Induction Chemotherapy (R-CHOP Vs. R-FC) Followed by Interferon Maintenance Versus Rituximab Maintenance in MCL

Overview[ - collapse ][ - ]

Purpose The aim of this study is to answer the following independent questions in the treatment of mantle cell lymphomas: - Can rituximab-fludarabine, cyclophosphamide (R-FC) improve the reduction of lymphoma mass compared to rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) and so become a new standard for initial cytoreductive therapy? - Can maintenance with rituximab substitute the interferon maintenance and even improve the progression free survival in patients after successful initial cytoreductive therapy?
ConditionLymphoma, Mantle-Cell
InterventionDrug: Rituximab
Drug: Cyclophosphamide
Drug: Doxorubicin
Drug: Vincristine
Drug: Prednisone
Drug: Fludarabine
Drug: Interferon-alpha
Drug: pegylated formula Interferon-alpha 2b
Procedure: chemotherapy: R-CHOP
Procedure: chemotherapy: R-FC
Procedure: Interferon maintenance
Procedure: Rituximab maintenance
PhasePhase 3
SponsorEuropean Mantle Cell Lymphoma Network
Responsible PartyEuropean Mantle Cell Lymphoma Network
ClinicalTrials.gov IdentifierNCT00209209
First ReceivedSeptember 13, 2005
Last UpdatedSeptember 6, 2012
Last verifiedSeptember 2012

Tracking Information[ + expand ][ + ]

First Received DateSeptember 13, 2005
Last Updated DateSeptember 6, 2012
Start DateJanuary 2004
Estimated Primary Completion DateDecember 2014
Current Primary Outcome Measures
  • First randomisation: Reduction of lymphoma mass measured by the complete remission (CR) rate
  • Second randomisation: progression-free survival after end of initial chemotherapy
Current Secondary Outcome Measures
  • Survival after registration / first randomisation / second randomisation
  • Survival after start / end of initial therapy
  • Time to treatment failure after start of initial therapy
  • Progression free survival after registration / first randomisation / second randomisation
  • Side-effects of initial therapy
  • Side-effects of maintenance therapy

Descriptive Information[ + expand ][ + ]

Brief TitleInduction Chemotherapy (R-CHOP Vs. R-FC) Followed by Interferon Maintenance Versus Rituximab Maintenance in MCL
Official TitleEfficacy of Maintenance Therapy With Rituximab After Induction Chemotherapy (R-CHOP vs. R-FC) for Elderly Patients With Mantle Cell Lymphoma Not Suitable for Autologous Stem Cell Transplantation
Brief Summary
The aim of this study is to answer the following independent questions in the treatment of
mantle cell lymphomas:

- Can rituximab-fludarabine, cyclophosphamide (R-FC) improve the reduction of lymphoma
mass compared to rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone
(R-CHOP) and so become a new standard for initial cytoreductive therapy?

- Can maintenance with rituximab substitute the interferon maintenance and even improve
the progression free survival in patients after successful initial cytoreductive
therapy?
Detailed Description
This study investigates two independent questions in the treatment of elderly patients with
mantle cell lymphomas:

1. To test in elderly patients with advanced mantle cell lymphoma, whether rituximab plus
a combination of fludarabine with cyclophosphamide (6 FC cycles) results in a higher
reduction of lymphoma mass measured by the percentage of CR than rituximab combined
with the standard chemotherapy scheme (8 CHOP cycles).

2. To compare maintenance therapy with rituximab with maintenance with interferon-alpha or
pegylated interferon for progression free survival, after 2 different regimens of
induction chemo-immunotherapy in elderly patients with mantle cell lymphoma.

This study will be performed as a prospective, randomized, open-label multicenter phase III
trial. All patients will be randomized for an initial cytoreductive therapy with R-FC or
R-CHOP.

