Combination Chemotherapy With or Without Rituximab in Treating Older Patients With Non-Hodgkin's Lymphoma

• ClinicalTrials.gov Identifier: NCT00052936
• Recruitment Status: Completed
• First Posted: January 27, 2003
• Last Update Posted: May 18, 2021
• Sponsor: German High-Grade Non-Hodgkin's Lymphoma Study Group
• Information provided by (Responsible Party): Universität des Saarlandes ( German High-Grade Non-Hodgkin's Lymphoma Study Group )

Tracking Information

• First Submitted Date: January 24, 2003
• First Posted Date: January 27, 2003
• Last Update Posted Date: May 18, 2021
• Study Start Date: January 2001
• Actual Primary Completion Date: August 5, 2010 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: May 14, 2021): Time to treatment failure at 3 years within the study and then periodically after study completion [ Time Frame: 3 years within the study and then periodically after study completion ]
• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: May 14, 2021)

• Complete response rate at 3 years within the study and then periodically after study completion [ Time Frame: 3 years within the study and then periodically after ]
• Progression rate [ Time Frame: 3 years within the study and then periodically after ]
• Survival [ Time Frame: 3 years within the study and then periodically after ]
• Tumor control [ Time Frame: 3 years within the study and then periodically after ]
• Disease-free survival [ Time Frame: 3 years within the study and then periodically after ]

• 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: Combination Chemotherapy With or Without Rituximab in Treating Older Patients With Non-Hodgkin's Lymphoma
• Official Title: Randomised Study Comparing 6 And 8 Cycles Of Chemotherapy With CHOP ( Cyclophosphamide, Doxorubicin, Vincristine And Prednisone) At 14-Day Intervals (CHOP-14), Both With Or Without The Monoclonal Anti-CD20 Antibody Rituximab In Patients Aged 61 To 80 Years With Aggressive Non-Hodgkin's Lymphoma

Brief Summary

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 tumor cells and either kill them or deliver tumor-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 aggressive non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying how well giving cyclophosphamide, doxorubicin, vincristine, and prednisone together with or without rituximab works in treating older patients who have aggressive non-Hodgkin's lymphoma. (This trial is no longer randomized as of 6/2005).

Detailed Description

OBJECTIVES:

Primary

• Compare the efficacy of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with vs without rituximab in elderly patients with aggressive non-Hodgkin's lymphoma.
• Compare the efficacy of 6 vs 8 courses of CHOP chemotherapy in patients treated with these regimens.
• Compare the rate of complete remission, rate of primary progression, tumor control, disease-free survival, overall survival, and relapse after radiotherapy in patients treated with these regimens.
• Compare the safety and side effects of these regimens in these patients.

Secondary

• Compare short-term and long-term side effects of these regimens in these patients.
• Compare quality of life of patients treated with these regimens.
• Compare the cost of these regimens in these patients.
• Determine relapse in patients treated with these regimens who received involved-field radiotherapy.

OUTLINE: This is a randomized (randomized part of study completed as of 6/2005), open-label, multicenter study. Patients are stratified according to participating center, value for serum lactic dehydrogenase (no greater than upper limit of normal [ULN] vs greater than ULN), bulky disease present (no vs yes), stage (I or II vs III or IV), general ECOG status of patient (0 or 1 vs 2), and age (61 to 70 vs 71-80). Patients are randomized to 1 of 4 treatment arms. Patients with CD20-negative lymphoma are randomized to arms I or II only.

• Prephase treatment:Patients receive vincristine IV on day -6 and prednisone on day -6 to day 0 before initiating CHOP chemotherapy.
• Arm I (closed to accrual as of 7/25/2005): Patients receive standard CHOP chemotherapy comprising cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1 and oral prednisone on days 1-5. Patients also receive filgrastim (G-CSF) subcutaneously once daily on days 6-12 of each CHOP course. Treatment repeats every 2 weeks for 6 courses.
• Arm II (closed to accrual as of 7/25/2005): Patients receive standard CHOP chemotherapy and G-CSF as in arm I for a total of 8 courses.
• Arm III: Patients receive standard CHOP chemotherapy and G-CSF as in arm I. Patients also receive rituximab IV before CHOP every 2 weeks for a total of 8 courses.
• Arm IV (closed to accrual as of 7/25/2005): Patients receive standard CHOP chemotherapy and G-CSF as in arm II. Patients also receive rituximab IV before CHOP every 2 weeks for a total of 8 courses.

