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Study of epcoritamab, venetoclax and ibrutinib in treatment‑naïve chronic lymphocytic leukemia patients with TP53 alterations

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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study focuses on patients with chronic lymphocytic leukemia (CLL) and B-cell small lymphocytic lymphoma (SLL) that have TP53 alterations, a genetic change that can make the disease harder to treat. The treatment being tested combines three medicines: an oral tablet called venetoclax, a subcutaneous injection (under the skin) of epcoritamab (GEN3013), and an oral drug named ibrutinib. These drugs work in different ways to try to stop the cancer cells from growing.

The main goal of the study is to see how well this combination works in people who have not received prior therapy for CLL or SLL with the TP53 alteration. Participants will take the oral medicines each day and receive the injection at regular clinic visits over several months, with doctors checking blood tests and scans to monitor response. The study will look at how many patients achieve a complete remission (the cancer becomes undetectable) and whether the disease can be cleared to an uMRD level, as well as other outcomes such as overall response and survival.

Throughout the trial, safety will be monitored by recording any side effects, and the overall time without the disease getting worse will be measured using standard terms like PFS and OS. The schedule includes an initial screening period, a treatment phase lasting several cycles, and a follow‑up period after treatment ends to observe long‑term effects.

The research process

The trial runs in 4 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Baseline Screening

    You will undergo initial medical examinations and laboratory tests to confirm that you meet the study criteria.

  2. Step 2

    Start of Combination Therapy

    You will begin taking venetoclax as a 400 mg oral tablet (by mouth) according to the study schedule.

    You will begin taking ibrutinib as a 420 mg oral tablet (by mouth) according to the study schedule.

    You will receive epcoritamab as a 48 mg subcutaneous injection (injection under the skin) according to the study schedule.

  3. Step 3

    Ongoing Treatment and Monitoring

    You will continue the three medications for the duration specified in the study protocol, following the dosing instructions provided.

    Regular clinic visits will be arranged so that health professionals can assess your response to the treatment and check for any side effects.

    During these visits, blood samples and other simple tests may be performed to monitor your condition.

  4. Step 4

    Study Completion

    At the end of the study period, final assessments will be performed to evaluate the effectiveness of the combination therapy.

    You will receive a summary of the study results that pertain to your participation.

Who can join the trial?

21 criteria

  • You must read and voluntarily sign an informed consent form, which explains the study and confirms that you agree to take part.
  • You need to be able to follow the study visit schedule and other required procedures.
  • You must be at least 18 years old but younger than 80 years when you sign the consent form.
  • Your overall health score for other illnesses, called the Cumulative Illness Rating Score (CIRS), must be 6 or lower.
  • You must have untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that tests positive for the protein CD20 and has a disease‑severity score (RMH or Matutes) greater than 3.
  • You must have a TP53 gene abnormality, either a deletion of chromosome 17p detected by a test called FISH or a TP53 mutation, as defined by expert recommendations.
  • Your doctor must determine that you need treatment according to the 2018 international CLL guidelines.
  • Your disease must be measurable, meaning you have an absolute lymphocyte count higher than 5,000 per microliter, a lymph node at least 1.5 cm that can be seen on imaging, or bone‑marrow involvement.
  • Your ability to perform daily activities, measured by the ECOG performance status, must be 0, 1, or 2.
  • Your blood counts must be adequate within 7 days before enrollment:
    • ANC (absolute neutrophil count) ≥ 1 × 10⁹/L
    • Platelets ≥ 50 × 10⁹/L
    • Hemoglobin ≥ 8 g/dL
    • Your kidney function must be adequate, shown by a Creatinine Clearance of at least 50 mL/min (calculated using standard formulas such as MDRD, CKD‑EPI, or Cockcroft‑Gault).
    • Your liver function must be adequate:
      • Total bilirubin less than 1.5 times the upper normal limit (ULN)
      • AST and ALT enzymes each less than 3 times the ULN, unless the elevation is due to your CLL/SLL or a harmless condition called Gilbert’s syndrome.
      • You must have received a pneumococcal vaccine within the past 5 years and a COVID‑19 (SARS‑CoV‑2) vaccine within the past year, and at least 21 days must have passed since your last vaccine before you enroll.
      • If you are a woman who could become pregnant (woman of childbearing potential), you must have a negative pregnancy test (sensitivity ≥ 25 mIU/mL) done within 28 days before enrollment, agree to use one highly effective method of birth control from screening until at least 12 months after the last dose of epcoritamab (or the longer required period for the other drugs), agree not to breastfeed during the study, agree to have a pregnancy test each month, and agree not to donate eggs for assisted reproduction.
      • If you are a man who could father a child (man of reproductive potential), you must agree to use an acceptable method of birth control during treatment and agree not to donate sperm during the study.
      • You must be covered by a French social security system.
      • You must understand and be able to speak one of the official languages of the country where the study is conducted, unless a translator is permitted by local regulations.
      • Your doctor must expect that you have a life expectancy of more than 6 months.

Who cannot join the trial?

