Efficacy of R-CHOP vs R-CHOP/R-DHAP in Untreated MCL

• ClinicalTrials.gov Identifier: NCT00209222
• Recruitment Status: Unknown
• First Posted: September 21, 2005
• Last Update Posted: September 10, 2012
• Sponsor: European Mantle Cell Lymphoma Network
• Collaborators: German Low Grade Lymphoma Study Group; Lymphoma Study Association
• Information provided by: European Mantle Cell Lymphoma Network

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Lymphoma, Mantle-Cell	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	Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 360 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Study Start Date: July 2004
• Estimated Primary Completion Date: December 2014
• Estimated Study Completion Date: December 2014

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: 1; induction: R-CHOP consoldiation : TBI/Cyclo	Drug: Rituximab; antibody; Drug: Cyclophosphamide; chemotherapy; Drug: Doxorubicin; chemotherapy; Drug: Vincristine; chemotherapy; Drug: Prednisone; corticosteroide; Drug: BCNU; chemotherapy; Drug: Melphalan; chemotherapy; Drug: Etoposide; chemotherapy; Drug: G-CSF; growth factor; Procedure: chemotherapy: R-CHOP; immuno-chemotherapy; Procedure: chemotherapy: Dexa-BEAM; chemotherapy; Procedure: stem cell harvest; procedure; Procedure: total body irradiation; radiation; Procedure: high-dose chemotherapy: Cyclophosphamide; chemotherapy
Experimental: 2; induction: R-CHOP/DHAP consolditaion: TBI/TAM	Drug: Rituximab; antibody; Drug: Cyclophosphamide; chemotherapy; Drug: Doxorubicin; chemotherapy; Drug: Vincristine; chemotherapy; Drug: Prednisone; corticosteroide; Drug: Cisplatinum; chemotherapy; Drug: Ara-C; chemotherapy; Drug: Dexamethasone; corticosteroide; Drug: Melphalan; chemotherapy; Drug: G-CSF; growth factor; Procedure: chemotherapy: R-CHOP; immuno-chemotherapy; Procedure: chemotherapy: R-DHAP; immuno-chemotherapy; Procedure: stem cell harvest; procedure; Procedure: total body irradiation; radiation; Procedure: high-dose chemotherapy: Ara-C /Melphalan; chemotherapy

Outcome Measures

Primary Outcome Measures :

1. time to treatment failure after start of therapy

Secondary Outcome Measures :

1. complete remission (CR) rate
2. overall survival
3. progression-free survival
4. adverse events
5. serious infectious complications

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Michael Unterhalt, Dr.; +49-89-7095 ext 4915; Michael.Unterhalt@med.uni-muenchen.de

Contact: Martin Dreyling, PhD; +49-89-7095 ext 2202; Martin.Dreyling@med.uni-muenchen.de

Locations

France

Groupe D´Etudes des Lymphomes De l´Adulte (GELA); Recruiting

Paris, France, F-75743

Contact: Guylène Chartier +33-1-42499811 Guylene.chartier@chu-stlouis.fr

Contact: Olivier Hermine, PhD +33-1-44 49 52 83 hermine@necker.fr

Principal Investigator: Olivier Hermine, PhD

Germany

German Low Grade Study Group (Glsg); Recruiting

Munich, Germany, D-81377

Contact: Michael Unterhalt, Dr. +49-89-7095 ext 4915 Michael.Unterhalt@med.uni-muenchen.de

Contact: Martin Dreyling, PhD +49-89-7095 ext 2202 Martin.Dreyling@med.uni-muenchen.de

Principal Investigator: Wolfgang Hiddemann, PhD

Poland

The Maria Sklodowska Memorial, Cancer Center - Inst. of Oncology; Recruiting

Warszawa, Poland, PL-02-781

Contact: Jan Walewski, MD +48-22-546-2223 walewski@coi.waw.pl

Contact: Marek P Nowacki, MD +48-22-546-2223

Principal Investigator: Jan Walewski, MD

Sponsors and Collaborators

European Mantle Cell Lymphoma Network

German Low Grade Lymphoma Study Group

Lymphoma Study Association

Investigators

• Principal Investigator: Olivier Hermine, PhD; University Hospital Necker, Dept. of Adult Hematology
• Study Chair: Wolfgang Hiddemann, PhD; University Hospital Großhadern/LMU, Dept. of Medicine III

More Information

Publications:

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. doi: 10.1182/blood-2004-10-3883. Epub 2004 Dec 9.

