Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Active	60 and over	Other	MCL2004-1 NCT00209209

Trial Description

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?

Further Study Information

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.

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

Trial Contact Information

Trial Lead Organizations/Sponsors

Medizinische Universitaetsklinik I at the University of Cologne

Hanneke C. Kluin-Nelemans, PhD

Principal Investigator

Martin Dreyling, PhD

Study Chair

Michael Unterhalt, Dr.		Ph: +49-89-7095 Ext.4915
		Email: Michael.Unterhalt@med.uni-muenchen.de

Martin Dreyling, PhD		Ph: +49-89-7095 Ext.2202
		Email: Martin.Dreyling@med.uni-muenchen.de

Czech Republic
	PRAHA
		Marek Trnény, MD	Principal Investigator
	First Medical Clinic of Charles University Hospital
		Marek Trnény, MD	Ph: 0042-2-2496-2061
			Email: trneny@cesnet.cz
Denmark
	COPENHAGEN
		Christian Geisler, MD	Principal Investigator
	Nordic Lymphoma Group
		Christian Geisler, MD	Ph: +45-3545-1146
			Email: geisler@rh.dk
France
	Paris
		Olivier Hermine, PhD	Principal Investigator
		Olivier Hermine, PhD	Ph: +33-1-44 49 52 83
			Email: hermine@necker.fr
	Groupe d'Etudes de Lymphomes de L'Adulte
		Guylène Chartier	Ph: +33-1-42499811
			Email: Guylene.chartier@chu-stlouis.fr
Germany
	Munich
		Martin Dreyling, PhD	Principal Investigator
		Martin Dreyling, PhD	Ph: +49-89-7095 Ext.2202
			Email: Martin.Dreyling@med.uni-muenchen.de
	German Low Grade Lymphoma Study Group
		Michael Unterhalt, Dr.	Ph: +49-89-7095 Ext.4915
			Email: Michael.Unterhalt@med.uni-muenchen.de
Italy
	CATANIA
		Francesco Di Raimondo, PhD	Principal Investigator
	Ospedale Ferrarotto
		Francesco Di Raimondo, PhD	Ph: +39-095-7435911
Netherlands
	Rotterdam
		Hanneke C. Kluin-Nelemans, PhD	Principal Investigator
		Hanneke C. Kluin-Nelemans, PhD	Ph: +31-50-3612354
			Email: j.c.kluin.nelemans@int.azg.nl
	HOVON - Dutch Haemato-Oncology Association (HOVON-Datacenter)
		Christel van Hooije	Ph: +31-10-4391568
Poland
	WARSZAWA
	Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology - Warsaw
		Jan Walewski, MD	Ph: +48-22-546-2223
			Email: walewski@coi.waw.pl
		Marek P Nowacki, MD	Ph: +48-22-546-2223
		Jan Walewski	Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00209209
Information obtained from ClinicalTrials.gov on March 18, 2009