Efficacy of R-CHOP vs R-CHOP/R-DHAP in Untreated MCL

This study is currently recruiting participants.
Verified July 2009 by European Mantle Cell Lymphoma Network
Sponsor:
Collaborators:
German Low Grade Lymphoma Study Group
Lymphoma Study Association
Information provided by:
European Mantle Cell Lymphoma Network
ClinicalTrials.gov Identifier:
NCT00209222
First received: September 13, 2005
Last updated: September 7, 2012
Last verified: July 2009
  Purpose

The aim of this study is to determine whether alternating courses of cyclophosphamide, doxorubicin, vincristine, prednisone/dexamethasone, cytarabine, cisplatin (CHOP/DHAP) plus rituximab followed by total body irradiation [TBI]/high dose cytarabine [ARA-C]/melphalan-peripheral blood stem cell transplantation (TAM-PBSCT) can improve the time to treatment failure compared to CHOP plus rituximab followed by standard PBSCT (dexamethasone, carmustine, cytarabine, etoposide, and melphalan [Dexa-BEAM]/TBI/high dose cyclophosphamide) in patients with untreated mantle cell lymphoma.


Condition Intervention Phase
Lymphoma, Mantle-Cell
Drug: Rituximab
Drug: Cyclophosphamide
Drug: Doxorubicin
Drug: Vincristine
Drug: Prednisone
Drug: Cisplatinum
Drug: Ara-C
Drug: Dexamethasone
Drug: BCNU
Drug: Melphalan
Drug: Etoposide
Drug: G-CSF
Procedure: chemotherapy: R-CHOP
Procedure: chemotherapy: R-DHAP
Procedure: chemotherapy: Dexa-BEAM
Procedure: stem cell harvest
Procedure: total body irradiation
Procedure: high-dose chemotherapy: Cyclophosphamide
Procedure: high-dose chemotherapy: Ara-C /Melphalan
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Efficacy of 6x R-CHOP Followed by Myeloablative Radiochemotherapy and Autologous Stem Cell Transplantation vs. 3 x (R-CHOP/R-DHAP) Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation

Resource links provided by NLM:


Further study details as provided by European Mantle Cell Lymphoma Network:

Primary Outcome Measures:
  • time to treatment failure after start of therapy

Secondary Outcome Measures:
  • complete remission (CR) rate
  • overall survival
  • progression-free survival
  • adverse events
  • serious infectious complications

Estimated Enrollment: 360
Study Start Date: July 2004
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
induction: R-CHOP consoldiation : TBI/Cyclo
Drug: Rituximab
antibody
Drug: Cyclophosphamide
chemotherapy
Drug: Doxorubicin
chemotherapy
Drug: Vincristine
chemotherapy
Drug: Prednisone
corticosteroide
Drug: BCNU
chemotherapy
Drug: Melphalan
chemotherapy
Drug: Etoposide
chemotherapy
Drug: G-CSF
growth factor
Procedure: chemotherapy: R-CHOP
immuno-chemotherapy
Procedure: chemotherapy: Dexa-BEAM
chemotherapy
Procedure: stem cell harvest
procedure
Procedure: total body irradiation
radiation
Procedure: high-dose chemotherapy: Cyclophosphamide
chemotherapy
Experimental: 2
induction: R-CHOP/DHAP consolditaion: TBI/TAM
Drug: Rituximab
antibody
Drug: Cyclophosphamide
chemotherapy
Drug: Doxorubicin
chemotherapy
Drug: Vincristine
chemotherapy
Drug: Prednisone
corticosteroide
Drug: Cisplatinum
chemotherapy
Drug: Ara-C
chemotherapy
Drug: Dexamethasone
corticosteroide
Drug: Melphalan
chemotherapy
Drug: G-CSF
growth factor
Procedure: chemotherapy: R-CHOP
immuno-chemotherapy
Procedure: chemotherapy: R-DHAP
immuno-chemotherapy
Procedure: stem cell harvest
procedure
Procedure: total body irradiation
radiation
Procedure: high-dose chemotherapy: Ara-C /Melphalan
chemotherapy

Detailed Description:

Recently, a prospective randomized intergroup trial of the European MCL Network has shown that a myeloablative radio-chemotherapy followed by autologous stem cell transplantation (PBSCT) improves event-free survival (EFS) when compared to a interferon alpha maintenance therapy after a CHOP-like induction. However, the CR rate after the CHOP induction was still low (<20%). Thus, several studies have been conducted to increase the CR rate of induction therapy to further improve event-free and overall survival. Two recent phase II trials suggest that induction regimens containing high dose Ara-C may significantly improve the CR rate up to 80%. In addition, a number of studies provide evidence that the humanized anti-CD20 antibody Rituximab may induce significant responses in relapsed MCL. A prospective randomized study of the GLSG demonstrated that a combined immuno-chemotherapy (CHOP plus Rituximab) induces a significantly higher response rate than CHOP alone.

The aim of this study is the comparison of the current standard (R-CHOP followed by myeloablative radio-chemotherapy and subsequent blood stem cell transplantation) to a new alternating induction regimen containing high dose Ara-C (R-CHOP/DHAP) followed by a high dose ARA-C containing myeloablative radio-chemotherapy and PBSCT.

This study will be performed as a prospective, randomized, open-label multicenter phase III trial. All patients will be initial randomized for standard treatment versus experimental treatment.

