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

August 22, 2019 updated by: Lymphoma Study Association

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

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.

Study Overview

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 Type

Interventional

Enrollment (Actual)

481

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Sydney, Australia
        • Australian leukemia and lymphoma group
      • Yvoir, Belgium
        • Groupe d'atude des lymphome de l'adulte
      • Praha, Czechia
        • Czech Lymphoma Study Group
      • Turku, Finland
        • Hospital District of South West Finland
      • Hamburg, Germany
        • German high grade non hodgkin's lymphoma group
      • Tel-Hashomer, Israel
        • Israel Society of Hematology
      • Uppsala, Sweden
        • Nordic center
      • Lausanne, Switzerland
        • Schweirische Arbeitsgruppe fur klinische Krebsforschung
      • London, United Kingdom
        • National Cancer Research Institute
    • New York
      • New York, New York, United States, 10021
        • Memorial Sloan Kettering Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 63 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: R-ICE
R-ICE + R-BEAM /ASCT Rituximab, Etoposide, Carboplatine, Ifosfamide + Mesna BCNU, Etoposide, Cytarabine, Melphalan Autologous Stem Cell Transplantation
Other Names:
  • ASCT
375 mg/m² D-2/D1
Other Names:
  • R
100 mg/m² D1-D2-D3
max 800mg D2
5 g/m² from D2 to D13
300mg/m² on D-6
Other Names:
  • BICNU
200 mg/m² from D-6 to D-3
100 mg/m² from D-6 to D-3
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
Other Names:
  • ASCT
375 mg/m² D-2/D1
Other Names:
  • R
100 mg/m² D1-D2-D3
300mg/m² on D-6
Other Names:
  • BICNU
200 mg/m² from D-6 to D-3
100 mg/m² from D-6 to D-3
140 mg/m² on D-2
100 mg/m² from D1 to D13
2000 mg/m²/12 h D2 D3
40 mg From D1 to D4

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
MARR (mobilization adjusted response rate)
Time Frame: 3 months
3 months
EFS (event free survival)
Time Frame: 2 years post transplantation
2 years post transplantation

Secondary Outcome Measures

Outcome Measure
Time Frame
Progression rate
Time Frame: 2 years post transplantation
2 years post transplantation
Overall survival
Time Frame: 2 years post transplantation
2 years post transplantation
Duration of response
Time Frame: 2 years post transplantation
2 years post transplantation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Christian Gisselbrecht, Lymphoma Study Association

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2003

Primary Completion (Actual)

October 1, 2008

Study Completion (Actual)

October 1, 2008

Study Registration Dates

First Submitted

August 25, 2005

First Submitted That Met QC Criteria

August 29, 2005

First Posted (Estimate)

August 30, 2005

Study Record Updates

Last Update Posted (Actual)

August 28, 2019

Last Update Submitted That Met QC Criteria

August 22, 2019

Last Verified

August 1, 2019

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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