Chlorambucil + Lenalidomide and Lenalidomide Maintenance in Untreated Elderly With Chronic Lymphocytic Leukemia (CLL)
This is a phase I-II multicenter, open label study in previously untreated and elderly patients (> 60 years) with CLL ,which includes 2 sections:
Induction phase with Chlorambucil and Lenalidomide (CL):
- Phase 1: a non-comparative phase aimed at defining the MTD of lenalidomide given in combination with chlorambucil and the efficacy and safety of the lenalidomide and chlorambucil combination;
- Phase 2: a non-comparative phase aimed at defining the overall response rate of lenalidomide given at the MTD in combination with chlorambucil.
Maintenance versus clinical observation:
-A comparative phase including lenalidomide or clinical observation aimed at defining the benefit of lenalidomide given as maintenance therapy.
Chronic Lymphocytic Leukemia
Drug: Lenalidomide; Chlorambucil
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
|Official Title:||Phase I-II Multicenter Study to Assess the Efficacy and Safety of the Chlorambucil + Lenalidomide Combination and Lenalidomide Maintenance Therapy in Untreated Elderly Pts With CLL. EudraCT Number 2009-013415-35|
- PhI: MTD of Lenalidomide given in combination with Chlorambucil. [ Time Frame: At maximum 8 months from induction therapy start ] [ Designated as safety issue: Yes ]PhI: MTD will be identified according to all adverse events and DLTs tabulated for each dose level.
- PhII: To evaluate the overall response rate of an induction therapy consisting of Lenalidomide given at the MTD in combination with Chlorambucil. [ Time Frame: At the end of the study. ] [ Designated as safety issue: No ]
- Lenalidomide and chlorambucil induction therapy in terms of safety; [ Time Frame: After 20 months therapy and 18-60 months follow-up ] [ Designated as safety issue: Yes ]Induction phase with chlorambucil and Lenalidomide in terms of safety [type, frequency, and severity of adverse events (AEs)].
- Post-remissional phase with Lenalidomide in terms of safety [ Time Frame: After 20 months therapy and 18-60 months follow-up ] [ Designated as safety issue: Yes ]type, frequency, and severity of adverse events (AEs)
- Lenalidomide maintenance efficacy in terms of CR rate. [ Time Frame: After 20 months therapy and 18-60 months follow-up ] [ Designated as safety issue: No ]
- Progression free survival estimation according to the post-remissional approach. lenalidomide maintenance therapy or clinical observation. [ Time Frame: After 20 months therapy and 18-60 months follow-up starting from date of randomization in the maintenance therapy. ] [ Designated as safety issue: No ]
- Association between the response and the baseline biologic factors (IgVH, p53, FISH, ZAP-70, CD38) [ Time Frame: After 20 months therapy and 18-60 months follow-up ] [ Designated as safety issue: No ]
- Progression free survival estimation according to the baseline biologic factors starting from the date of first dose of study drug in the induction phase. [ Time Frame: After 20 months therapy and 18-60 months follow-up ] [ Designated as safety issue: No ]
- Time to a new CLL treatment or death estimation. [ Time Frame: an estimation of 40 months. ] [ Designated as safety issue: No ]
- Overall survival estimation [ Time Frame: an estimation of 40 months ] [ Designated as safety issue: No ]
|Study Start Date:||November 2011|
|Study Completion Date:||January 2015|
|Primary Completion Date:||January 2015 (Final data collection date for primary outcome measure)|
Drug: Lenalidomide; Chlorambucil
All patients will receive six monthly courses of the chlorambucil (C) and lenalidomide (L) schedule consisting of 8 days of C (d1-d8) combined with L given daily until response assessment which will take place 12 weeks from the start (d+1) of course VI, while patients continue their treatment with lenalidomide daily.
In the first phase of the induction phase of the study the dose of L given with C will be gradually escalated to reach the MTD. In the second phase of the induction phase, C will be given in combination with the Maximum Tolerated Dose of L (either the MTD or the maximum planned dose of 10mg).
Patients who will achieve a response after 6 courses of CL induction phase -PR, CRi, CR and MRD negative CR- will be eligible for the post-induction phase of the study. Patients will be randomized (1:1), stratifying according to the quality of response (PR vs CR, CRi, MRD-CR) and the genetic profile (11q, 17p-, p53mut vs other), to receive L daily, (L arm) or no further therapy (Clinical observation arm) until day 364 or until PD or unacceptable toxicity develops, whichever occurs first. During maintenance (L arm), L will be given at the dose tolerated by the patient during the period interval from d+28 of the 6th course of CL and the day of evaluation of the response (d+84 from the start of 6th course of CL). At screening, blood samples will be drawn and a physical examination, a CT scan or a thorax radiography and an abdomen ultrasound, a bone marrow biopsy and aspirate will be performed. A clinical examination will be carried out and blood samples will be harvested weekly during CL treatment. Twelve weeks from the start (d+1) of 6th CL course (d+84), clinical response will be assessed. During the post-remissional phase, a monthly clinical examination will be performed in all patients. Patients randomized to receive L as maintenance therapy will have an additional blood examination during treatment. Eight weeks after the completion of the post-remissional phase (d+420), a new response assessment will be performed (physical examination and blood samples, a CT scan or a thorax radiography and an abdomen ultrasound, a bone marrow biopsy and aspirate). Thereafter, patients will be monitored for response duration at least over the following 18 months.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01403246
|Azienda Spedali Civili|
|Brescia, Italy, 25100|
|Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"|
|Azienda Ospedaliera Pugliese Ciaccio|
|Catanzaro, Italy, 88100|
|Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia|
|Clinica Ematologica - Università degli Studi|
|UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico|
|U.O. Ematologia Clinica - Azienda USL di Pescara|
|Umberto I di Roma - Dipartimento di Biotecnologie Cellulari ed Ematologia|
|Roma, Italy, 00161|
|U.O. Ematologia, Azienda Ospedaliera Universitaria Senese|
|Siena, Italy, 53100|
|SS.C. di Oncoematologia - Dipartimento di Medicina Clinica e Sperimentale - Azienda Ospedaliera - S. Maria Di Terni|
|Principal Investigator:||Roberto Foà||Umberto I - Dipartimento di Biotecnologie Cellulari ed Ematologia Cellulari|
|Principal Investigator:||Francesca Romana Mauro, Co-Coordinator||Umberto I - Dipartimento di Biotecnologie Cellulari ed Ematologia|