Efficacy 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
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.
Interventional
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
First randomisation: Reduction of lymphoma mass measured by the complete remission (CR) rate
Hanneke C. Kluin-Nelemans, PhD
Principal Investigator
University Hospital Groningen, Dept. of Hematology
Germany: Federal Institute for Drugs and Medical Devices
MCL2004-1
NCT00209209
January 2004
December 2014
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