Randomized Trial of Chlorambucil Versus Chlorambucil Plus Rituximab Versus Rituximab in MALT Lymphoma

Study Overview
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Brief Summary
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Assess the therapeutic activity and safety of the combination of Chlorambucil and Rituximab in MALT lymphomas and determine whether the addition of Rituximab to Chlorambucil will improve the outcome of MALT lymphoma in comparison to treatment with Chlorambucil alone. In April 2006, a third arm of treatment was added to compare the antitumor activity and safety of rituximab alone vs chlorambucil alone

Official Title
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Multicenter Randomized Trial of Chlorambucil Versus Chlorambucil Plus Rituximab Versus Rituximab in Extranodal Marginal Zone B-cell Lymphoma of Mucosa Associated Lymphoid Tissue (MALT Lymphoma)

Conditions
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Lymphoma, Mucosa-Associated Lymphoid Tissue

Intervention / Treatment
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* Drug: chlorambucil (drug)
* Drug: rituximab+chlorambucil
* Drug: rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: histologically proven diagnosis of CD20-positive marginal zone B-cell lymphoma of MALT type arisen at any extranodal site any stage (Ann Arbor I-IV) either de novo, or relapsed disease following local therapy (including surgery, radiotherapy and antibiotics for H. pylori-positive gastric lymphoma) no evidence of histologic transformation to a high grade lymphoma measurable or evaluable disease age > 18 life expectancy of at least 1 year ECOG performance status 0-2 no prior diagnosis of neoplasm within 5 years, except cervical intraepithelial neoplasia type 1 (CIN1) or localized non-melanomatous skin cancer no prior chemotherapy no prior immunotherapy with any anti-CD20 monoclonal antibody no prior radiotherapy in the last 6 weeks no corticosteroids during the last 28 days, unless prednisone chronically administered at a dose <20 mg/day for indications other than lymphoma or lymphoma-related symptoms no evidence of clinically significant cardiac disease, as defined by history of symptomatic ventricular arrhythmias, congestive heart failure or myocardial infarction within 12 months before study entry no evidence of symptomatic central nervous system (CNS) disease no impairment of bone marrow function (WBC >3.0x109/L, ANC >1.5x109/L, PLT >100x109/L), unless due to lymphoma involvement no major impairment of renal function (serum creatinine <1,5x upper normal) or liver function (ASAT/ALAT <2,5 upper normal, total bilirubin <2,5x upper normal), unless due to lymphoma involvement no evidence of active opportunistic infections no known HIV infection no active HBV and/or HCV infection no pregnant or lactating status appropriate contraceptive method in women of childbearing potential or men absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial informed consent must be given according to national/local regulations before randomization

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ARM A<br>chlorambucil 6 mg/m2 daily during the first 6 weeks of treatment; two weeks rest; chlorambucil 6 mg/m2 daily during the first two of a four weeks cycles (total of 4 cycles) | Drug: chlorambucil (drug)<br>* chlorambucil 6 mg/m2 daily during the first 6 weeks of treatment, two weeks rest, chlorambucil 6 mg/m2 daily during the first two of a four weeks cycles (total of 4 cycles)<br>|
| Experimental: ARM B<br>rituximab 375 mg/m2 iv, d1, d8, d15, d22 chlorambucil 6 mg/m2 os, daily during the first 6 weeks of treatment two weeks rest chlorambucil 6 mg/m2 os daily during the first two of a four weeks cycles (total of 4 cycles) rituximab 375 mg/m2 iv at day 1 of each cycle | Drug: rituximab+chlorambucil<br>* rituximab 375 mg/m2 iv, d1, 8, 15, 22, chlorambucil 6 mg/m2 os, daily during the first 6 weeks of treatment, ; two weeks rest; chlorambucil 6 mg/m2 os, daily during the first two of a four weeks cycles (total of 4 cycles) rituximab 375 mg/m2 iv at day 1 of each cycle<br>|
| Experimental: ARM C (Since April 2006)<br>rituximab 375 mg/m2 iv on days 1, 8, 15, 22, 56, 84, 112, 140 | Drug: rituximab<br>* rituximab 375 mg/m2 iv on days 1, 8, 15, 22, 56, 84, 112, 140<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free-survival (EFS) | Percentage of patients without events (failure of treatment or Death from any cause) after 5 years from trial registration | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete and Partial Remission Rate - Percentage of Patients With Complete and Partial Response at the End of Treatment | Response criteria were defined according to the NCI standardized response criteria for non-Hodgkin's lymphoma. Complete response. Disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms, if present before therapy, and normalization of those biochemical abnormalities definitely assignable to NHL. Regression of all lymph nodes and nodal masses to normal (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm before therapy and to ≤ 1 cm for nodes that were 1.1-1.5 cm. Regression by more than 75% in the sum of the products of the greatest diameters). Partial response. Decrease by at least 50% in SPD of the six largest measurable lesions. It is not necessary for all lesions to have regressed to qualify for partial response, but no lesion should have progressed and no new lesion should appear. For primary gastric sites, response was based on GELA histologic grading system. | End of treatment (after 24 weeks of therapy) | 
| Response Duration (Time to Relapse or Progression) - Percentage of Patients in Continuous Remission at Five Years From Trial Registration | Response criteria were defined according to the NCI standardized response criteria for non-Hodgkin's lymphoma. Complete response (CR). Disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms, if present before therapy, and normalization of those biochemical abnormalities definitely assignable to NHL. Regression of all lymph nodes and nodal masses to normal (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm before therapy and to ≤ 1 cm for nodes that were 1.1-1.5 cm. Regression by more than 75% in the sum of the products of the greatest diameters). | 5 years | 
| Progression-free-survival (PFS) | Percentage of patients without disease progression after 5 years from trial registration | 5 years | 
| Overall Survival | Percentage of patients alive after 5 years from trial registration | 5 years |