REFERENCE ARM:

The induction therapy consists of 6 cycles of a CHOP chemotherapy in combination with Rituximab. If the mantle cell lymphoma is progressive after 4 cycles of chemotherapy, patients will be taken off study. Patients achieving at least a partial remission after 6 cycles R-CHOP will proceed to intensified consolidation (Dexa-BEAM) with stem cell collection and subsequent myelo-ablative radio-chemotherapy (TBI/High Dose Cyclophosphamide) with autologous stem cells transplantation

EXPERIMENTAL ARM:

Initial cytoreductive chemotherapy comprises of alternating cycles of 3xCHOP and 3x DHAP plus Rituximab. Patients with progressive disease after 2 treatment cycles R-CHOP and 2x R-DHAP will be off study. Patients achieving at least a partial remission after 3x CHOP and 3x DHAP plus Rituximab will proceed to with stem cell collection. The subsequent myeloablative radio-chemotherapy with stem cell transplantation consists of a radiotherapy (TBI), high dose Ara-C and Melphalan.

The primary end point in this study is the time to treatment failure. The time to treatment failure will be defined as time from start of initial therapy until first failure. A failure will be defined as failure of initial therapy or progression of the lymphoma or death of the patient.

Using the data of the PBSCT group in the former European mantle cell study as baseline in a proportional hazard model, the improvement for the time to treatment failure expected by the new strategy can be expressed by reduction of relative risk (rr). A risk reduction to 52% which would correspond to a improvement of 20% in failure free survival after 3 years seems to be a clinical relevant improvement. For a working significance level alpha=0.05 and a power of 95% the number of events necessary for a one sided fixed sample trial is about 105. During this study the time to treatment failure will be monitored using an equivalent one-sided triangular sequential test.

In order to evaluate the impact of therapy on overall survival in this patients, a total follow up of about 12 years for this study is expected.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically proven diagnosis of mantle cell lymphoma (World Health Organization [WHO] classification)
  • Clinical stage II - IV (Ann Arbor)
  • Previously untreated patients
  • Age 18 - 65 years
  • WHO performance < 2
  • Measurable disease (also: patients with isolated bone marrow involvement)
  • Informed consent according to International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use/European Union Good Clinical Practice (ICH/EU GCP) and national/local regulations

Exclusion Criteria:

  • Age > 65 years
  • WHO performance status > 2
  • Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies
  • Previous lymphoma therapy with radiation, cytostatic drugs, anti-CD20 antibody or interferon
  • Serious disease interfering with a regular therapy according to the study protocol:

    • cardiac (e.g. manifest heart failure, coronary heart disease, uncontrolled hypertension)
    • pulmonary (e.g. chronic lung disease with hypoxemia)
    • endocrine (e.g. severe, not sufficiently controlled diabetes mellitus)
    • renal insufficiency (unless caused by the lymphoma): creatinine > 2x normal value and/or creatinine clearance < 50 ml/min)
    • impairment of liver function (unless caused by the lymphoma): transaminases > 3x normal or bilirubin > 2,0 mg/dl
  • Patients with unresolved hepatitis B or C infection or known HIV infection
  • Prior organ, bone marrow or peripheral blood stem cell transplantation
  • Concomitant or previous malignancies within the last 5 years other than basal cell skin cancer or in situ uterine cervix cancer.
  • Pregnancy or lactation
  • Any psychological, familiar, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00209222

Contacts
Contact: Michael Unterhalt, Dr. +49-89-7095 ext 4915 Michael.Unterhalt@med.uni-muenchen.de
Contact: Martin Dreyling, PhD +49-89-7095 ext 2202 Martin.Dreyling@med.uni-muenchen.de

Locations
France
Groupe D´Etudes des Lymphomes De l´Adulte (GELA) Recruiting
Paris, France, F-75743
Contact: Guylène Chartier    +33-1-42499811    Guylene.chartier@chu-stlouis.fr   
Contact: Olivier Hermine, PhD    +33-1-44 49 52 83    hermine@necker.fr   
Principal Investigator: Olivier Hermine, PhD         
Germany
German Low Grade Study Group (Glsg) Recruiting
Munich, Germany, D-81377
Contact: Michael Unterhalt, Dr.    +49-89-7095 ext 4915    Michael.Unterhalt@med.uni-muenchen.de   
Contact: Martin Dreyling, PhD    +49-89-7095 ext 2202    Martin.Dreyling@med.uni-muenchen.de   
Principal Investigator: Wolfgang Hiddemann, PhD         
Poland
The Maria Sklodowska Memorial, Cancer Center - Inst. of Oncology Recruiting
Warszawa, Poland, PL-02-781
Contact: Jan Walewski, MD    +48-22-546-2223    walewski@coi.waw.pl   
Contact: Marek P Nowacki, MD    +48-22-546-2223      
Principal Investigator: Jan Walewski, MD         
Sponsors and Collaborators
European Mantle Cell Lymphoma Network
German Low Grade Lymphoma Study Group
Lymphoma Study Association
Investigators
Principal Investigator: Olivier Hermine, PhD University Hospital Necker, Dept. of Adult Hematology
Study Chair: Wolfgang Hiddemann, PhD University Hospital Großhadern/LMU, Dept. of Medicine III
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Prof Dr. Martin Dreyling, University Hospital Grosshadern/European MCLNetwork
ClinicalTrials.gov Identifier: NCT00209222     History of Changes
Other Study ID Numbers: MCL2004-2
Study First Received: September 13, 2005
Last Updated: September 7, 2012
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by European Mantle Cell Lymphoma Network:
Lymphoma, Mantle-Cell
younger patients
chemotherapy
high dose therapy
C04.557.386.480.300.725.500
C15.604.515.569.480.300.725.500
C20.683.515.761.480.300.725.500

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Rituximab
Cisplatin
Cyclophosphamide
Cytarabine
Dexamethasone
Doxorubicin
Etoposide
Melphalan
Prednisone
Vincristine
Dexamethasone acetate
Dexamethasone 21-phosphate
BB 1101
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents

ClinicalTrials.gov processed this record on April 16, 2014