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

NCT ID: NCT00137995

Last Updated: 2019-08-28

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

481 participants

Study Classification

INTERVENTIONAL

Study Start Date

2003-06-30

Study Completion Date

2008-10-31

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Lymphoma, Large-Cell, Diffuse

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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R-ICE

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

Group Type EXPERIMENTAL

Rituximab

Intervention Type DRUG

375 mg/m² D-2/D1

Etoposide

Intervention Type DRUG

100 mg/m² D1-D2-D3

Carboplatine

Intervention Type DRUG

max 800mg D2

Ifosfamide + Mesna

Intervention Type DRUG

5 g/m² from D2 to D13

Autologous Stem Cell Transplantation

Intervention Type PROCEDURE

BCNU

Intervention Type DRUG

300mg/m² on D-6

Etoposide

Intervention Type DRUG

200 mg/m² from D-6 to D-3

Cytarabine

Intervention Type DRUG

100 mg/m² from D-6 to D-3

Melphalan

Intervention Type DRUG

140 mg/m² on D-2

R-DHAP

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

Group Type EXPERIMENTAL

Rituximab

Intervention Type DRUG

375 mg/m² D-2/D1

Cisplatine

Intervention Type DRUG

100 mg/m² from D1 to D13

Cytosine Arabinoside

Intervention Type DRUG

2000 mg/m²/12 h D2 D3

Dexamethasone

Intervention Type DRUG

40 mg From D1 to D4

Autologous Stem Cell Transplantation

Intervention Type PROCEDURE

BCNU

Intervention Type DRUG

300mg/m² on D-6

Etoposide

Intervention Type DRUG

200 mg/m² from D-6 to D-3

Cytarabine

Intervention Type DRUG

100 mg/m² from D-6 to D-3

Melphalan

Intervention Type DRUG

140 mg/m² on D-2

Interventions

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Rituximab

375 mg/m² D-2/D1

Intervention Type DRUG

Etoposide

100 mg/m² D1-D2-D3

Intervention Type DRUG

Carboplatine

max 800mg D2

Intervention Type DRUG

Ifosfamide + Mesna

5 g/m² from D2 to D13

Intervention Type DRUG

Cisplatine

100 mg/m² from D1 to D13

Intervention Type DRUG

Cytosine Arabinoside

2000 mg/m²/12 h D2 D3

Intervention Type DRUG

Dexamethasone

40 mg From D1 to D4

Intervention Type DRUG

Autologous Stem Cell Transplantation

Intervention Type PROCEDURE

BCNU

300mg/m² on D-6

Intervention Type DRUG

Etoposide

200 mg/m² from D-6 to D-3

Intervention Type DRUG

Cytarabine

100 mg/m² from D-6 to D-3

Intervention Type DRUG

Melphalan

140 mg/m² on D-2

Intervention Type DRUG

Other Intervention Names

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R ASCT BICNU

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Lymphoma Study Association

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Christian Gisselbrecht

Role: PRINCIPAL_INVESTIGATOR

Lymphoma Study Association

Locations

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Memorial Sloan Kettering Cancer Center

New York, New York, United States

Site Status

Australian leukemia and lymphoma group

Sydney, , Australia

Site Status

Groupe d'atude des lymphome de l'adulte

Yvoir, , Belgium

Site Status

Czech Lymphoma study group

Prague, , Czechia

Site Status

Hospital district of south west Finland

Turku, , Finland

Site Status

German high grade non hodgkin's lymphoma group

Hamburg, , Germany

Site Status

Israel Society of Hematology

Tel Litwinsky, , Israel

Site Status

Nordic center

Uppsala, , Sweden

Site Status

Schweirische Arbeitsgruppe fur klinische Krebsforschung

Lausanne, , Switzerland

Site Status

National cancer research institute

London, , United Kingdom

Site Status

Countries

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

References

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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.

Reference Type BACKGROUND
PMID: 9808548 (View on PubMed)

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. doi: 10.1182/blood-2003-11-3911. Epub 2004 Jan 22.

Reference Type BACKGROUND
PMID: 14739217 (View on PubMed)

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. doi: 10.1056/NEJMoa011795.

Reference Type BACKGROUND
PMID: 11807147 (View on PubMed)

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. doi: 10.1200/JCO.1998.16.10.3264.

Reference Type BACKGROUND
PMID: 9779700 (View on PubMed)

Gisselbrecht C, Schmitz N, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Milpied NJ, Radford J, Ketterer N, Shpilberg O, Duhrsen U, Hagberg H, Ma DD, Viardot A, Lowenthal R, Briere J, Salles G, Moskowitz CH, Glass B. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012 Dec 20;30(36):4462-9. doi: 10.1200/JCO.2012.41.9416. Epub 2012 Oct 22.

Reference Type DERIVED
PMID: 23091101 (View on PubMed)

Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Briere J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. doi: 10.1200/JCO.2010.28.1618. Epub 2010 Jul 26.

Reference Type DERIVED
PMID: 20660832 (View on PubMed)

Other Identifiers

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CORAL

Identifier Type: -

Identifier Source: org_study_id

NCT00081146

Identifier Type: -

Identifier Source: nct_alias

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