29 criteria

  • You have already received any treatment for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), including rituximab used for low blood cell counts.
  • You have had a stroke or bleeding in the brain within the last 6 months.
  • You are expected to undergo major surgery before signing the consent form.
  • You have a known condition that makes you bleed easily (a bleeding disorder).
  • You have an active Hepatitis C infection (the virus is detectable in your blood).
  • You have an active Hepatitis B infection (the virus is detectable in your blood).
  • You are known to be HIV positive.
  • You have an allergy or severe reaction (hypersensitivity or anaphylaxis) to the study drugs or any of their ingredients.
  • You need to take warfarin, other vitamin K‑blocking blood thinners, or two antiplatelet medicines at the same time.
  • You need medicines that strongly block or increase the activity of the liver enzyme CYP3A4.
  • You received a live, weakened (attenuated) vaccine (such as measles, mumps, rubella, or chickenpox) in the past 6 months.
  • You have significant heart problems, such as a heart attack within 6 months, unstable chest pain within 3 months, severe heart failure (NYHA class III or IV), uncontrolled high blood pressure, dangerous heart rhythm problems (including sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes), a prolonged QT interval (> 480 ms), certain types of heart block without a permanent pacemaker, or a reduced heart‑pumping ability (ejection fraction < 50%).
  • You are currently participating in another clinical study that could interfere with this one.
  • You have taken any cancer treatment (standard or experimental) within the last 28 days or within five drug half‑lives, whichever is shorter.
  • You have previously received a bispecific antibody that targets CD3 and CD20.
  • You have had a stem‑cell transplant (from a donor or from yourself).
  • You are pregnant, trying to become pregnant, or breastfeeding.
  • You have other serious medical, laboratory, or mental health problems that the doctor thinks would prevent safe participation.
  • You have an active infection (bacterial, viral, fungal, mycobacterial, parasitic, etc.) that needs treatment, including COVID‑19 or a positive cytomegalovirus test, within the last 2 weeks.
  • You are under legal detention or confinement by a judicial or administrative decision.
  • You are currently hospitalized and cannot give consent.
  • You are an adult under legal guardianship or protection.
  • You have severe liver disease classified as Child‑Pugh cirrhosis.
  • Your CLL has spread to the brain or spinal cord (central nervous system involvement).
  • You have or have had Progressive Multifocal Leukoencephalopathy (PML), a serious brain infection.
  • You have an active autoimmune disease that requires permanent immune‑suppressing treatment, such as steroids higher than 20 mg of prednisone (or equivalent) daily, within the past 15 days.
  • You have uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura that needs steroids higher than 20 mg of prednisone (or equivalent) daily, within the past 15 days.
  • You have previously experienced Richter transformation or diffuse large B‑cell lymphoma (DLBCL).
  • You have another active cancer, or you had a previous cancer that was not cured at least 2 years ago (except for certain early‑stage skin, cervical, breast, or prostate cancers).
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Investigated drugs

  • Venetoclax

    is an oral tablet taken by mouth that helps to kill cancer cells in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). It works by blocking a protein that cancer cells use to stay alive, allowing the immune system to remove them. In this study, venetoclax is given together with other drugs to see if the combination works better than standard treatments.

  • Epcoritamab (GEN3013)

    is a medication that is injected under the skin. It is a type of antibody that attaches to a marker on the surface of the cancer cells and signals the body’s own immune cells to attack them. By bringing the immune system directly to the leukemia cells, epcoritamab aims to improve the control of the disease when used with other drugs.

  • Ibrutinib

    is a pill taken by mouth that blocks a specific enzyme inside certain blood cells. This enzyme helps the cancer cells grow and survive, so stopping it can slow down the disease. Ibrutinib is used in many CLL and SLL treatments, and in this trial it is combined with venetoclax and epcoritamab to test if the three‑drug mix provides a stronger effect against the cancer.

What is already known about the treatment

  • Venetoclax

    This medication is taken as a 400 mg film‑coated tablet taken by mouth. It is an approved drug that has been studied extensively in clinical trials for blood cancers such as chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Venetoclax works by blocking the BCL‑2 protein, which helps cancer cells survive, so its inhibition leads to cancer‑cell death. It belongs to the class of BCL‑2 inhibitors, a type of targeted oral therapy.

  • Epcoritamab (GEN3013)

    Epcoritamab is given as a 48 mg solution for subcutaneous injection under the skin. It is currently an investigational bispecific antibody that has received approval for some B‑cell lymphomas and is being tested in CLL/SLL with TP53 changes. The drug binds both CD3 on T‑cells and CD20 on B‑cells, bringing the immune cells close to the cancer cells so they can destroy them. It is classified as a bispecific T‑cell engager monoclonal antibody.

  • Ibrutinib

    Ibrutinib is taken as an oral tablet, typically 420 mg per day. This drug is already approved and widely used for CLL, mantle‑cell lymphoma and other B‑cell cancers. It works by blocking the enzyme Bruton’s tyrosine kinase (BTK), which stops signals that tell cancerous B‑cells to grow and survive. Ibrutinib is classified as a BTK inhibitor, an oral targeted cancer therapy.

Investigated diseases

  • Chronic lymphocytic leukemia

    Chronic lymphocytic leukemia is a cancer of the blood‑forming cells in which a large number of abnormal B‑lymphocytes build up in the bone marrow and circulate in the bloodstream. Over time the number of these cells usually rises slowly, leading to larger blood counts. The disease can spread to the spleen and lymph nodes, causing them to enlarge. As the abnormal cells increase, they may interfere with the production of normal blood cells. The condition often progresses gradually, but the rate of change can vary between individuals.

  • B‑cell small lymphocytic lymphoma

    B‑cell small lymphocytic lymphoma is a type of lymphoma where the same abnormal B‑cells mainly gather in lymph nodes, the spleen, and other lymphoid tissues. The affected nodes typically enlarge slowly and may become more widespread over time. The disease can later involve the bone marrow and blood, resembling chronic lymphocytic leukemia. The accumulation of these cells can displace normal immune cells in the involved tissues. Its progression is usually indolent, with the extent of spread changing at different rates in different patients.

Trial detailsLast updated 18 Oct 2026
Age18+ yearsPhasePhase IITrial ID2025-520893-20-00Protocol codeEVITAEstimated enrolment32 patientsSponsorLYSARC

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