The parameter for the comparison of R-FC and R-CHOP will be the percentage of complete
remissions after initial cytoreductive therapy. According to the known results of R-FC and
R-CHOP in lymphoma therapy, a relevant difference between R-CHOP and R-FC in the overall
response rates is not expected. For both therapies an overall response rate of about 90% is
expected. Since it is well known that the prognosis of patients who do not reach at least a
PR in the initial therapy is very poor, it will be also necessary to control this parameter
during the study. If an unexpected relevant difference in the overall response rates is
observed during the study, the initial randomisation should be stopped and all patients
should be assigned to the superior therapy. In this case the CR rates will not be important
for the choice of the initial therapy. If no relevant differences in the overall response
rates are observed, a one sided Fisher test will be performed at the end of the recruitment
to test whether the rate of CR's after R-FC is significantly improved compared to R-CHOP.

The statistical parameters for controlling the overall response rates and for testing the CR
rates are chosen in the following way: The working significance level for all statistical
evaluations in this part of the study will be set to alpha=0.05. The expected CR rate after
R-CHOP is according to the observations about 50%; a clinical relevant improvement by R-FC
would be a CR rate of 65%. Such an improvement should be detected by the one sided Fisher
test with a power of about 95%. According to these parameters about 246 observations for
each treatment would be necessary. To control the overall response rates, a difference of
85% to 95% will be clinically so relevant that initial randomisation should be terminated
with a probability of about 95%. Overall response rates will be controlled by a restricted
sequential procedure.

Patients achieving at least a partial remission after R-FC or R-CHOP will be randomised for
interferon maintenance versus rituximab maintenance in order to evaluate the impact of
maintenance therapy in progression free survival.

The improvement expected by the new maintenance with rituximab for progression free survival
can be expressed by reduction of relative risk (rr). Since a risk reduction to 60% was
observed for indolent lymphomas by interferon maintenance, this seems to be a clinical
relevant improvement for the new maintenance therapy. For a working significance level
alpha=0.05 and a power of 95% the number of events (relapse or death) necessary for a two
sided fixed sample trial is about 200. During this study the progression free survival in
patients after successful initial therapy will be monitored by an equivalent restricted
sequential procedure with a maximum number of 240 observation.

In order to evaluate the impact of initial therapy and maintenance therapy on overall
survival in this patients, a total follow up of about 15 years for this study is expected.
Study TypeInterventional
Study PhasePhase 3
Study DesignAllocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
ConditionLymphoma, Mantle-Cell
InterventionDrug: Rituximab
antibody
Drug: Cyclophosphamide
chemotherapy
Drug: Doxorubicin
chemotherapy
Drug: Vincristine
chemotherapy
Drug: Prednisone
coricosteroide
Drug: Fludarabine
chemotherapy
Drug: Interferon-alpha
cytokine
Drug: pegylated formula Interferon-alpha 2b
cytokine
Procedure: chemotherapy: R-CHOP
immuno-chemotherapy
Procedure: chemotherapy: R-FC
immuno-chemotherapy
Procedure: Interferon maintenance
cytokine
Procedure: Rituximab maintenance
antibody
Study Arm (s)
  • Active Comparator: 1
    randomisation: R-CHOP
    randomisation: IFN maintenance
  • Experimental: 2
    randomisation: R-FC
    randomisation: Rituximab maintnenance

Recruitment Information[ + expand ][ + ]

Recruitment StatusRecruiting
Estimated Enrollment570
Estimated Completion DateDecember 2014
Estimated Primary Completion DateDecember 2014
Eligibility Criteria
Inclusion Criteria:

- Histologically proven mantle cell lymphoma according to the World Health Organization
(WHO) classification, preferably confirmed by central pathology review before
entering the study

- Clinical stage II, III or IV

- Previously untreated patients

- Above the age of 65 years and older or patients at the age between 60 and 65, if not
eligible for high dose chemotherapy

- WHO performance grade 0, 1 or 2

- 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

- Measurable disease. If, for example only bone marrow (BM) infiltration, patients can
only undergo a second randomization if a CR is obtained.

