Lenalidomide Dose Escalation Combined With Rituximab/Fludarabine in Untreated CLL

Study Overview
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Brief Summary
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The aim of this study is to determine the maximal tolerated dose level of lenalidomide combined with fludarabine/rituximab in the therapy of patients with previously untreated CD20-positive chronic lymphocytic leukemia. Following a dose escalation phase lenalidomide will be given at the pre-determined maximum tolerated dose in combination with rituximab to further determine the efficacy and tolerability of this regimen.

Detailed Description
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This is a non-randomized, multicenter, open-label, single-arm Phase I/II study in patients with previously untreated CD20-positive CLL. Phase I of the study will evaluate the maximal tolerated lenalidomide dose level in combination with fludarabine/rituximab chemoimmunotherapy in 10 patients. Phase II will determine efficacy using the combination in the previously defined maximal tolerated dose. Both phases will be followed by a maintenance phase evaluating the tolerability and possibility to further improve response quality.

Official Title
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Fludarabine/Rituximab Combined With Escalating Doses of Lenalidomide Followed by Rituximab/Lenalidomide in Untreated Chronic Lymphocytic Leukemia (CLL) - a Dose-finding Study With Concomitant Evaluation of Safety and Efficacy.

Conditions
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Leukemia, Lymphocytic, Chronic, B-Cell

Intervention / Treatment
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* Drug: Lenalidomide
* Drug: Fludarabine
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: B-CLL (CD23+, CD5+, CD19+, CD20+) Treatment indication according to NCI criteria Age >= 18 yrs No previous treatment of CLL by chemo-, radio- or immunotherapy Life expectancy > 6 months Written informed consent Women of non-childbearing potential or women of childbearing potential and men using effective contraception Exclusion Criteria: Active bacterial, viral or fungal infection Positivity for HIV, Hepatitis B or C Reduce organ functions and bone marrow dysfunction not due to CLL Creatinine clearance below 30 ml/min Patients with medical conditions requiring long-term use of systemic corticosteroids during study treatment Patients with a history of severe cardiac disease Other known co-morbidity with the potential to dominate survival Transformation to aggressive B-cell malignancy Known hypersensitivity to humanised monoclonal antibodies or any of the study drugs Pregnant or breast-feeding women Any co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Lenalidomide Dose Escalation combined with Fludarabine/Rituximab followed by maximum tolerated lenalidomide dose/Rituximab maintenance therapy | Drug: Lenalidomide<br>* Dose escalation stage: starting dose 2.5mg/d, dose escalation via 5/10/15/20/25 mg/d every 28 days if no dose-limiting toxicity. During maintenance stage dosing on days 1-28 for max. 6 months at maximum tolerated dose reached during dose escalation stage.<br>* Other names: Revlimid;Drug: Fludarabine<br>* 25 mg/m2 i.v. d1-3 or 40 mg/m2 po d1-3 every 28 days for 6 cycles during dose escalation stage.<br>* Other names: Fludarabine phosphate;Biological: Rituximab<br>* Dose escalation stage: 375 mg/m2 i.v. d4 Cycle 1, 500 mg/m2 i.v. d1 Cycles 2-6. Maintenance stage: 375 mg/m2 i.v. at 2/4/6 months after end of escalation stage.<br>* Other names: MabThera;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lenalidomide Maximum Tolerated Dose |  | Dose escalation stage | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety profile of Lenalidomide/Fludarabine/Rituximab treatment |  | Study Duration | 
| Safety Profile of Lenalidomide/Rituximab |  | Study duration | 
| Response rate for Lenalidomide/Fludarabine/Rituximab combination treatment |  | Dose escalation stage | 
| Response rate for Lenalidomide/Rituximab combination therapy |  | Study Duration | 
| Response rate by 4-colour flow cytometric MRD analysis |  | Study Duration | 
| Changes in Quality of Life scores |  | Study Duration | 
| Risk factors and clonal evolution |  | Study Duration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLL, untreated, immune therapy, dose escalation, maximum tolerated dose, maintenance therapy, Lenalidomide, Rituximab, Fludarabine