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Study of nemtabrutinib combined with venetoclax and obinutuzumab in untreated CLL/SLL patients with TP53 alterations

Verified siteRegistered drugNo placebo
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What is this trial about?

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

The trial focuses on patients with previously untreated chronic lymphocytic leukemia or small lymphocytic leukemia that have changes in the TP53 gene, such as a missing piece of chromosome 17 detected by FISH or a mutation. The treatment combines an intravenous infusion of obinutuzumab, an oral tablet of nemtabrutinib, and an oral tablet of venetoclax.

The aim is to see how well this combination works in eliminating disease and keeping it from coming back. Response will be measured by checking the amount of cancer left in the bone marrow using a laboratory technique called flow cytometry to find minimal residual disease at a very low level.

Participants will receive the infusion and tablets over several months, completing about 15 cycles of the oral drug, 12 cycles of the second oral drug, and six infusions of the first drug. After treatment, doctors will follow the patients to record how long they stay free of disease, known as progression-free survival, overall length of life, called overall survival, and any side effects, which are graded using the standard CTCAE criteria and the disease‑specific iwCLL guidelines.

The research process

The trial runs in 7 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Enrollment and baseline assessments

    After you join the study, you will undergo initial assessments that may include blood tests, a bone marrow sample, and other examinations to confirm eligibility and establish a health baseline.

  2. Step 2

    Start of treatment cycle 1

    On day 1 of the first cycle you will receive an obinutuzumab infusion of 1000 mg given intravenously over a short period.

    The same day you will begin taking venetoclax 400 mg by mouth each day.

    You will also start a daily oral dose of nemtabrutinib 45 mg.

  3. Step 3

    Monthly treatment cycles 2–6 (obinutuzumab phase)

    On day 1 of each subsequent cycle (cycles 2 through 6) you will receive another obinutuzumab 1000 mg intravenous infusion.

    Throughout cycles 2 to 6 you will continue the daily oral doses of venetoclax 400 mg and nemtabrutinib 45 mg.

  4. Step 4

    Continuation of venetoclax (cycles 7–12)

    After cycle 6 the obinutuzumab infusions stop.

    You will keep taking venetoclax 400 mg by mouth each day for cycles 7 through 12.

    The daily nemtabrutinib 45 mg continues through these cycles as well.

  5. Step 5

    Continuation of nemtabrutinib (cycles 13–15)

    After cycle 12 the venetoclax tablets are discontinued.

    You will remain on the daily oral dose of nemtabrutinib 45 mg for cycles 13, 14, and 15.

  6. Step 6

    Monitoring and safety visits

    Throughout the treatment period you will attend regular clinic visits where blood will be drawn to check blood counts and organ function.

    The study staff will ask about any side effects and may adjust the dose if needed.

  7. Step 7

    Final evaluation at cycle 16 day 1

    On day 1 of cycle 16 (after completing 15 cycles of nemtabrutinib, 12 cycles of venetoclax, and 6 cycles of obinutuzumab) a bone marrow sample will be taken.

    The sample will be examined for minimal residual disease using flow cytometry to determine the treatment response.

Who can join the trial?

9 criteria

  • You must have a confirmed diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) that needs treatment, as defined by the international guidelines (iwCLL 2018 criteria).
  • You need to have at least one sign that the disease is active, such as:
    • a swollen lymph node caused by CLL/SLL that can be clearly measured on a CT or MRI scan and is larger than 1.5 cm in its longest side,
    • or a blood test showing an absolute lymphocyte count (a type of white blood cell) higher than 4 × 10⁹ per liter,
    • or a platelet count (cells that help blood clot) lower than 100 × 10⁹ per liter,
    • or a hemoglobin level (the protein that carries oxygen in red blood cells) less than 11 g/dL.
    • You must have a problem with the gene called TP53, either a missing part of chromosome 17p detected by a test called fluorescence in situ hybridization (FISH) or a chromosome banding array (CBA), or a mutation in TP53 itself. Even if only 1 % of cells show this abnormality, you are eligible.
    • Your overall health and ability to carry out daily activities must be rated as 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) performance status scale, measured within 7 days before the first study medication.
    • You need to have enough healthy organ function (such as liver, kidney, and heart) to safely receive the study drugs.
    • You must be able to understand why the study is being done, the possible risks, and you must sign and date an informed consent form.

