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 |
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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 :
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.
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 120 participants |
Allocation: | Randomized |
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) |
Primary Purpose: | Treatment |
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 |
Arm | Intervention/treatment |
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Active Comparator: FCR
FCR :
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Drug: 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)
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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:
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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contact: Valérie ROUILLE | 33 (0)4 67 33 26 45 | v-rouille@chu-montpellier.fr | |
Contact: Anne-Sophie MICHALLET, Dr | 33 (0)4 78 78 26 41 | anne-sophie.michallet@lyon.unicancer.fr |
Principal Investigator: | Anne-Sophie MICHALLET | Centre Leon Berard |
Tracking Information | |||||||||||||||
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First Submitted Date ICMJE | June 20, 2019 | ||||||||||||||
First Posted Date ICMJE | July 8, 2019 | ||||||||||||||
Last Update Posted Date | May 14, 2020 | ||||||||||||||
Actual Study Start Date ICMJE | September 27, 2019 | ||||||||||||||
Estimated Primary Completion Date | December 2023 (Final data collection date for primary outcome measure) | ||||||||||||||
Current Primary Outcome Measures ICMJE |
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
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Original Primary Outcome Measures ICMJE | Same as current | ||||||||||||||
Change History | |||||||||||||||
Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE | Same as current | ||||||||||||||
Current Other Pre-specified Outcome Measures | Not Provided | ||||||||||||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||||||||||||
Descriptive Information | |||||||||||||||
Brief Title ICMJE | Evaluation of Risk-Adapted and MRD-Driven Strategy for Untreated Fit Patients With Intermediate Risk Chronic Lymphocytic Leukemia | ||||||||||||||
Official Title ICMJE | 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 | ||||||||||||||
Brief Summary |
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. |
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Detailed Description |
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 :
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.
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Study Type ICMJE | Interventional | ||||||||||||||
Study Phase ICMJE | Phase 2 | ||||||||||||||
Study Design ICMJE | Allocation: Randomized 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)Primary Purpose: Treatment |
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Condition ICMJE |
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Intervention ICMJE |
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Study Arms ICMJE |
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Publications * | Not Provided | ||||||||||||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||||||||||||
Recruitment Status ICMJE | Recruiting | ||||||||||||||
Estimated Enrollment ICMJE |
120 | ||||||||||||||
Original Estimated Enrollment ICMJE | Same as current | ||||||||||||||
Estimated Study Completion Date ICMJE | June 2026 | ||||||||||||||
Estimated Primary Completion Date | December 2023 (Final data collection date for primary outcome measure) | ||||||||||||||
Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
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Sex/Gender ICMJE |
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Ages ICMJE | 18 Years and older (Adult, Older Adult) | ||||||||||||||
Accepts Healthy Volunteers ICMJE | No | ||||||||||||||
Contacts ICMJE |
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Listed Location Countries ICMJE | France | ||||||||||||||
Removed Location Countries | |||||||||||||||
Administrative Information | |||||||||||||||
NCT Number ICMJE | NCT04010968 | ||||||||||||||
Other Study ID Numbers ICMJE | FILOCLL08 - ERADIC | ||||||||||||||
Has Data Monitoring Committee | No | ||||||||||||||
U.S. FDA-regulated Product |
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IPD Sharing Statement ICMJE |
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Responsible Party | French Innovative Leukemia Organisation | ||||||||||||||
Study Sponsor ICMJE | French Innovative Leukemia Organisation | ||||||||||||||
Collaborators ICMJE |
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Investigators ICMJE |
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PRS Account | French Innovative Leukemia Organisation | ||||||||||||||
Verification Date | May 2020 | ||||||||||||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |