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

NCT04010968 | Completed Phase 2

• 1 other identifier: FILOCLL08 - ERADIC
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 34

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.

Conditions

Intermediate Risk Chronic Lymphocytic Leukemia; Fit Patients; Risk-Adapted and MRD-Driven Strategy

Outcome Measures

Primary Outcomes (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

  27 month after beginning FCR or venetoclax + ibrutinib

Secondary Outcomes (5)

• Progression-free survival (PFS),

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

• Complete response (CR) rate at month 9

  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)

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

  At month 9 after beginning FCR or venetoclax + ibrutinib

• Complete response (CR) rate at month 27

  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)

• Overall survival (OS)

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

Study Arms (2)

FCR

ACTIVE COMPARATOR

FCR : * 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.

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.

Drug: venetoclax and ibrutinib (I+VEN)

Interventions

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.

venetoclax and ibrutinib (I+VEN)

FCR DRUG

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.

FCR

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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)
• 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.
• 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.

Sponsors & Collaborators

• French Innovative Leukemia Organisation: lead
• AbbVie: collaborator
• Janssen-Cilag Ltd.: collaborator

Study Sites (34)

CH Annecy Genevois - Hématologie A3

Annecy, 74374, France

Location

Ch Cote Basque

Bayonne, 64109, France

Location

CH BLOIS

Blois, 41000, France

Location

Hôpital Avicenne - Centre de Recherche Clinique

Bobigny, 93009, France

Location

Institut Bergonie

Bordeaux, 33076, France

Location

CHU Caen - IHBN - Hématologie Clinique

Caen, 14033, France

Location

Hôpital Privé Sévigné

Cesson-Sévigné, 35510, France

Location

CHU Estaing - Hématologie Clinique Adulte

Clermont-Ferrand, 63000, France

Location

Centre Hospitalier Sud Francilien

Corbeil-Essonnes, 91100, France

Location

Chu Creteil

Créteil, 94000, France

Location

GRENOBLE GHM - Institut Daniel Hollard

Grenoble, 38028, France

Location

CHU Grenoble - Hématologie

Grenoble, 388043, France

Location

CHD Vendée

La Roche-sur-Yon, 85925, France

Location

Centre Hospitalier du Mans

Le Mans, 72000, France

Location

Hôpital Saint Vincent de Paul

Lille, 59000, France

Location

Centre Léon Bérard - Hématologie

Lyon, 69373, France

Location

Institut Paoli Calmette

Marseille, 130009, France

Location

Centre Hospitalier Regional Metz Thionville

Metz, 57085, France

Location

Hôpital Saint Eloi

Montpellier, 34295, France

Location

CHU Hôtel Dieu - Hématologie Clinique

Nantes, 44093, France

Location

CHR ORLEANS - Hématologie

Orléans, 44100, France

Location

Hôpital Pitié Salpétrière - Hématologie

Paris, 75651, France

Location

Bordeaux Pessac

Pessac, 33604, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69495, France

Location

Hôpital de la Milétrie - Hématologie et Thérapie Cellulaire

Poitiers, 86021, France

Location

Chu Reims

Reims, 51092, France

Location

CHU Pontchaillou - Hématologie Clinique BMT-HC

Rennes, 35033, France

Location

Centre Henri Becquerel - Service Hématologie Clinique

Rouen, 76038, France

Location

Institut de Cancérologie Lucien Neuwirth

Saint-Priest-en-Jarez, 42271, France

Location

Hôpital Hautepierre - Hématologie

Strasbourg, 67098, France

Location

IUCT ONCOPOLE - Hématologie

Toulouse, 31059, France

Location

Hôpital Bretonneau - Hématologie et Thérapie Cellulaire

Tours, 37044, France

Location

CHU Nancy Brabois

Vandœuvre-lès-Nancy, 54500, France

Location

Hôpital André Mignot

Versailles, 78157, France

Location

MeSH Terms

Interventions

venetoclax; ibrutinib

Study Officials

• Anne-Sophie MICHALLET

  Centre Leon Berard

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Direct comparison between immuno-chemotherapy and effective chemo-free arm combining a BTK inhibitor and a Bcl2 inhibitor.

Study Record Dates

• First Submitted: June 20, 2019
• First Posted: July 8, 2019
• Study Start: September 27, 2019
• Primary Completion: April 3, 2023
• Study Completion: January 30, 2025
• Last Updated: November 26, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: After the end of the study and as long as the sponsor retains the data
• Access Criteria: if the rationale is the improvement of knowledge in the CLL

Locations

FR (34)