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About
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.
Enrollment
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Volunteers
Inclusion criteria
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
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):
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
Exclusion criteria
Any prior CLL or SLL-specific therapies, even including rituximab used for autoimmune cytopenias.
Clinically significant cardiovascular disease including the following:
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:
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
Primary purpose
Allocation
Interventional model
Masking
44 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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