Epcoritamab Plus Venetoclax Plus Ibrutinib in Patients With Chronic Lymphocytic Leukemia With TP53 Alterations

NCT07738887 | Not Yet Recruiting Phase 2 DMC

• 2 other identifiers: EVITA2025-520893-20-00
• Study Type: interventional
• Target: 44
• Locations: 2 countries
• Sites: 29

Brief Summary

This is a phase 2, open-label, multicenter study evaluating the efficacy and safety of a fixed-duration combination of epcoritamab, venetoclax, and ibrutinib (EVI) in previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have TP53 alterations. Patients with TP53 abnormalities, including TP53 mutation and/or 17p deletion, have a poorer prognosis and are less likely to benefit from conventional chemoimmunotherapy. Targeted therapies such as ibrutinib and venetoclax have improved outcomes in this population, but many patients eventually experience disease progression. This study investigates whether adding epcoritamab, a CD3×CD20 bispecific antibody, to the combination of ibrutinib and venetoclax can improve the depth and durability of treatment responses while using a fixed-duration treatment approach. Participants will receive sequential treatment with ibrutinib alone, followed by ibrutinib plus venetoclax, and then the triple combination of epcoritamab, venetoclax, and ibrutinib. The study will evaluate the effectiveness of this regimen, including the achievement of deep remission, as well as its safety and tolerability in this high-risk patient population.

Conditions

Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma

Keywords

CLL; SLL; TP53 mutation

Outcome Measures

Primary Outcomes (1)

• Rate of Participants Achieving Complete Remission (CR) with Undetectable Minimal Residual Disease (uMRD) in Bone Marrow

  Rate of participants achieving complete remission (CR) with undetectable minimal residual disease (uMRD) in bone marrow, assessed according to 2018 iwCLL response criteria.

  18 months

Secondary Outcomes (10)

• Bone Marrow uMRD Rate

  18 months

• Complete Response Rate (CRR)

  18 months

• Overall Response Rate (ORR)

  18 months

• Duration of Response

  4 years

• Duration of Complete Response

  4 years

Study Arms (1)

EVI combination

EXPERIMENTAL

Participants receive sequential treatment with ibrutinib, followed by ibrutinib plus venetoclax, and subsequently the triple combination of ibrutinib, venetoclax, and epcoritamab as a fixed-duration treatment regimen.

Drug: Ibrutinib Oral Tablet; Drug: Venetoclax Oral Tablet; Drug: Epcoritamab

Interventions

Ibrutinib Oral Tablet DRUG

Orally once daily, administered alone during the initial treatment phase and continued in combination with venetoclax and epcoritamab according to the study treatment schedule.

Also known as: IMBRUVICA

EVI combination

Venetoclax Oral Tablet DRUG

Oral administration as part of the study treatment regimen, in combination with ibrutinib and subsequently with epcoritamab according to the study treatment schedule.

EVI combination

Epcoritamab DRUG

Subcutaneous administration as part of the study treatment regimen in combination with ibrutinib and venetoclax according to the study treatment schedule

EVI combination

Eligibility Criteria

• Age: 18 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant who understood and voluntarily signed and dated an informed consent form prior to any trial-specific assessments/procedures being conducted
• Must be able to adhere to the trial visit schedule and other protocol requirements
• Age between ≥ 18 years and \< 80 years at the time of signing the informed consent form (ICF)
• Cumulative Illness Rating Score (CIRS) ≤ 6
• CD20+, untreated and documented CLL or SLL, with a Royal Marsden Hospital (RMH) or Matutes Score \> 3. For SLL a detectable clone with a CLL phenotype in the peripheral blood is a prerequisite for trial participation.
• Presence of TP53 abnormalities (either 17p deletion by FISH and/or TP53 mutations) according to ERIC recommandations.17
• Participant requiring treatment according to 2018 iwCLL guidelines 18
• Presence of measurable disease (absolute lymphocyte count \> 5,000/μL, palpable or measurable lymph node ≥1.5cm on imaging, or bone marrow involvement
• ECOG performance status 0 to 2
• Adequate hematopoietic function within 7 days before the participant's enrollment
• ANC ≥ 1 G/L
• And Platelets ≥ 50 G/L
• And Hemoglobin ≥ 8 g/dL
• Note: Platelets and/or red blood cells transfusions may be administered during screening to meet this requirement
• Adequate renal function defined by a Creatinine Clearance ≥ 50 ml/min calculated according to MDRD or CKD-EPI or Cockcroft-Gault (using actual body weight).

