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

European Mantle Cell Lymphoma Network

Status and phase: Unknown; Phase 3

Conditions: Lymphoma, Mantle-Cell

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

Study type: Interventional

Funder types: Other

Identifiers

NCT00209222

MCL2004-2

Details and patient eligibility

About

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.

Full 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.

Enrollment: 360 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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 design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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360 participants in 2 patient groups

1

Active Comparator group

Description:

induction: R-CHOP consoldiation : TBI/Cyclo

Treatment:

Procedure: stem cell harvest

Procedure: chemotherapy: Dexa-BEAM

Drug: BCNU

Drug: Doxorubicin

Procedure: chemotherapy: R-CHOP

Procedure: total body irradiation

Drug: Cyclophosphamide

Drug: G-CSF

Drug: Etoposide

Drug: Melphalan

Procedure: high-dose chemotherapy: Cyclophosphamide

Drug: Prednisone

Drug: Vincristine

Drug: Rituximab

2

Experimental group

Description:

induction: R-CHOP/DHAP consolditaion: TBI/TAM

Treatment:

Procedure: high-dose chemotherapy: Ara-C /Melphalan

Procedure: stem cell harvest

Drug: Cisplatinum

Drug: Dexamethasone

Procedure: chemotherapy: R-DHAP

Drug: Doxorubicin

Procedure: chemotherapy: R-CHOP

Procedure: total body irradiation

Drug: Ara-C

Drug: Cyclophosphamide

Drug: G-CSF

Drug: Melphalan

Drug: Prednisone

Drug: Vincristine

Drug: Rituximab