Fludarabine/Rituximab Combined With Escalating Doses of Lenalidomide in Untreated CLL
This is a trial in patients with previously untreated CLL. Eligible patients will receive Lenalidomide with a backbone of Fludarabine and Rituximab for 6 therapy cycles. Lenalidomide will be increased by dose steps of 5 mg every cycle in the absence of limiting toxicity. If limiting toxicity ensues the patients will be treated with last tolerable dose for the remainder of the 6 treatment cycles.
The first 5 patients will start with dose level 5 mg Lenalidomide and further escalating dose. After the fifth patient is included in the study, enrolment will be interrupted until this patient has finished his first treatment cycle. A safety board will evaluate the toxicities of the first 5 patients. If there are more than 2 patients experiencing a dose limiting toxicity (DLT) in the first treatment cycle, the starting dose will not be escalated and further 5 patients will be enrolled with a starting dose of 5 mg Lenalidomide. If only 2 or less patients experience a DLT in the first treatment cycle, the next 5 patients will start the treatment with 10 mg Lenalidomide.
The rational for the higher starting doses stems from the lack of tumor lysis or tumor flare toxicity in this combination on the one hand and from the observation that the very slow escalation from 2,5 mg on led to a lack of efficacy in monotherapy trials due to early progression in a relevant number of cases. The increase of the Lenalidomide dosage should result in an increased efficacy especially at the beginning and a higher cumulative dose of Lenalidomide.
The identification of patients intolerant to Lenalidomide by immunophenotyping of the T cells for validation is also part of this trial, because intolerance seems to be not dose dependent but may be caused by T cell activation. Therefore, early identification of patients intolerant to this form of modern immunochemotherapy and establishing efficient Lenalidomide based combination therapy is an important part of improvement of current CLL treatment.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Fludarabine/Rituximab Combined With Escalating Doses of Lenalidomide in Untreated Chronic Lymphocytic Leukemia (CLL) - a Dose-finding Study With Escalating Starting Dose of Lenalidomide and Concomitant Evaluation of Safety and Efficacy|
- Tolerability of escalated starting dose [ Time Frame: 12 month, 20 month ] [ Designated as safety issue: Yes ]Interim analysis after completion of cylce 1 of the first 5 patients, final analysis after last pastient last visit Metrics: Number of patients experiencing defined dose limiting toxicities during cycle 1
- Establishment of maximal tolerated dose (MTD) of Lenalidomide in combination with FR [ Time Frame: 20 month ] [ Designated as safety issue: No ]
- Time to MTD [ Time Frame: 20 month ] [ Designated as safety issue: No ]
- Safety profile of the FRL combination [ Time Frame: 20 month ] [ Designated as safety issue: No ]Analysis of occuring adverse events during the study treatment according to Common Terminology Criteria for Adverse Events (CTCAE)
- Response rates in all phases by 4-colour flow cytometric and ASO-PCR MRD analysis [ Time Frame: 20 month ] [ Designated as safety issue: No ]
- Risk factor analysis (FISH cytogenetics, CD38/ZAP-70 expression, mutation status) [ Time Frame: 20 month ] [ Designated as safety issue: No ]
- Longitudinal definition of T cell subsets (including prognostic EM T cells and Treg cells)+/- PD1 [ Time Frame: 20 month ] [ Designated as safety issue: No ]
|Study Start Date:||September 2012|
|Estimated Study Completion Date:||October 2015|
|Estimated Primary Completion Date:||September 2015 (Final data collection date for primary outcome measure)|
Lenalidomide: day 8-21 of cycle 1 and day 1-21 of cycles 2-6; Starting Dose: 5 mg (first 5 patients) and 10 mg (further 5 patients) increase Lenalidomide dose via dose levels (10)/15/20/25 mg/d every 28 days if no limiting toxicity occurs
Fludarabine: 25 mg/m2 iv d1-3 or 40 mg/m2 po d1-3; repeat every 28 days
Rituximab: 375 mg/m2 iv day 4 on cycle 1 and 500 mg/m2 iv day 1 on cycles 2-6; repeat every 28 days
Please refer to this study by its ClinicalTrials.gov identifier: NCT01703364
|Universitätsklinik für Innere Medizin Innsbruck, Klinische Abteilung für Hämatologie und Onkologie|
|Innsbruck, Tirol, Austria, 6020|
|Universitätsklinik der PMU Salzburg, Univ-Klinik für Innere Medizin III|
|Salzburg, Austria, 5020|