Rituximab and Combination Chemotherapy in Treating Patients With Non-Hodgkin's Lymphoma

• ClinicalTrials.gov Identifier: NCT00278421
• Recruitment Status: Completed
• First Posted: January 18, 2006
• Last Update Posted: March 11, 2021
• Sponsor: German High-Grade Non-Hodgkin's Lymphoma Study Group
• Information provided by (Responsible Party): German High-Grade Non-Hodgkin's Lymphoma Study Group

Tracking Information

• First Submitted Date: January 16, 2006
• First Posted Date: January 18, 2006
• Last Update Posted Date: March 11, 2021
• Study Start Date: November 2005
• Actual Primary Completion Date: August 2018 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: November 25, 2015): 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 [ Time Frame: through study completion ]
• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: November 25, 2015)

• Complete response (CR) rate duration until first relapse [ Time Frame: through study completion ]
• Progression rate during treatment [ Time Frame: through study completion ]
• Survival [ Time Frame: through study completion ]
• Tumor control measured from day 1 of course 1 of CHOP therapy (non-tumor related events are censored) [ Time Frame: through study completion ]
• Disease-free survival measured from day 1 of course 1 of CHOP therapy [ Time Frame: through study completion ]
• Safety (adverse events, serious adverse events) assessed at 3 months after treatment [ Time Frame: through study completion ]

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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]

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Lymphoma

Intervention

• Biological: rituximab
• Drug: cyclophosphamide
• Drug: doxorubicin hydrochloride
• Drug: prednisone
• Drug: vincristine sulfate

Study Arms

• Active Comparator: Interventional: 6 R-CHOP-21
  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.
  Interventions:

  • Biological: rituximab
  • Drug: cyclophosphamide
  • Drug: doxorubicin hydrochloride
  • Drug: prednisone
  • Drug: vincristine sulfate
• Active Comparator: Interventional: 4 R-CHOP-21 + 2 x R
  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.
  Interventions:

  • Biological: rituximab
  • Drug: cyclophosphamide
  • Drug: doxorubicin hydrochloride
  • Drug: prednisone
  • Drug: vincristine sulfate

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 24, 2015): 592
• Original Enrollment: Not Provided
• Actual Study Completion Date: August 2018
• Actual Primary Completion Date: August 2018 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany, Israel, Italy

Administrative Information

• NCT Number: NCT00278421
• Other Study ID Numbers: CDR0000459685; DSHNHL-2004-2; EU-205110; EUDRACT-2005-00521738; DSHNHL-FLYER-6664
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: German High-Grade Non-Hodgkin's Lymphoma Study Group
• Original Responsible Party: Not Provided
• Current Study Sponsor: German High-Grade Non-Hodgkin's Lymphoma Study Group
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Michael G.M. Pfreundschuh, MD †; Universitaetsklinikum des Saarlandes
• Study Director: Viola Poeschel, MD; Study Office Homburg

• PRS Account: German High-Grade Non-Hodgkin's Lymphoma Study Group
• Verification Date: March 2021