You may not qualify if:

• Any prior CLL or SLL-specific therapies, even including rituximab used for autoimmune cytopenias.
• Clinically significant cardiovascular disease including the following:
• Myocardial infarction within 6 months prior to ICF signature
• Unstable angina within 3 months prior to ICF signature
• NYHA class III or IV heart failure
• Uncontrolled hypertension
• History of clinically significant arrhythmias (including sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes).
• QTcF \> 480 msec using the Fridericia formula
• History of Mobitz II second- or third-degree heart block without permanent pacemaker
• LVEF \<50% as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan
• Child-Pugh liver cirrhosis.
• Clinical evidence for Central Nervous System involvement by CLL
• History of ongoing or confirmed Progressive Multifocal Leukoencephalopathy (PML).
• Active autoimmune disease or other disease requiring permanent immunosuppressive treatment including steroids therapy \> 20mg daily of prednisone dose or equivalent within 15 days prior participant's enrollment
• Active, uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura, requiring steroid therapy with \> 20 mg daily of prednisone dose or equivalent within 15 days prior participant's enrollment

Sponsors & Collaborators

• The Lymphoma Academic Research Organisation: lead
• Lymphoma Study Association: collaborator
• AbbVie: collaborator
• Johnson & Johnson: collaborator

Study Sites (29)

Institut Jules Bordet

Brussels, 1070, Belgium

Location

Universitair Ziekenhuis Gent

Ghent, 9000, Belgium

Location

HELORA - Hôpital de La Louvière Site Jolimont

La Louvière, 7100, Belgium

Location

U.Z. LEUVEN - Campus GASTHUISBERG

Leuven, 3001, Belgium

Location

Chu Ucl Namur - Site Godinne

Namur, 5000, Belgium

Location

CHU d'ANGERS

Angers, 49100, France

Location

Institut D'Hematologie de Basse Normandie

Caen, 14000, France

Location

Ch Metropole Savoie

Chambéry, 73000, France

Location

Chu Estaing

Clermont-Ferrand, 63100, France

Location

Chd de Vendee

La Roche-sur-Yon, 85000, France

Location

Ch Du Mans-Centre de Cancerologie de La Sarthe

Le Mans, 72100, France

Location

Chu de Lille - Hopital Claude Huriez

Lille, 59000, France

Location

Chu Lyon-Sud

Lyon, 69310, France

Location

Institut Paoli Calmettes

Marseille, 13009, France

Location

Chr Metz-Thionville - Hopital de Mercy

Metz, 57530, France

Location

Ch Mont-de-Marsan - Hopital de Layné

Mont-de-Marsan, 40000, France

Location

CHU DE Montpellier

Montpellier, 34090, France

Location

Chu de Nantes

Nantes, 44000, France

Location

Centre Antoine Lacassagne

Nice, 06100, France

Location

AP-HP Saint-Louis

Paris, 75010, France

Location

AP-HP Pitié Salpêtrière

Paris, 75013, France

Location

Gustave Roussy Cancer Campus Grand Paris

Paris, 94800, France

Location

CHU de Bordeaux HOPITAL HAUT-LEVEQUE

Pessac, 33000, France

Location

Chu de Poitiers - Hopital de La Miletrie

Poitiers, 86000, France

Location

Ch Rene Dubos

Pontoise, 95300, France

Location

Chu Pontchaillou

Rennes, 35000, France

Location

Institut de Cancérologie et d'Hématologie Universitaire de Saint-Étienne

Saint-Etienne, 42270, France

Location

Chru de Strasbourg

Strasbourg, 67000, France

Location

Iuct Oncopole

Toulouse, 31100, France

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

ibrutinib; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Romain GUIEZE, Prof. Dr

  University Hospital, Clermont-Ferrand

  PRINCIPAL INVESTIGATOR

• Damien ROOS-WEIL, Prof. Dr

  Hôpital de la Pitié-Salpétrière

  PRINCIPAL INVESTIGATOR

• Virginie DE WILDE, Prof. Dr

  Hôpital Erasme H.U.B

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Project management

CONTACT

+33 4 72 66 93 33; evita@lysarc.org

Study Design

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

Study Record Dates

• First Submitted: July 27, 2026
• First Posted: July 31, 2026
• Study Start (Estimated): December 31, 2026
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): June 30, 2032
• Last Updated: July 31, 2026

Record last verified: 2026-07

Locations

BE (5); FR (24)