R-ICE Versus R-DHAP in Patients Aged 18-65 With Relapse Diffuse Large B-cell Lymphoma

Lymphoma Study Association (Other)
Overall Status
CT.gov ID

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the efficacy and safety of induction therapy R-ICE in comparison to R-DHAP after 3 cycles adjusted to successful mobilization of stem cells in patients with previously treated diffuse large B-cell lymphoma CD20.

The goal is to detect a difference in mobilization adjusted response rate of 15% between R-ICE and R-DHAP.

The other objective is to evaluate the efficacy and safety of MabThera maintenance therapy after transplantation as measured by the event free survival.

The goal is to obtain a 15% increase of event free survival at 2 years.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

In vitro, the addition of rituximab to standard anticancer drugs increases cell lyses even in chemoresistant cell lines. This chemosensitization effect was also demonstrated in vivo by the results of the GELA trial in elderly patients with DLCL. Reported phase II study results on the RICE regimen for treatment of patients with relapsed DLCL and comparison with historical controls being treated with ICE suggests that this effect (15% improvement in response rate) is likely in relapsing DLCL and had led the SWOG to stop a randomized trial comparing ICE vs RICE in patients with relapsed aggressive lymphoma.

In the setting of relapsed DLCL, high dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) remains the standard to improve survival in highly selected chemosensitive patients. In the Parma study, only 58% of the patients with relapsed aggressive NHL were good responders after DHAP and 24% were in complete remission. Moreover, the quality of response depended on prognostic factors such as IPI and relapse > 12 months after treatment, and only patients responding to salvage therapy benefited from HDT + ASCT. As shown in the PARMA study. The goal in relapsed DLCL is to improve complete response rates before transplantation as it is the main parameter for eligibility for HDT + ASCT and the main prognostic factor. Unlike first line treatment with CHOP, no standard chemotherapy exists for relapsing patients. DHAP has been the most frequently used regimen for decades but incorporates only two drugs, and has dose-limiting renal toxicity. The ICE regimen was developed at several dosages and studies consistently produced CR rates that were 10-15% superior to DHAP. It is expected that this difference will remain the same with the addition of rituximab to both regimens. Recent phase II data in patients with relapsed DLCL not previously treated with rituximab showed that RICE produced a response rate of 78% with a complete remission rate of 58% and was active in primary refractory disease as well as in intermediate-high risk patients (IPI 2-3). Association of DHAP to Rituximab, R-DHAP has been done on small series of patients by investigators, including patients relapsing after autotransplant. Despite numerous phase II studies, no randomized study has been performed comparing the two regimens (DHAP/ICE) or others in relapsing DLCL. Treatment of first line DLCL has been changed in the past 10 years with more intensive regimens, often followed by ASCT, and very recently with the addition of rituximab to chemotherapy and therefore the population of relapsing patients might be different from the one in the initial PARMA study. A large lymphoma intergroup study working on a large prospective data base might help to find the best salvage regimen and to assess the role of retreatment with monoclonal antibodies in these patients. Finally, the role of rituximab maintenance therapy after HDT + ASCT in prolonging second complete response should be evaluated.

Study Design

Study Type:
Actual Enrollment :
481 participants
Intervention Model:
Parallel Assignment
None (Open Label)
Primary Purpose:
Official Title:
Randomized Study of ICE Plus RITUXIMAB Versus DHAP Plus Rituximab in Previously Treated Patients With Diffuse Large B-cell Lymphoma, Followed by Randomized Maintenance With Rituximab
Study Start Date :
Jun 1, 2003
Actual Primary Completion Date :
Oct 1, 2008
Actual Study Completion Date :
Oct 1, 2008

Arms and Interventions

Arm Intervention/Treatment
Experimental: R-ICE

R-ICE + R-BEAM /ASCT Rituximab, Etoposide, Carboplatine, Ifosfamide + Mesna BCNU, Etoposide, Cytarabine, Melphalan Autologous Stem Cell Transplantation

Drug: Rituximab
375 mg/m² D-2/D1
Other Names:
  • R
  • Drug: Etoposide
    100 mg/m² D1-D2-D3

    Drug: Carboplatine
    max 800mg D2

    Drug: Ifosfamide + Mesna
    5 g/m² from D2 to D13

    Procedure: Autologous Stem Cell Transplantation
    Other Names:
  • ASCT
  • Drug: BCNU
    300mg/m² on D-6
    Other Names:
  • Drug: Etoposide
    200 mg/m² from D-6 to D-3