Exclusion Criteria:

- WHO performance of 3 or more

- Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine
antibodies

- Leukocytes <2.0x 10^9/l or thrombocytes <100x 10^9/l, unless clearly related to
mantle cell lymphoma (MCL) bone marrow infiltration

- Patients previously treated for lymphoma

- Patients without measurable lesions; if, for example only bone marrow infiltration,
patients may be included, but can only undergo a second randomization in case of a CR

- Patients with stage I disease

- Patients with central nervous system involvement

- Patients with a history of autoimmune hemolytic anaemia or autoimmune
thrombocytopenia

- Patients with serious cardiac disease (uncontrolled arrhythmias, unstable angina,
severe congestive heart failure)

- Patients with serious pulmonary, neurological, endocrinological or other disorder
interfering with full dosing of CHOP or FC chemotherapy

- Liver enzymes >3x normal or bilirubin >2.5x normal (not due to lymphoma)

- Creatinine >2x normal value, corrected for age and weight (not due to lymphoma)

- Patients with unresolved hepatitis B or C infection or known HIV positive infection

- Uncontrolled infection

- Patients with a serious depression that needed therapy within the last 5 years

- Any psychological, familial, sociological or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule

- Concomitant or previous malignancies other than basal cell or squamous cell skin
cancer, in situ cervical cancer and other cancer for which the patient has been
disease-free for at least 5 years
GenderBoth
Ages60 Years
Accepts Healthy VolunteersNo
ContactsContact: Michael Unterhalt, Dr.
+49-89-7095
Michael.Unterhalt@med.uni-muenchen.de
Location CountriesCzech Republic, Denmark, France, Germany, Italy, Netherlands, Poland

Administrative Information[ + expand ][ + ]

NCT Number NCT00209209
Other Study ID NumbersMCL2004-1
Has Data Monitoring CommitteeYes
Information Provided ByEuropean Mantle Cell Lymphoma Network
Study SponsorEuropean Mantle Cell Lymphoma Network
CollaboratorsGerman Low Grade Lymphoma Study Group
Lymphoma Study Association
HOVON - Dutch Haemato-Oncology Association
Nordic Lymphoma Group
Investigators Principal Investigator: Hanneke C. Kluin-Nelemans, PhD University Hospital Groningen, Dept. of HematologyStudy Chair: Martin Dreyling, PhD University Hospital Grosshadern/LMU, Dept. of Medicine III
Verification DateSeptember 2012

Locations[ + expand ][ + ]

General University Hospital, 1St Department of Medicine
Praha, Czech Republic, CZ-12808
Contact: Marek Trnény, MD | 0042-2-2496-2061 | trneny@cesnet.cz
Principal Investigator: Marek Trnény, MD
Recruiting
Nordic Lymphoma Group
Copenhagen, Denmark, DK-2100
Contact: Christian Geisler, MD | +45-3545-1146 | geisler@rh.dk
Principal Investigator: Christian Geisler, MD
Recruiting
Groupe D´Etudes des Lymphomes De l´Adulte (GELA)
Paris, France, F-75743
Contact: Guylène Chartier | +33-1-42499811 | Guylene.chartier@chu-stlouis.fr
Principal Investigator: Olivier Hermine, PhD
Recruiting
German Low Grade Study Group (Glsg)
Munich, Germany, D-81377
Contact: Michael Unterhalt, Dr. | +49-89-70954915 | Michael.Unterhalt@med.uni-muenchen.de
Principal Investigator: Martin Dreyling, PhD
Recruiting
Ospedale Ferratotto, Divisione Di Ematologia
Catania, Italy, I-95124
Contact: Francesco Di Raimondo, PhD | +39-095-7435911
Principal Investigator: Francesco Di Raimondo, PhD
Recruiting
HOVON - Dutch Haemato-Oncology Association (HOVON-Datacenter)
Rotterdam, Netherlands, NL-3008 AE
Contact: Christel van Hooije | +31-10-4391568
Principal Investigator: Hanneke C. Kluin-Nelemans, PhD
Recruiting
The Maria Sklodowska Memorial, Cancer Center - Inst. of Oncology
Warszawa, Poland, PL-02-781
Contact: Jan Walewski, MD | +48-22-546-2223 | walewski@coi.waw.pl
Principal Investigator: Jan Walewski, MD
Recruiting