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

Sponsor

Ludwig-Maximilians - University of Munich (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT00317096

Collaborator

(none)

319

Enrollment

Location

Arms

271

Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Follicular Lymphoma, Low-Grade Lymphoma, Intermediate-Grade	Procedure: FCM Procedure: R-FCM Drug: rituximab maintenance Other: observation only	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

319 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Nov 1, 1998

Actual Primary Completion Date :

Jun 1, 2001

Anticipated Study Completion Date :

Jun 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: FCM 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 Active comparator: Chemotherapy
Experimental: R-FCM 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 experimental: Chemotherapy with additional rituximab
Other: Observation only 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 no Intervention after completion of FCM or R-FCM
Other: rituximab maintenance 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 2 courses of rituximab maintenance after completion of salvage therapy

Outcome Measures

Primary Outcome Measures

Remission rate []
Event free interval []

Secondary Outcome Measures

Time to Progression []
Overall survival []
adverse events []
serious infectious complications []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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