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Intermediate Risk Chronic Lymphocytic LeukemiaPhase 2ERADICNCT04010968

Evaluation of Risk-Adapted and MRD-Driven Strategy for Untreated Fit Patients With Intermediate Risk Chronic Lymphocytic Leukemia

A Phase 2 study testing venetoclax and ibrutinib (I+VEN) and FCR in people with Intermediate Risk Chronic Lymphocytic Leukemia and Fit Patients, run by French Innovative Leukemia Organisation at 34 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
venetoclax and ibrutinib (I+VEN) and FCR
Could I receive a placebo?
No, everyone receives an active treatment
How many people
120 participants
Where
34 sitesFrance
Study dates
27 Sep 2019to 30 Jan 2025
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age 18 years or older.
  • Immunophenotypically confirmed CLL (according to IWCLL guidelines, RMH score 4-5 or RMH 3 providing CD200high and CD20low), excluding small lymphocytic lymphoma without lymphocytosis.
  • Indication for treatment according to the 2018 IWCLL criteria and clinically measurable disease.
  • Risk stratification: no criteria characterizing low-risk or high-risk groups.
  • Patient with unmutated status
  • Absence of 17p deletion and/or TP53 mutation.
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  • Performance status ECOG < 2.
  • CIRS (Cumulative Illness Rating Scale) ≤ 6.
  • Eligibility for fludarabine, cyclophosphamide and rituximab combination (FCR) and for ibrutinib and venetoclax therapy.
  • Adequate hepatic function per local laboratory reference range as follows:
  • Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0 x ULN
  • Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin).
  • No prior treatment for CLL (chemotherapy, radiotherapy, immuno-therapy) except steroids for less than 1 month.
  • Willingness to accept highly effective methods of contraception for the duration of therapy and 12 months thereafter.
  • Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [β-hCG]) or urine pregnancy test at Screening.
  • Signed (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.

Who cannot join

  • Patients with IGHV mutated (except VH3-21/subset #2) with normal karyotype and/or del 13q without TP53 mutation ie low risk patients.
  • Patients del 17p and or TP53 mutation ie high risk patients.
  • CLL without active disease according to IWCLL 2008 criteria.
  • Known HIV seropositivity.
  • Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
  • Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
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  • Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.
  • Active and uncontrolled autoimmune cytopenia, including autoimmune hemolytic anemia (AIHA) (isolated positive DAT is not an exclusion criteria) and idiopathic thrombocytopenic purpura (ITP).
  • Life expectancy < 6 months.
  • Patient refusal to perform the bone marrow biopsy for evaluation points.
  • Active second malignancy currently requiring treatment (except basal cell carcinoma, in situ endometrial carcinoma and incidental prostate carcinoma) and/or less than 5 years CR after breast cancer.
  • Concurrent severe diseases which exclude the administration of therapy.
  • heart insufficiency NYHA grade III/IV, LEVF < 50% and or RF <30%, myocardial infarction within the past 6 months prior to study.
  • severe chronic obstructive lung disease with hypoxemia.
  • severe diabetes mellitus.
  • hypertension difficult to control.
  • impaired renal function with creatinine clearance < 50 ml/min according the formula of Cockcroft and Gault.
  • Treatment with any of the following within 7 days prior to the first dose of study drug:
  • steroid therapy for anti-neoplastic intent.
  • A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely affect the patient's participation in this study or interpretation of study outcomes.
  • Major surgery within 30 days prior to the first dose of study treatment.
  • History of prior other malignancy that could affect compliance with the protocol or interpretation of results, with the exception of the following:
  • curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix at any time prior to study.
  • other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which patient is disease-free for ≥ 5 years without further treatment.
  • Contraindication to the use of Rituximab.
  • Contraindication to the use of Venetoclax.
  • Contraindication to the use of Ibrutinib.
  • Pregnant or breastfeeding women.
  • Adult under law-control.
  • Fertile male and female patients who cannot or do not wish to use an effective method of contraception, during and for 12 months after the final treatment used for the purposes of the study.
  • No affiliation to social security.

Trial locations and contacts

34 sites in 1 country.

