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

Lymphoma, Large-Cell, Diffuse Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00137995
• Other study ID #: CORAL
• Status: Completed
• Phase: Phase 3
• Start date: June 2003
• Est. completion date: October 2008

Study information

• Verified date: August 2019
• Source: Lymphoma Study Association
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT00081146

Recruitment information / eligibility

• Status: Completed
• Enrollment: 481
• Est. completion date: October 2008
• Est. primary completion date: October 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Large-Cell, Diffuse

Intervention

Drug:
• Rituximab
375 mg/m² D-2/D1
• Etoposide
100 mg/m² D1-D2-D3
• Carboplatine
max 800mg D2
• Ifosfamide + Mesna
5 g/m² from D2 to D13
• Cisplatine
100 mg/m² from D1 to D13
• Cytosine Arabinoside
2000 mg/m²/12 h D2 D3
• Dexamethasone
40 mg From D1 to D4

Procedure:
• Autologous Stem Cell Transplantation

Drug:
• BCNU
300mg/m² on D-6
• Etoposide
200 mg/m² from D-6 to D-3
• Cytarabine
100 mg/m² from D-6 to D-3
• Melphalan
140 mg/m² on D-2

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Lymphoma Study Association

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Czechia,  Finland,  Germany,  Israel,  Sweden,  Switzerland,  United Kingdom, 

References & Publications (4)

Blay J, Gomez F, Sebban C, Bachelot T, Biron P, Guglielmi C, Hagenbeek A, Somers R, Chauvin F, Philip T. The International Prognostic Index correlates to survival in patients with aggressive lymphoma in relapse: analysis of the PARMA trial. Parma Group. Blood. 1998 Nov 15;92(10):3562-8. — View Citation

Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. — View Citation

Guglielmi C, Gomez F, Philip T, Hagenbeek A, Martelli M, Sebban C, Milpied N, Bron D, Cahn JY, Somers R, Sonneveld P, Gisselbrecht C, Van Der Lelie H, Chauvin F. Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol. 1998 Oct;16(10):3264-9. — View Citation

Kewalramani T, Zelenetz AD, Nimer SD, Portlock C, Straus D, Noy A, O'Connor O, Filippa DA, Teruya-Feldstein J, Gencarelli A, Qin J, Waxman A, Yahalom J, Moskowitz CH. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood. 2004 May 15;103(10):3684-8. Epub 2004 Jan 22. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MARR (mobilization adjusted response rate)		3 months
Primary	EFS (event free survival)		2 years post transplantation
Secondary	Progression rate		2 years post transplantation
Secondary	Overall survival		2 years post transplantation
Secondary	Duration of response		2 years post transplantation