Know Cancer

forgot password

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

Phase 3
60 Years
Open (Enrolling)
Lymphoma, Mantle-Cell

Thank you

Trial Information

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

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.

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

- 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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

First randomisation: Reduction of lymphoma mass measured by the complete remission (CR) rate

Principal Investigator

Hanneke C. Kluin-Nelemans, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University Hospital Groningen, Dept. of Hematology


Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

January 2004

Completion Date:

December 2014

Related Keywords:

  • Lymphoma, Mantle-cell
  • Lymphoma, Mantle-Cell
  • Elderly patients
  • Chemotherapy
  • Maintenance therapy
  • C04.557.386.480.300.725.500
  • C15.604.515.569.480.300.725.500
  • C20.683.515.761.480.300.725.500
  • Lymphoma
  • Lymphoma, Mantle-Cell