Who cannot join the trial?

5 criteria

  • You have an active blood disorder that is not under control, such as autoimmune hemolytic anemia (where the immune system destroys red blood cells) or idiopathic thrombocytopenic purpura (where the immune system destroys platelets).
  • Your disease is currently affecting your CNS (brain or spinal cord).
  • You have any other illness, treatment, or lab test result that could make it hard to tell if the study drug works, could stop you from staying in the study for the whole time, or that the doctor thinks is not safe for you.
  • You have serious heart problems that are not controlled, such as a recent myocardial infarction (heart attack) within the past 6 months, a prolonged QTc interval (greater than 450 milliseconds), or major irregularities on an ECG (heart electrical test) like certain types of AV block or a very slow heart rate (bradycardia, less than 50 beats per minute).
  • You are currently taking medicines that can interact strongly with the study drug, including drugs that are moved by a protein called P-gp and have a narrow safety range, or medicines that strongly increase or decrease the activity of a liver enzyme called CYP3A.
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Investigated drugs

  • Obinutuzumab

    is a medicine given through an IV drip. In this study it is used as part of the standard background treatment. It helps the immune system recognize and attack the cancer cells in chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). Patients receive it for a set number of cycles at the start of the trial.

  • Venetoclax

    is an oral tablet that patients take by mouth. It works by blocking a protein that cancer cells need to stay alive, which can cause the leukemia cells to die. In this trial it is also part of the standard background regimen and is taken for several cycles alongside the other drugs.

  • Nemtabrutinib

    is an experimental oral tablet being tested in the study. It targets a different pathway that helps cancer cells grow, aiming to stop the disease from progressing. Patients in the trial take nemtabrutinib in addition to the standard drugs (obinutuzumab and venetoclax) to see if the combination works better than the standard treatment alone.

What is already known about the treatment

  • Obinutuzumab

    This medication is given by slow IV infusion, using a sterile solution that is mixed with fluid and delivered into a vein. It is an approved cancer drug used mainly for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). It works by binding to a protein called CD20 on the surface of B‑cells, marking them for destruction by the immune system. It belongs to the class of anti‑CD20 monoclonal antibodies.

  • Nemtabrutinib

    The drug is taken as an oral tablet taken by mouth. It is still under investigation and not yet approved for general medical use. It is being studied for CLL/SLL patients with TP53 changes and works by blocking an enzyme called BTK that helps cancer cells grow and survive. It is classified as a BTK (Bruton's tyrosine kinase) inhibitor.

  • Venetoclax

    Venetoclax is supplied as film‑coated tablets that patients swallow with water. It is an approved therapy for CLL and other blood cancers. The medicine works by attaching to a protein called BCL‑2 inside cancer cells, releasing the block on cell death and allowing the cells to die naturally. It is categorized as a BCL‑2 inhibitor, a type of targeted anti‑cancer drug.

Investigated diseases

  • Chronic lymphocytic leukemia

    Chronic lymphocytic leukemia is a cancer of the blood and bone marrow that produces too many mature‑looking but dysfunctional lymphocytes. These cells accumulate in the blood, bone marrow, and lymph nodes, gradually crowding out normal blood cells. The disease often progresses slowly, but can accelerate over time as more abnormal cells build up. Genetic changes such as loss of the TP53 gene can make the disease behave more aggressively.

  • Small lymphocytic leukemia

    Small lymphocytic leukemia is the tissue‑based counterpart of chronic lymphocytic leukemia, where the same abnormal lymphocytes primarily gather in lymph nodes, spleen, and bone marrow. It leads to swollen lymph nodes and enlargement of the spleen as the cells increase. Like chronic lymphocytic leukemia, it usually advances gradually, but the amount of abnormal cells can rise, causing more symptoms. TP53 abnormalities may also be present, influencing the disease’s behavior.

Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IITrial ID2026-525763-40-00Estimated enrolment42 patientsSponsorFrench Innovative Leukemia Organization (F.I.L.O.).

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