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. doi: 10.1200/JCO.2005.08.133. Epub 2005 Jan 24.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hermine O, Hoster E, Walewski J, Bosly A, Stilgenbauer S, Thieblemont C, Szymczyk M, Bouabdallah R, Kneba M, Hallek M, Salles G, Feugier P, Ribrag V, Birkmann J, Forstpointner R, Haioun C, Hanel M, Casasnovas RO, Finke J, Peter N, Bouabdallah K, Sebban C, Fischer T, Duhrsen U, Metzner B, Maschmeyer G, Kanz L, Schmidt C, Delarue R, Brousse N, Klapper W, Macintyre E, Delfau-Larue MH, Pott C, Hiddemann W, Unterhalt M, Dreyling M; European Mantle Cell Lymphoma Network. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016 Aug 6;388(10044):565-75. doi: 10.1016/S0140-6736(16)00739-X. Epub 2016 Jun 14.

Delfau-Larue MH, Klapper W, Berger F, Jardin F, Briere J, Salles G, Casasnovas O, Feugier P, Haioun C, Ribrag V, Thieblemont C, Unterhalt M, Dreyling M, Macintyre E, Pott C, Hermine O, Hoster E; European Mantle Cell Lymphoma Network. High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. Blood. 2015 Jul 30;126(5):604-11. doi: 10.1182/blood-2015-02-628792. Epub 2015 May 28.

Hoster E, Klapper W, Hermine O, Kluin-Nelemans HC, Walewski J, van Hoof A, Trneny M, Geisler CH, Di Raimondo F, Szymczyk M, Stilgenbauer S, Thieblemont C, Hallek M, Forstpointner R, Pott C, Ribrag V, Doorduijn J, Hiddemann W, Dreyling MH, Unterhalt M. Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network. J Clin Oncol. 2014 May 1;32(13):1338-46. doi: 10.1200/JCO.2013.52.2466. Epub 2014 Mar 31.

Pott C, Hoster E, Delfau-Larue MH, Beldjord K, Bottcher S, Asnafi V, Plonquet A, Siebert R, Callet-Bauchu E, Andersen N, van Dongen JJ, Klapper W, Berger F, Ribrag V, van Hoof AL, Trneny M, Walewski J, Dreger P, Unterhalt M, Hiddemann W, Kneba M, Kluin-Nelemans HC, Hermine O, Macintyre E, Dreyling M. Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study. Blood. 2010 Apr 22;115(16):3215-23. doi: 10.1182/blood-2009-06-230250. Epub 2009 Dec 23.

• Responsible Party: Prof Dr. Martin Dreyling, University Hospital Grosshadern/European MCLNetwork
• ClinicalTrials.gov Identifier: NCT00209222
• Other Study ID Numbers: MCL2004-2
• First Posted: September 21, 2005
• Last Update Posted: September 10, 2012
• Last Verified: July 2009

Keywords provided by European Mantle Cell Lymphoma Network:

Lymphoma, Mantle-Cell; younger patients; chemotherapy; high dose therapy; C04.557.386.480.300.725.500; C15.604.515.569.480.300.725.500; C20.683.515.761.480.300.725.500

Additional relevant MeSH terms:

Lymphoma, Mantle-Cell; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Cytarabine; Dexamethasone; Prednisone; Cyclophosphamide; Melphalan; Rituximab; Doxorubicin; Etoposide; Vincristine; Cisplatin; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Anti-Inflammatory Agents