl E, Wolf M, Pettengell R, Vasova I, Belch A, Walewski J, Zinzani PL, Mingrone W, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Corrado C, Scheliga A, Loeffler M, Kuhnt E; MabThera International Trial (MInT) Group. Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study. Lancet Oncol. 2008 May;9(5):435-44. doi: 10.1016/S1470-2045(08)70078-0. Epub 2008 Apr 8.
• Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, Lopez-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M; MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006 May;7(5):379-91. doi: 10.1016/S1470-2045(06)70664-7.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 8, 2001
• Primary Completion (ACTUAL): December 1, 2010
• Study Completion (ACTUAL): January 16, 2014

Study Registration Dates

• First Submitted: July 8, 2003
• First Submitted That Met QC Criteria: July 8, 2003
• First Posted (ESTIMATE): July 9, 2003

Study Record Updates

• Last Update Posted (ACTUAL): April 1, 2020
• Last Update Submitted That Met QC Criteria: March 30, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: stage III adult diffuse large cell lymphoma; stage IV adult diffuse large cell lymphoma; noncontiguous stage II adult diffuse large cell lymphoma; contiguous stage II adult diffuse large cell lymphoma; stage I adult diffuse large cell lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: LY9; CAN-NCIC-LY9; ROCHE-CAN-NCIC-LY9 (OTHER: Roche); MINT-M39045; CDR0000309053 (OTHER: PDQ)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No