Evaluation of Risk-Adapted and MRD-Driven Strategy for Untreated Fit Patients With Intermediate Risk Chronic Lymphocytic Leukemia (ERADIC)
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|ClinicalTrials.gov Identifier: NCT04010968|
Recruitment Status : Recruiting
First Posted : July 8, 2019
Last Update Posted : December 20, 2019
The aim of this study is to test the potential benefit of an innovative combination of targeted therapy over the standard the immunochemotherapy (FCR). The interest in this study resides in an MRD driven discontinuation of the novel agents, and a fixed maximum duration of these agents. This design allows a true comparison of the efficacy of IV with the immuno-chemotherapy at 2 years of treatment and later.
Finally, other trials propose to include to all risk categories of patients, and we are developing here a stratification preventing the dilution of the results. The intermediate risk patients are the ones for which alternative to chemotherapy is critical, as chemotherapy is likely to alter the clonal evolution of their disease, whereas the low risk patients are already doing well with standard treatment and are likely to benefit from other therapies as well. The high risk patients, id est patients with 17p deletion and or TP 53 mutational status responded very well to new drugs as BTK inhibitors or BLC2 inhibitors.
|Condition or disease||Intervention/treatment||Phase|
|Intermediate Risk Chronic Lymphocytic Leukemia Fit Patients Risk-Adapted and MRD-Driven Strategy||Drug: venetoclax and ibrutinib (I+VEN) Drug: FCR||Phase 2|
The combination of venetoclax (V) and ibrutinib (I) has recently emerged as a very effective therapy in both relapse and front-line settings. The preliminary results of the CLARITY (R/R CLL) and CAPTIVATE (untreated CLL) studies have demonstrated the promising potential of the I+VEN combination, which led to a very high rate of bone marrow MRD negativity. Moreover, the I+VEN combination might be given for only a definite period of time, contrarily to each of the two drugs which are given until disease progression or unacceptable toxicity per Smpc, according to their respective labels. The combination of V and I makes sense because of their in vitro synergy, non-overlapping toxicities and differential activity on different compartments of the disease. Therefore, the direct comparison in the front-line setting of the gold standard immuno-chemotherapy combining Rituximab plus Fludarabine and Cyclophosphamide FCR and an innovative chemo-free regimen combining I and V is essential in the intermediate-risk patients who benefit much less from FCR than the low-risk patients.
Primary objective : to evaluate the efficacy of the chemo-free combination of ibrutinib and venetoclax in previously untreated intermediate-risk CLL in a face to face comparison with the gold standard immuno-chemotherapy regimen FCR in order to assess if it may replace chemotherapy.
Secondary objectives :
- To determine the progression-free survival (PFS), event-free survival (EFS), overall survival (OS) and time to next treatment (TTNT)
- To evaluate the safety of the combination I + VEN
- To evaluate the dose intensity (RDI) of both treatments
- To assess the response (Complete Response / CR, CR with incomplete blood count recovery / CRi , CR with undetectable Measurable Residual Disease/MRD, Partial Remission / PR, nPR, with and without undetectable MRD)
- To determine the incidence of Richter transformation.
Innovative aspects of this trial
• Patient stratification based on robust prognostic factors. The risk stratification is based on IGHV status, genetic alterations by FISH analysis, karyotype and NGS (TP53 mutation), as now recommended by the IWCLL 2018 guidelines.
Focus on the intermediate-risk CLL patients (as defined above) who represent more than half of the CLL patients in need of first-line therapy and for whom replacement of FCR with a more effective innovative approach is a crucial issue.
- Direct comparison between immuno-chemotherapy and a very effective chemo-free arm combining a BTK inhibitor and a Bcl2 inhibitor.
- MRD use to optimize treatment strategy in the experimental arm. Early treatment discontinuation will be considered in patients who will rapidly reach bone marrow MRD negativity (< 10-4).
- Evaluation of a fixed duration of treatment with targeted therapy that will not be continued beyond 24 months
- Evaluation of the kinetics of reappearance of the disease by regular monitoring of the MRD in both arms.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||120 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Direct comparison between immuno-chemotherapy and effective chemo-free arm combining a BTK inhibitor and a Bcl2 inhibitor.|
|Masking:||None (Open Label)|
|Official Title:||Evaluation of Risk-Adapted and MRD-Driven Strategy for Untreated Fit Patients With Intermediate Risk Chronic Lymphocytic Leukemia: a Randomized Phase II Trial Comparing FCR and a Chemo-free Combination of Venetoclax and Ibrutinib|
|Actual Study Start Date :||September 27, 2019|
|Estimated Primary Completion Date :||December 2023|
|Estimated Study Completion Date :||June 2026|
Active Comparator: FCR
All patients will receive 6 cycles of FCR administered at 4 weeks intervals (D1 = D29) from Month 1 to Month 6.
6 cycles of FCR will be administered at 4 weeks intervals (D1 = D29) from Month 1 to Month 6.
Experimental: venetoclax and ibrutinib (I+VEN)
Drug: venetoclax and ibrutinib (I+VEN)
The treatment will start with ibrutinib alone for 3 months (lead-in phase) from Month 1 to Month 3 and then venetoclax will be added from Month 4 with an initial ramp-up period.
The total duration of treatment with (I+VEN) will depend on the response achieved at Month 9:
- Minimal residual disease (MRD) in bone marrow (BM) < 0.01% at month 27 [ Time Frame: 27 month after beginning FCR or venetoclax + ibrutinib ]MRD evaluation performed by 8 colours flow cytometry analysis in the bone marrow
- Progression-free survival (PFS), [ Time Frame: from date of inclusion to the date of first-documented progression, assessed up to 4 years ]time from date of randomization to documented progression or death
- Complete response (CR) rate at month 9 [ Time Frame: at month 9 in the two arms (i.e. 3 months after the 6th cycle of FCR or after 6 months of combined therapy with ibrutinib and venetoclax) ]CR rate (according to IWCLL criteria) with minimal residual disease < 0.01% in bone marrow and undetectable MRD in the blood (with a limit of detection of at least 10-5)
- Number of patients with bone marrow MRD < 0.01% at month 9 [ Time Frame: At month 9 after beginning FCR or venetoclax + ibrutinib ]Number of patients with MRD < 0.01% by 8 colours flow cytometry analysis in the bone marrow
- Complete response (CR) rate at month 27 [ Time Frame: at month 27 in the two arms (i.e. 3 months after the 6th cycle of FCR or after 6 months of combined therapy with ibrutinib and venetoclax) ]CR rate (according to IWCLL criteria) with minimal residual disease < 0.01% in bone marrow and undetectable MRD in the blood (with a limit of detection of at least 10-5)
- Overall survival (OS) [ Time Frame: from date of inclusion to the date of death assessed up to 75 months ]time from date of randomization to date of death or the last date the patient is known to be alive
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04010968
|Contact: Valérie ROUILLE||33 (0)4 67 33 26 email@example.com|
|Contact: Anne-Sophie MICHALLET, Dr||33 (0)4 78 78 26 firstname.lastname@example.org|
|Principal Investigator:||Anne-Sophie MICHALLET||Centre Leon Berard|