Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00003968

Trial Description

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Title

Efficacy of 6x R-CHOP Followed by Myeloablative Radiochemotherapy and Autologous Stem Cell Transplantation vs. 3 x (R-CHOP/R-DHAP) Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

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.

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Brief Summary in Scientific Language

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.

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Organizational Data

  •   DRKS00003968
  •   2012/05/10
  •   2005/09/13
  •   yes
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Secondary IDs

  •   NCT00209222  (ClinicalTrials.gov)
  •   MCL2004-2  (European Mantle Cell Lymphoma Network)
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Health Condition or Problem studied

  •   Lymphoma, Mantle-Cell
  •   C83.1 -  Non-Hodgkin's lymphoma: Small cleaved cell (diffuse)
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Interventions/Observational Groups

  •   Drug: Rituximab
  •   Drug: Cyclophosphamide
  •   Drug: Doxorubicin
  •   Drug: Vincristine
  •   Drug: Prednisone
  •   Drug: Cisplatinum
  •   Drug: Ara-C
  •   Drug: Dexamethasone
  •   Drug: BCNU
  •   Drug: Melphalan
  •   Drug: Etoposide
  •   Drug: G-CSF
  •   Procedure: chemotherapy: R-CHOP
  •   Procedure: chemotherapy: R-DHAP
  •   Procedure: chemotherapy: Dexa-BEAM
  •   Procedure: stem cell harvest
  •   Procedure: total body irradiation
  •   Procedure: high-dose chemotherapy: Cyclophosphamide
  •   Procedure: high-dose chemotherapy: Ara-C /Melphalan
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   III
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Primary Outcome

- time to treatment failure after start of therapy

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Secondary Outcome

- complete remission (CR) rate
- overall survival
- progression-free survival
- adverse events
- serious infectious complications

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Countries of Recruitment

  •   France
  •   Germany
  •   Poland
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Locations of Recruitment

  •  
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Recruitment

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  •   2004/07/31
  •   360
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   65   Years
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Additional 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

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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

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Addresses

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    • European Mantle Cell Lymphoma Network
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    •   [---]*
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    • University Hospital Necker, Dept. of Adult Hematology
    • Olivier Hermine, PhD 
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    • Michael Unterhalt, Dr. 
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Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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    •   [---]*
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

  •   Dreyling M, Lenz G, Hoster E, Van Hoof A, Gisselbrecht C, Schmits R, Metzner B, Truemper L, Reiser M, Steinhauer H, Boiron JM, Boogaerts MA, Aldaoud A, Silingardi V, Kluin-Nelemans HC, Hasford J, Parwaresch R, Unterhalt M, Hiddemann W. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005 Apr 1;105(7):2677-84. Epub 2004 Dec 9.; 15591112
  •   Lenz G, Dreyling M, Hoster E, Wormann B, Duhrsen U, Metzner B, Eimermacher H, Neubauer A, Wandt H, Steinhauer H, Martin S, Heidemann E, Aldaoud A, Parwaresch R, Hasford J, Unterhalt M, Hiddemann W. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005 Mar 20;23(9):1984-92. Epub 2005 Jan 24.; 15668467
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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   120
  •   2013/10/30
* This entry means the parameter is not applicable or has not been set.