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	18 to 65	Other	MCL2004-2 NCT00209222

Trial Description

Summary

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.

Further Study Information

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 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

Trial Contact Information

Trial Lead Organizations/Sponsors

Medizinische Universitaetsklinik I at the University of Cologne

Olivier Hermine, PhD

Principal Investigator

Wolfgang Hiddemann, 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

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
		Wolfgang Hiddemann	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
Poland
	Warszawa
		Jan Walewski	Principal Investigator
		Marek P Nowacki, MD	Ph: +48-22-546-2223
	Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology - Warsaw
		Jan Walewski, MD	Ph: +48-22-546-2223
			Email: walewski@coi.waw.pl

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00209222
Information obtained from ClinicalTrials.gov on March 18, 2009