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

Обзор

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.

Вмешательства

• Препарат Ibrutinib Oral Tablet
  Orally once daily, administered alone during the initial treatment phase and continued in combination with venetoclax and epcoritamab according to the study treatment schedule.
• Препарат Venetoclax Oral Tablet
  Oral administration as part of the study treatment regimen, in combination with ibrutinib and subsequently with epcoritamab according to the study treatment schedule.
• Препарат Epcoritamab
  Subcutaneous administration as part of the study treatment regimen in combination with ibrutinib and venetoclax according to the study treatment schedule

Первичные конечные точки

• Rate of Participants Achieving Complete Remission (CR) with Undetectable Minimal Residual Disease (uMRD) in Bone Marrow [Срок оценки: 18 months]

Вторичные конечные точки (10)

• Bone Marrow uMRD Rate [Срок оценки: 18 months]
• Complete Response Rate (CRR) [Срок оценки: 18 months]
• Overall Response Rate (ORR) [Срок оценки: 18 months]
• Duration of Response [Срок оценки: 4 years]
• Duration of Complete Response [Срок оценки: 4 years]
• Time to Next Treatment [Срок оценки: 4 years]
• Peripheral Blood MRD Kinetics [Срок оценки: Day 1 of Cycle7 (each cycle is 28 days); 18 months; Follow-up Months12; Follow-up Months 24]
• Progression-Free Survival (PFS) [Срок оценки: 3 years]
• Overall Survival (OS) [Срок оценки: 3 years]
• Safety and tolerability (Adverse Events) [Срок оценки: 38 months]

Критерии участия

Критерии включения

• 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).
• Adequate liver function, as indicated by a total bilirubin <1.5 x ULN, AST and ALT <3 x ULN value, unless directly attributed to the participant's CLL/SLL or to Gilbert's Syndrome (the ULN is based on institutional values)
• The participant must have been vaccinated against pneumococcal (< 5 years) and SARS-CoV-2 (< 1 year) with at least 21 days between the last vaccination and the participant's enrollment
• Woman of childbearing potential (WOCBP):

• should have a negative result for pregnancy test (minimum sensitivity of 25 mIU/mL, urine or serum), within 28 days prior the participant's enrollment
• should agree to use 1 form of highly effective method of contraception from the time of screening until at least 12 months after the final dose of epcoritamab, or at least 3 months after the final dose of ibrutinib or at least 30 days after the final dose of venetoclax, whichever is the longest
• Woman should agree to abstain from breastfeeding during trial participation and at least 4 months after the last study treatment administration
• Woman should agree to perform further pregnancy testing monthly
• Woman should agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire trial, until 12 months after the last administration of study treatment.
• Man of reproductive potential should agree to use an acceptable method of birth control during treatment and until at least 12 months after the final dose of epcoritamab, 3 months after the final dose of ibrutinib and 30 days after the final dose of venetoclax (see section 15.7.3 Acceptable birth control methods). Men should agree not to donate sperm during the entire trial and until 12 months after the last administration of study treatment.
• Participant covered by any social security system (France)
• Participant who understands and speaks one of the country official languages unless local regulation authorizes independent translators
• Life expectancy > 6 months

Критерии исключения

• 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
• Any prior history of Richter transformation or DLBCL
• Active malignancy other than the one treated in this trial. Prior history of malignancies unless the participant has been free of the disease for ≥ 2 years.

However, participants with the following history /conditions that have been treated with a curative intent are allowed:

• Non-invasive basal cell or epidermoid carcinoma (non melanoma)
• In situ carcinoma of the cervix
• In situ carcinoma of the breast
• Incidental histologic finding of prostate cancer (T1a or T1b) using the tumor, nodes, metastasis \[TNM\] clinical staging system Woman with adjuvant endocrine therapy (I.e., hormonotherapy) after breast cancer treatment can be enrolled if hormonotherapy was started for ≥ 2 years
• History of stroke or intracranial hemorrhage within 6 months prior to ICF signature.
• Major surgery anticipated before the ICF signature
• Known bleeding disorders
• Active Hepatitis C Virus (HCV) infection (RNA PCR-positive). Participants who received treatment for HCV infection that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable
• Active Hepatitis B Virus (HBV) infection (DNA PCR-positive). Participants with evidence of prior HBV infection but who are PCR-negative are permitted in the trial but should receive prophylactic antiviral therapy during the entire treatment with active monitoring of viral load in the blood
• Known history of seropositivity for HIV infection
• Known or suspected hypersensitivity or anaphylaxis to trial intervention(s) including active substance or to any of the excipients.
• Requires treatment with warfarin, other vitamin K antagonists, or dual antiplatelet therapy
• Requires treatment with a strong cytochrome CYP3A4 inhibitor/inducer
• Vaccinated with live, attenuated vaccines within 6 months of enrollment
• Participation in another clinical study who would compromise the participation to the current study.
• Use of any standard or experimental anti-cancer drug therapy within 28 days or 5 half-lives (whichever is shorter) before the participant's enrollment
• Any prior therapy with a bispecific antibody targeting CD3 and CD20
• Prior allogeneic stem cells or autologous transplant.
• Pregnant, planning to become pregnant or lactating woman
• Any significant medical conditions, or laboratory abnormality or psychiatric illness likely to interfere with participation in this clinical trial (according to the investigator's decision)
• Ongoing active bacterial, viral, fungal, mycobacterial, parasitic or other infection requiring systemic treatment (excluding prophylactic treatment) at the time of enrollment or within the previous 2 weeks prior to the first dose of trial drug, including COVID-19 infection and participants with positive cytomegalovirus PCR.
• Participant deprived of their liberty by a judicial or administrative decision
• Participant hospitalized without consent
• Adult participant under legal protection

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 24 центра

• CHU d'ANGERS — Angers
• Institut D'Hematologie de Basse Normandie — Caen
• Ch Metropole Savoie — Chambéry
• Chu Estaing — Clermont-Ferrand
• Chd de Vendee — La Roche-sur-Yon
• Ch Du Mans-Centre de Cancerologie de La Sarthe — Le Mans
• Chu de Lille - Hopital Claude Huriez — Lille
• Chu Lyon-Sud — Lyon
• … и ещё 16 центров

Бельгия · 5 центров

• Institut Jules Bordet — Brussels
• Universitair Ziekenhuis Gent — Ghent
• HELORA - Hôpital de La Louvière Site Jolimont — La Louvière
• U.Z. LEUVEN - Campus GASTHUISBERG — Leuven
• Chu Ucl Namur - Site Godinne — Namur

Идентификаторы

NCT: NCT07738887 · EVITA · 2025-520893-20-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