The primary objective of this study is to evaluate the efficacy and safety of induction therapy R-ICE in comparison R-DHAP after 3 cycles adjusted to successful mobilization of stem cells in patient 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 Mabthera maintenance therapy after transplantation as measured by the event free survival.

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

Condition	Intervention	Phase
Lymphoma, Large-Cell, Diffuse	Drug: DHAP plus rituximab  Drug: ICE plus rituximab	Phase III

Further Study Details: 

Primary Outcomes: MARR (Mobilization adjusted response rate) and EFS ( Event free survival)
Secondary Outcomes: Progression rate; Overall survival; Duration of response
Expected Total Enrollment:  400

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)s with . 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.

Ages Eligible for Study:  18 Years   -   65 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Patient with CD20-positive diffuse large B-cell lymphoma. Disease must be histologically proven in case of relapse or partial response.

• Aged from 18 to 65 years • First relapse after CR, less than 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. • CD 20 negative diffuse large cell lymphoma • documented infection with HIV and 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 IDB).

• Poor renal function (creatinine level >150mol/l or 1.5-2.0 x 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 woman • Adult patient unable to provide informed consent because of intellectual impairment.

Please refer to this study by ClinicalTrials.gov identifier  NCT00137995

Christian Gisselbrecht, MD PHD      33142499811    christian.gisselbrecht@sls.ap-hop-paris.fr

New York
      Memorial Sloan Kettering Cancer Center, New York,  New York,  10021,  United States; Recruiting
Australia
      Australian leukemia and lymphoma group, Sydney,  Australia; Recruiting
Belgium
      Groupe d''''atude des lymphome de l''''adulte, Yvoir,  Belgium; Recruiting
Czech Republic
      Czech Lymphoma study group, Praha,  Czech Republic; Recruiting
Finland
      Hospital district of south west Finland, Turku,  Finland; Not yet recruiting
Germany
      German high grade non hodgkin''''s lymphoma group, Hamburg,  Germany; Recruiting
Israel
      Israle Society of hematology, Tel Hashomer,  Israel; Recruiting
Sweden
      Nordic center, Uppsala,  Sweden; Recruiting
Switzerland
      Schweirische Arbeitsgruppe fur klinische Krebsforschung, Lausanne,  Switzerland; Recruiting
United Kingdom
      National cancer research institute, London,  United Kingdom; Not yet recruiting

Study chairs or principal investigators

Christian Gisselbrecht,  Principal Investigator,  Groupe d''''Etudes de Lymphomes de L''''Adulte   

Study ID Numbers:  CORAL
Last Updated:  August 29, 2005
Record first received:  August 25, 2005
ClinicalTrials.gov Identifier:  NCT00137995
Health Authority: France: Afssaps - French Health Products Safety Agency
ClinicalTrials.gov processed this record on 2005-08-30