In all arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Beginning 3-6 weeks after completion of the last chemotherapy course, after complete recovery of bone marrow, and after complete remision of mucositis, patients with sites of initial bulky disease or extranodal involvement undergo radiotherapy 5 times a week for 4 weeks.

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

PROJECTED ACCRUAL: Approximately 1580 patients will be accrued for this study within 5 years.

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

Intervention

• Biological: filgrastim
• Biological: rituximab
• Drug: CHOP regimen
• Drug: cyclophosphamide
• Drug: doxorubicin hydrochloride
• Drug: prednisone
• Drug: vincristine sulfate
• Radiation: radiation therapy
  36Gy on BULK and extranodal involvement

Study Arms

• Experimental: S6
  6x CHOP-14
  Interventions:

  • Biological: filgrastim
  • Drug: CHOP regimen
  • Drug: cyclophosphamide
  • Drug: doxorubicin hydrochloride
  • Drug: prednisone
  • Drug: vincristine sulfate
  • Radiation: radiation therapy
• Experimental: R6
  6x CHOP-14 + 8x Rituximab
  Interventions:

  • Biological: filgrastim
  • Biological: rituximab
  • Drug: CHOP regimen
  • Drug: cyclophosphamide
  • Drug: doxorubicin hydrochloride
  • Drug: prednisone
  • Drug: vincristine sulfate
  • Radiation: radiation therapy
• Experimental: S8
  8x CHOP-14
  Interventions:

  • Biological: filgrastim
  • Drug: CHOP regimen
  • Drug: cyclophosphamide
  • Drug: doxorubicin hydrochloride
  • Drug: prednisone
  • Drug: vincristine sulfate
  • Radiation: radiation therapy
• Experimental: R8
  8x CHOP-14 + 8x Rituximab
  Interventions:

  • Biological: filgrastim
  • Biological: rituximab
  • Drug: CHOP regimen
  • Drug: cyclophosphamide
  • Drug: doxorubicin hydrochloride
  • Drug: prednisone
  • Drug: vincristine sulfate
  • Radiation: radiation therapy

Publications *

• Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trumper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M; German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008 Feb;9(2):105-16. doi: 10.1016/S1470-2045(08)70002-0. Epub 2008 Jan 15.
• Kuhnl A, Cunningham D, Counsell N, Hawkes EA, Qian W, Smith P, Chadwick N, Lawrie A, Mouncey P, Jack A, Pocock C, Ardeshna KM, Radford J, McMillan A, Davies J, Turner D, Kruger A, Johnson PW, Gambell J, Rosenwald A, Ott G, Horn H, Ziepert M, Pfreundschuh M, Linch D. Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial. Ann Oncol. 2017 Jul 1;28(7):1540-1546. doi: 10.1093/annonc/mdx128.
• Pfreundschuh M, Poeschel V, Zeynalova S, Hanel M, Held G, Schmitz N, Viardot A, Dreyling MH, Hallek M, Mueller C, Wiesen MH, Witzens-Harig M, Truemper L, Keller U, Rixecker T, Zwick C, Murawski N. Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the german high-grade non-Hodgkin lymphoma study group. J Clin Oncol. 2014 Dec 20;32(36):4127-33. doi: 10.1200/JCO.2013.54.6861. Epub 2014 Nov 17. Erratum In: J Clin Oncol. 2015 Jun 10;33(17):1991.
• Bittenbring JT, Neumann F, Altmann B, Achenbach M, Reichrath J, Ziepert M, Geisel J, Regitz E, Held G, Pfreundschuh M. Vitamin D deficiency impairs rituximab-mediated cellular cytotoxicity and outcome of patients with diffuse large B-cell lymphoma treated with but not without rituximab. J Clin Oncol. 2014 Oct 10;32(29):3242-8. doi: 10.1200/JCO.2013.53.4537. Epub 2014 Aug 18.
• Held G, Murawski N, Ziepert M, Fleckenstein J, Poschel V, Zwick C, Bittenbring J, Hanel M, Wilhelm S, Schubert J, Schmitz N, Loffler M, Rube C, Pfreundschuh M. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol. 2014 Apr 10;32(11):1112-8. doi: 10.1200/JCO.2013.51.4505. Epub 2014 Feb 3.
• Horn H, Ziepert M, Becher C, Barth TF, Bernd HW, Feller AC, Klapper W, Hummel M, Stein H, Hansmann ML, Schmelter C, Moller P, Cogliatti S, Pfreundschuh M, Schmitz N, Trumper L, Siebert R, Loeffler M, Rosenwald A, Ott G; German High-Grade Non-Hodgkin Lymphoma Study Group. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood. 2013 Mar 21;121(12):2253-63. doi: 10.1182/blood-2012-06-435842. Epub 2013 Jan 18.
• Muller C, Murawski N, Wiesen MH, Held G, Poeschel V, Zeynalova S, Wenger M, Nickenig C, Peter N, Lengfelder E, Metzner B, Rixecker T, Zwick C, Pfreundschuh M, Reiser M. The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood. 2012 Apr 5;119(14):3276-84. doi: 10.1182/blood-2011-09-380949. Epub 2012 Feb 15.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 14, 2021): 1506
• Original Enrollment: Not Provided
• Actual Study Completion Date: August 5, 2010
• Actual Primary Completion Date: August 5, 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed aggressive non-Hodgkin's lymphoma (NHL) by an excisional biopsy of a lymph node or an extensive biopsy of an extranodal involvement (if there is no lymph node involvement)
• CD20^+ B-cell lymphoma or CD20^- B-cell and T-cell lymphoma allowed

