Intensified Rituimab Prephase Before FCR in Untreated B-CLL

Study Overview
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Brief Summary
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Phase II, multicenter, randomized trial, exploring intensified Rituximab prephase monotherapy before standard Fludarabine-Cyclophosphamide-Rituximab FC-R regimen in previously untreated symptomatic B-cell chronic lymphocytic leukemia CLL. A Study from the Goelams GCFLLCMW intergroup

Detailed Description
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Young fit medically B Cell untreated patients Comparison between FCR treatment = 6 FCR cycles and a the addition of a prephase with R Dense treatment before the 6 FCR cycles.

Official Title
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Phase II Multicentric, Randomized Trial, Exploring Intensified Rituximab Prephase Monotherapy Before Standard Fludarabine-Cyclophosphamide-Rituximab Regimen in Previously Untreated Symptomatic B-cell Chronic Lymphocytic Leukemia

Conditions
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B-cell Chronic Lymphocytic Leukemia CLL

Intervention / Treatment
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* Drug: Rituximab
* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patient information and written informed consent 18 years < Age < 66 ans confirmed B-CLL Matutes score 4 or 5 Binet stage C or Binet stage A and B with active disease could be considered for inclusion. For stage A with active disease an agreement of investigator coordinator is required. no prior treatment except steroids for less than 1 month (detail corticoid) No 17p deletion as assessed by FISH < 10 % positive nuclei Performance status ECOG < 2 CIRS Cumulative Illness Rating Scale < 6 Exclusion criteria: Binet stage A without active disease according to IWCLL 2008 criteria Know HIV seropositivity Hepatitis B or C seropositivity unless clearly due to vaccination Life expectancy < 6 months Clinically significant auto-immune anemia Active second malignancy currently requiring treatment (except basal cell carcinoma in situ endometrial carcinoma and incidental prostate carcinoma) and/or less than 5 years CR after breast cancer Any severe co-morbid conditions such as Class III or IV heart failure, myocardial infarction within 6 months, unstable angina, ventricular tachyarythmias requiring ongoing treatment, severe chronic obstructive pulmonary disease with hypoxemia, uncontrolled diabetes mellitus, or uncontrolled hypertension Concomitant disease requiring prolonged use of corticosteroids > 1 month Known hypersensitivity with anaphylactic reaction to humanized monoclonal antibodies or any of the study drugs According to the SmPC or investigator practice Contraindication to use of Rituximab Transformation to aggressive B-cell malignancy e.g. diffuse large cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukaemia Active bacterial, viral or fungal infection Abnormal renal function with creatinine clearance < 60 ml/min calculated according to the Cockcroft and Gault formula Total bilirubin, gamma glutamyltransferase or transaminase levels > 2.5 ULN. Any coexisting medical or psychological condition that would preclude participation in the required study procedures Patient with mental deficiency preventing proper understanding of the requirements of treatment. Pregnant or breastfeeding women. Adult under law-control Fertile male and female patients who cannot or do not wish to use an effective method of contraception, during and for 12 months after the final treatment used for the purposes of the study. No afiliate to social security

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Standard R-FC arm<br>Standard R-FC arm 6 cycles every 28 days Cycle 1: Rituximab : 375 mg/m² i.v on day 1 Fludarabine : 40 mg/m² per os, days 2-4, repeated every 28 days Cyclophosphamide : 250 mg/m² per os, days 2-4, repeated every 28 days For patients with Leucocyte count > 25* G/L : rituximab in two equal doses at D1, D2 Cycle 2-6: Rituximab: 500 mg/m² i.v on day 1, repeated every 28 days Fludarabine : 40 mg/m² per os, days 2-4, repeated every 28 days Cyclophosphamide : 250 mg/m² per os, days 2-4, repeated every 28 days | Drug: Rituximab<br>* Cycle 1 Rituximab : 375 mg/m² i.v on day 1 Cycle 2-6 Rituximab:500 mg/m² i.v on day 1, repeated every 28 days<br>* Other names: R;Drug: Cyclophosphamide<br>* •FCR Cycle 1-6: Cyclophosphamide : 250 mg/m² per os, days 2-4, repeated every 28 days<br>* Other names: C;Drug: Fludarabine<br>* FCR Cycle 1-6: Fludarabine :40 mg/m² per os, days 2-4, repeated every 28 days<br>* Other names: F;|
| Experimental: DenseR-FC arm<br>DenseR-FC arm =1 prephase R Dense course +6 R-FC courses Prephase: - Rituximab: 500 mg on day 0, 2000 mg on days 1, 8, and D15 For patients with Leucocyte count > 25* G/L : rituximab 250 mg D-1, D0 prephase Cycle 1-6 (cycle 1 beginning at D22): Rituximab: 500 mg/m2 i.v on day 1, repeated every 28 days Fludarabine : 40 mg/m² per os, days 2-4, repeated every 28 days Cyclophosphamide : 250 mg/m² per os, days 2-4, repeated every 28 days | Drug: Rituximab<br>* Prephase: Rituximab:500 mg on day 0, 2000 mg on days 1, 8, and D15 Cycle 1-6 cycle 1 beginning at D22: Rituximab: 500 mg/m2 i.v on day 1, repeated every 28 days<br>* Other names: R;Drug: Cyclophosphamide<br>* •FCR Cycle 1-6: Cyclophosphamide : 250 mg/m² per os, days 2-4, repeated every 28 days<br>* Other names: C;Drug: Fludarabine<br>* FCR Cycle 1-6: Fludarabine :40 mg/m² per os, days 2-4, repeated every 28 days<br>* Other names: F;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complete response rates according to IWCLL 2008 guidelines with undetectable minimal residual disease | CR MRD negative rate at 9 months = treatment evaluation surveillance of cumulative toxicities of high dose rituximab | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine and compare the progression free survival PFS |  | 3 years | 
| evaluate the immunophenotypic response rate after high dose Rituximab alone prephase in DenseR-FC | Treatment evaluation | 9 months | 
| To evaluate FcyRs polymorphisms influence on clinical response | R Dense arm treatment evaluation | 9 months | 
| To determine the pharmacokinetics of rituximab and determine the PK-PD relationship of rituximab based on biomarkers. |  | 12 months | 
| To evaluate the safety profile of higher doses of rituximab | 5 months treatment and 36 months follow up | 41 | 
| To determine the event-free survival EFS |  | 3 years | 
| To determine and compare the disease-free survival DFS |  | 3 years | 
| To determine the overall survival OS |  | 3 years | 
| To determine the time to next treatment TTNT |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B CLL, Fist line treatment