34 sites in 1 country

France34 sites

  • CH Annecy Genevois - Hématologie A3

    Annecy, 74374

  • Ch Cote Basque

    Bayonne, 64109

  • CH BLOIS

    Blois, 41000

  • Hôpital Avicenne - Centre de Recherche Clinique

    Bobigny, 93009

  • Institut Bergonie

    Bordeaux, 33076

  • CHU Caen - IHBN - Hématologie Clinique

    Caen, 14033

  • Hôpital Privé Sévigné

    Cesson-Sévigné, 35510

  • CHU Estaing - Hématologie Clinique Adulte

    Clermont-Ferrand, 63000

  • Centre Hospitalier Sud Francilien

    Corbeil-Essonnes, 91100

  • Chu Creteil

    Créteil, 94000

  • GRENOBLE GHM - Institut Daniel Hollard

    Grenoble, 38028

  • CHU Grenoble - Hématologie

    Grenoble, 388043

  • CHD Vendée

    La Roche-sur-Yon, 85925

  • Centre Hospitalier du Mans

    Le Mans, 72000

  • Hôpital Saint Vincent de Paul

    Lille, 59000

  • Centre Léon Bérard - Hématologie

    Lyon, 69373

  • Institut Paoli Calmette

    Marseille, 130009

  • Centre Hospitalier Regional Metz Thionville

    Metz, 57085

  • Hôpital Saint Eloi

    Montpellier, 34295

  • CHU Hôtel Dieu - Hématologie Clinique

    Nantes, 44093

  • CHR ORLEANS - Hématologie

    Orléans, 44100

  • Hôpital Pitié Salpétrière - Hématologie

    Paris, 75651

  • Bordeaux Pessac

    Pessac, 33604

  • Centre Hospitalier Lyon Sud

    Pierre-Bénite, 69495

  • Hôpital de la Milétrie - Hématologie et Thérapie Cellulaire

    Poitiers, 86021

  • Chu Reims

    Reims, 51092

  • CHU Pontchaillou - Hématologie Clinique BMT-HC

    Rennes, 35033

  • Centre Henri Becquerel - Service Hématologie Clinique

    Rouen, 76038

  • Institut de Cancérologie Lucien Neuwirth

    Saint-Priest-en-Jarez, 42271

  • Hôpital Hautepierre - Hématologie

    Strasbourg, 67098

  • IUCT ONCOPOLE - Hématologie

    Toulouse, 31059

  • Hôpital Bretonneau - Hématologie et Thérapie Cellulaire

    Tours, 37044

  • CHU Nancy Brabois

    Vandœuvre-lès-Nancy, 54500

  • Hôpital André Mignot

    Versailles, 78157

Other trials in France

About this study

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. A FILO Study

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.

Read the 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 :

  • 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.
Being tested
venetoclax and ibrutinib (I+VEN), FCR

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • venetoclax and ibrutinib (I+VEN)Drug

    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:

    • if BM MRD at M9 < 0.01%, the treatment with (I+VEN) will be continued for 6 additional months until Month 15 and stopped then. MRD will be assessed at Month 15 (PB), Month 21 (PB) and Month 27 (PB and BM)
    • if BM MRD at M9 ≥ 0.01%, the treatment with (I+VEN) will be continued for 18 additional months until Month 27 and stopped then, whatever the results of MRD assessments that will be performed at the same time points as above.

  • FCRDrug

    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.

Study groups in NCT04010968
Study groupRoleWhat they receive
FCRActive comparatorFCR : * rituximab (R): 375 mg/m² IV D1 cycle 1 and 500 mg/m² IV D1 cycles 2 to 6. * fludarabine (F): 40 mg/m² orally, D2 to D4 - cycles 1 to 6. * cyclophosphamide (C): 250 mg/m² orally, D2 to D4 - cycles 1 to 6.
Receives: Drug: FCR
venetoclax and ibrutinib (I+VEN)Experimental* ibrutinib: 420 mg/d orally, continuously from Month 1 to the end of treatment, either Month 15 or Month 27 * venetoclax: stepwise weekly dose ramp-up beginning at Month 4 from a starting dose of 20 mg/d to the final dose of 400 mg/d (20, 50, 100, 200 and then 400 mg) over a 5 weeks, and then 400 mg/d continuously from Month 5 to the end of treatment, either Month 15 or Month 27.
Receives: Drug: venetoclax and ibrutinib (I+VEN)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Minimal residual disease (MRD) in bone marrow (BM) < 0.01% at month 27

    MRD evaluation performed by 8 colours flow cytometry analysis in the bone marrow

    Measured: 27 month after beginning FCR or venetoclax + ibrutinib

Secondary outcomes (5)

  1. Progression-free survival (PFS),

    time from date of randomization to documented progression or death

    Measured: from date of inclusion to the date of first-documented progression, assessed up to 4 years

  2. Complete response (CR) rate at month 9

    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)

    Measured: 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)

  3. Number of patients with bone marrow MRD < 0.01% at month 9

    Number of patients with MRD < 0.01% by 8 colours flow cytometry analysis in the bone marrow

    Measured: At month 9 after beginning FCR or venetoclax + ibrutinib

  4. Complete response (CR) rate at month 27

    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)

    Measured: 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)

  5. Overall survival (OS)

    time from date of randomization to date of death or the last date the patient is known to be alive

    Measured: from date of inclusion to the date of death assessed up to 75 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Jul 2019
  2. Study start27 Sep 2019
  3. Primary completion3 Apr 2023
  4. Study completion30 Jan 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Direct comparison between immuno-chemotherapy and effective chemo-free arm combining a BTK inhibitor and a Bcl2 inhibitor.
Masking
None (open label)
Enrolment
120 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04010968
Sponsor's protocol ID
FILOCLL08 - ERADIC
Acronym
ERADIC
Status last verified
Nov 2025
First submitted
20 Jun 2019
Last updated
26 Nov 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: At the end of the study, the participant data (DPI) collected in this study may be made available to other researchers who request it from the sponsor and if the rationale is the improvement of knowledge in the CLL. The provision will be evaluated by the sponsor.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing venetoclax and ibrutinib (I+VEN) and FCR in people with Intermediate Risk Chronic Lymphocytic Leukemia and Fit Patients, run by French Innovative Leukemia Organisation at 34 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 34 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Minimal residual disease (MRD) in bone marrow (BM) < 0.01% at month 27 (time frame: 27 month after beginning FCR or venetoclax + ibrutinib). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04010968.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Nov 2025.

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