• B-cell NHL including the following:

  • Stage III follicular lymphoma
  • Stage III follicular lymphoma and diffuse B-cell lymphoma
  • Lymphoblastic precursor B-cell lymphoma

  • Diffuse large cell B-cell lymphoma

    • Centroblastic
    • Immunoblastic
    • Plasmablastic
    • Anaplastic large cell
    • T-cell-rich B-cell lymphoma
    • Primary effusion lymphoma
    • Intravasal B-cell lymphoma
    • Primary mediastinal B-cell lymphoma
  • Mantle zone lymphoma, blastoid
  • Burkitt's lymphoma
  • Burkitt-like lymphoma
  • Aggressive marginal zone lymphoma (monocytoid)

• T-cell NHL including the following:

  • Lymphoblastic precursor T-cell lymphoma

  • Peripheral T-cell lymphoma (PTCL) not otherwise specified (NOS)

    • Lennert's lymphoma
    • T-zone lymphoma
  • T-cell lymphoma of the angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) type

  • Anaplastic large cell lymphoma

    • ALK^+
    • ALK^-
  • Extranodal NK/T-cell lymphoma, nasal type

  • Intestinal T/NK-cell lymphoma (with or without enteropathy)

    • Hepatosplenic gamma-delta lymphoma
    • Subcutaneous panniculitis-like PTCL
    • Aggressive T/NK PTCL
  • Anaplastic large-cell NHL, NOS
• Bone marrow involvement no more than 25%
• No lymphoma that is clearly restricted to the CNS or originating from the gastrointestinal tract

PATIENT CHARACTERISTICS:

Age

• 61 to 80

Performance status

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy

• Not specified

Hematopoietic

• WBC at least 2,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic

• Bilirubin no greater than 2 times upper limit of normal (ULN)
• No active hepatitis infection

Renal

• Creatinine no greater than 2 times ULN

Cardiovascular

• No Canadian Cardiovascular Society class III or IV angina pectoris
• No New York Heart Association class III or IV cardiac failure
• Ejection fraction at least 50%
• Fractional shortenings at least 25% by echocardiography or nuclear medicine examination

Pulmonary

• FEV1 at least 50%
• Diffusion capacity at least 50%

Other

• No uncontrolled diabetes mellitus
• No known hypersensitivity to any study medications
• No other concurrent malignancy
• HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy

Surgery

• Not specified

Other

• Must not have already initiated lymphoma therapy (except for the prephase treatment specified for this study)
• No other concurrent lymphoma therapy
• No concurrent participation in another treatment study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 61 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany, Switzerland

Administrative Information

• NCT Number: NCT00052936
• Other Study ID Numbers: CDR0000269015; DSHNHL-1999-1A ( Other Grant/Funding Number: Deutsche Krebshilfe ); EU-20243 ( Other Identifier: Ethikkommission der Ärztekammer des Saarlandes [85/99] )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Universität des Saarlandes ( 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

• PRS Account: Universität des Saarlandes
• Verification Date: May 2021