FCM Versus R-FCM Followed by R-Maintenance or Observation Only

Study Overview
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Brief Summary
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The aim of this phase III trial is to assess the safety and efficacy of treatment with rituximab in combination with FCM chemotherapy (R-FCM) versus FCM chemotherapy alone for remission induction and to asses the safety and efficacy of rituximab maintenance versus observation only after response to induction therapy. Both questions are addressed in way of a prospective randomized comparison in patients with relapsed FL, MCL and LP lymphoma.

Detailed Description
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Patients with relapsed centroblastic/centrocytic (FL), centrocytic (MCL)or lymphoplasmacytoid lymphoma are randomly assigned to either FCM chemotherapy alone or to FCM chemotherapy in combination with the monoclonal anti-CD20 antibody rituximab (R-FCM). FCM chemotherapy will be given for 4 cycles in intervals of 4 weeks. In patients assigned to cytoreductive therapy with FCM plus rituximab, the monoclonal antibody is given as one infusion (375 mg/m2) on the day before the respective FCM course for a total of four applications. Four weeks after the end of FCM chemotherapy patients with CR or PR are randomly assigned to either no further treatment or maintenance therapy with rituximab. Rituximab will be given 4 times (one infusion per week with 375 mg/m2). After six months rituximab treatment will be repeated with another 4 infusions. In case of relapse patients will receive an alternative treatment according to the decision of the investigator. The aim of this phase III trial is to assess the safety and efficacy of treatment with rituximab in combination with FCM chemotherapy versus FCM chemotherapy alone for remission induction and to asses the safety and efficacy of rituximab maintenance versus observation only after response to induction therapy. Both questions are addressed in way of a prospective randomized comparison in patients with relapsed FCL, MCL and LP lymphoma. Primary objectives of this trial are to compare (1) the remission rates (CR and PR) achieved after FCM plus rituximab versus FCM alone and (2) the progression free interval of rituximab maintenance versus observation only.

Official Title
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Treatment of Relapsed CBCC, CC and LPIC Lymphoma With FCM Chemotherapy Alone or in Combination With the Monoclonal Anti CD 20 Antibody Rituximab Followed by Anti-CD 20 Maintenance or Observation Only

Conditions
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Lymphoma, Follicular, Lymphoma, Low-Grade, Lymphoma, Intermediate-Grade

Intervention / Treatment
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* Procedure: FCM
* Procedure: R-FCM
* Drug: rituximab maintenance
* Other: observation only


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria patients with histologically proven stage III/IV centroblastic/centrocytic (FL), centrocytic (MCL)or lymphoplasmacytoid lymphoma (LPIC). relapsed disease after initial chemotherapy or peripheral blood stem cell transplantation two-dimensionally measurable lesion outside a previously irradiated area (osteoblastic bone lesions, ascites, and pleural effusions are not evaluable) age > 18 years Karnofsky-index > 60 life expectancy of at least 3 months effective contraception in female premenopausal patients patient's written informed consent Exclusion Criteria: age < 18 years Karnofsky-index < 60 treatment with fludarabine or mitoxantrone within the preceding three months active auto-immune hemolytic anemia at the start of FCM chemotherapy participation in another clinical trial during the last 4 weeks participation in this study before previous treatment with murine antibodies concurrent diseases which exclude the administration of therapy as outlined by the study protocol non-compensated heart failure dilatative cardiomyopathy coronary heart disease with ST segment depression in ECG myocardial infarction during the last 6 months chronic lung disease with hypoxemia severe non-compensated hypertension severe non-compensated diabetes mellitus renal insufficiency (creatinine > 2.0 mg/dl), not related to lymphoma hepatic insufficiency with transaminase values greater than 3-fold of normal values and/or bilirubin levels > 2.0 mg/dl, not related to lymphoma clinical signs of cerebral dysfunction women during lactation or pregnancy or of childbearing potential not using a reliable contraceptive method severe psychiatric disease serological positivity for HBV, HCV, HIV previous organ transplantation other than autologous peripheral blood stem cell transplantation missing written informed consent or missing written consent for data protection

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: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: FCM<br>All patients underwent a central randomization procedure. Randomization was done by a Computer program stratified for histology, Response to the preceding chemotherapy, and the number of previous chemotherapies using the method of permutuated blocks. The FCM combination comprised: 25 mg/m2 fludarabine per day iv over 30 minutes, days 1 to 3 200 mg/m2 cyclophosphamide per day as a 4-hour-infusion, days 1 to 3 8 mg/m2 mitoxantrone per day iv over 30 minutes, day 1 4 treatment Cycles á 4 weeks per cycle In patients with peripheral lymphocyte Counts more than 20.000/mm3 and/or a large Tumor mass (ie, bulky disease more than 10 cm) a cytoreductive pre-phase could be performed, comprising cyclophosphamide at a dose of 200 mg/m2 as a 1-hour-infusion over 3 to 5 days. | Procedure: FCM<br>* Active comparator: Chemotherapy<br>|
| Experimental: R-FCM<br>All patients underwent a central randomization procedure. Randomization was done by a Computer program stratified for histology, Response to the preceding chemotherapy, and the number of previous chemotherapies using the method of permutuated blocks. The R-FCM combination comprised: 375 mg/m2 rituximab on the day before the respective FCM course. 25 mg/m2 fludarabine per day iv over 30 minutes, days 1 to 3 200 mg/m2 cyclophosphamide per day as a 4-hour-infusion, days 1 to 3 8 mg/m2 mitoxantrone per day iv over 30 minutes, day 1 4 treatment Cycles á 4 weeks per cycle In patients with peripheral lymphocyte Counts more than 20.000/mm3 and/or a large Tumor mass (ie, bulky disease more than 10 cm) a cytoreductive pre-phase could be performed, comprising cyclophosphamide at a dose of 200 mg/m2 as a 1-hour-infusion over 3 to 5 days. | Procedure: R-FCM<br>* experimental: Chemotherapy with additional rituximab<br>|
| Other: Observation only<br>Patients achieving a complete or partial remission after FCM or R-FCM underwent a subsequent randomization for 2 courses of rituximab to be given 3 and 6 months after completion of salvage therapy versus observation only. This second randomization was stratified for the type of salvage therapy with FCM or R-FCM, the Response to this Treatment (CR or PR), and histology. | Other: observation only<br>* no Intervention after completion of FCM or R-FCM<br>|
| Other: rituximab maintenance<br>Patients achieving a complete or partial remission after FCM or R-FCM underwent a subsequent randomization for 2 courses of rituximab to be given 3 and 6 months after completion of salvage therapy versus observation only. Courses of rituximab consisted of 4 doses of 375 mg/m2 per day given at 4 consecutive weeks. This second randomization was stratified for the type of salvage therapy with FCM or R-FCM, the Response to this Treatment (CR or PR), and histology. | Drug: rituximab maintenance<br>* 2 courses of rituximab maintenance after completion of salvage therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission rate |  |  | 
| Event free interval |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression |  |  | 
| Overall survival |  |  | 
| adverse events |  |  | 
| serious infectious complications |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy, Maintenance, rituximab