    Drug: Cytarabine
    100 mg/m² from D-6 to D-3

    Drug: Melphalan
    140 mg/m² on D-2

    Experimental: R-DHAP

    R-DHAP + R-BEAM /ASCT Rituximab, Cisplatine, Cytosine Arabinoside, Dexamethasone BCNU, Etoposide, Cytarabine, Melphalan Autologous Stem Cell Transplantation

    Drug: Rituximab
    375 mg/m² D-2/D1
    Other Names:
  • R
  • Drug: Cisplatine
    100 mg/m² from D1 to D13

    Drug: Cytosine Arabinoside
    2000 mg/m²/12 h D2 D3

    Drug: Dexamethasone
    40 mg From D1 to D4

    Procedure: Autologous Stem Cell Transplantation
    Other Names:
  • ASCT
  • Drug: BCNU
    300mg/m² on D-6
    Other Names:
  • Drug: Etoposide
    200 mg/m² from D-6 to D-3

    Drug: Cytarabine
    100 mg/m² from D-6 to D-3

    Drug: Melphalan
    140 mg/m² on D-2

    Outcome Measures

    Primary Outcome Measures

    1. MARR (mobilization adjusted response rate) [3 months]

    2. EFS (event free survival) [2 years post transplantation]

    Secondary Outcome Measures

    1. Progression rate [2 years post transplantation]

    2. Overall survival [2 years post transplantation]

    3. Duration of response [2 years post transplantation]

    Eligibility Criteria


    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    Accepts Healthy Volunteers:
    Inclusion Criteria:
    • Patients with CD20-positive diffuse large B-cell lymphoma. Disease must be histologically proven in case of relapse or partial response.

    • Aged 18 to 65 years

    • First relapse after complete remission (CR), less than partial remission (PR) or partial response to first line treatment not achieving documented or confirmed complete remission.

    • Eligible for transplant

    • Previously treated with chemotherapy regimen containing anthracyclines with or without rituximab.

    • ECOG performance status 0 to 2.

    • Minimum life expectancy of 3 months.

    • Signed written informed consent prior to randomization.

    Exclusion Criteria:
    • Burkitt, mantle-cell and T-cell lymphoma.

    • CD20-negative diffuse large cell lymphoma

    • Documented infection with HIV and hepatitis B virus [HBV] (in the absence of vaccination)

    • Central nervous system or meningeal involvement by lymphoma.

    • Not previously treated with anthracycline-containing regimens

    • Prior transplantation

    • Contra-indication to any drug contained in the chemotherapy regimens.

    • Any serious active disease or co-morbid condition (according to the investigator's decision and information provided in the Investigational Drug Brochure [IDB]).

    • Poor renal function (creatinine level > 150µmol/l or 1.5-2.0 x upper limit of normal [ULN]); poor hepatic function (total bilirubin level > 30mmol/l [> 1.5 x ULN], transaminases > 2.5 maximum normal level) unless these abnormalities are related to the lymphoma; poor bone marrow reserve as defined by neutrophils < 1.5G/l or platelets < 100G/l, unless related to bone marrow infiltration.

    • Any history of cancer during the last 5 years with the exception of non-melanoma skin tumors or stage 0 (in situ) cervical carcinoma.

    • Treatment with any investigational drug within 30 days before planned first cycle of chemotherapy and during the study.

    • Pregnant women

    • Adult patients unable to provide informed consent because of intellectual impairment.

    Contacts and Locations


    Site City State Country Postal Code
    1 Memorial Sloan Kettering Cancer Center New York New York United States 10021
    2 Australian leukemia and lymphoma group Sydney Australia
    3 Groupe d'atude des lymphome de l'adulte Yvoir Belgium
    4 Czech Lymphoma study group Praha Czechia
    5 Hospital district of south west Finland Turku Finland
    6 German high grade non hodgkin's lymphoma group Hamburg Germany
    7 Israel Society of Hematology Tel-Hashomer Israel
    8 Nordic center Uppsala Sweden
    9 Schweirische Arbeitsgruppe fur klinische Krebsforschung Lausanne Switzerland
    10 National cancer research institute London United Kingdom

    Sponsors and Collaborators

    • Lymphoma Study Association


    • Principal Investigator: Christian Gisselbrecht, Lymphoma Study Association

    Study Documents (Full-Text)

    None provided.

    More Information


    Responsible Party:
    Lymphoma Study Association
    ClinicalTrials.gov Identifier:
    Other Study ID Numbers:
    • CORAL
    • NCT00081146
    First Posted:
    Aug 30, 2005
    Last Update Posted:
    Aug 28, 2019
    Last Verified:
    Aug 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    Plan to Share IPD:
    Studies a U.S. FDA-regulated Drug Product:
    Studies a U.S. FDA-regulated Device Product:
    Keywords provided by Lymphoma Study Association
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Aug 28, 2019