This phase II trial tests how well nemtabrutinib and venetoclax work in treating patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Nemtabrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cells (a type of white blood cell) in cancers such as CLL or SLL at abnormal levels. This may help keep cancer cells from growing and spreading. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Giving nemtabrutinib in combination with venetoclax may kill more cancer cells in patients with CLL or SLL.

PRIMARY OBJECTIVE:

I. To determine rates of undetectable minimal residual disease (MRD) (threshold 10^-6) in the peripheral blood using adaptive ClonoSeq next generation sequencing (NGS) following 14 cycles of therapy with nemtabrutinib plus venetoclax in patients with treatment-naïve CLL/SLL.

SECONDARY OBJECTIVES:

I. To determine safety and toxicity profile for patients treated with the combination of nemtabrutinib plus venetoclax for treatment-naïve CLL/SLL.

II. To determine progression free survival (PFS) for patients treated with the combination of nemtabrutinib plus venetoclax for treatment-naïve CLL/SLL.

III. To assess time to next treatment for participants treated with the combination of nemtabrutinib plus venetoclax for treatment-naïve CLL/SLL.

IV. To assess treatment response for participants treated with the combination of nemtabrutinib plus venetoclax for treatment-naïve CLL/SLL.

V. To assess for changes in patient fatigue and health related quality of life (HRQoL) measures during and after treatment with nemtabrutinib and venetoclax as measured by Patient-Reported Outcomes Measurement Information System (PROMIS)® version (v) 1.0 Fatigue Short Form 13a and European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire - Chronic Lymphocytic Leukemia 17 (EORTC QLQ-CLL17) surveys.

EXPLORATORY OBJECTIVES:

I. To determine whether baseline fluorescence in situ hybridization (FISH) or NGS abnormalities affect MRD or PFS with the combination of nemtabrutinib and venetoclax.

II. To determine how the combination of nemtabrutinib and venetoclax alters number and function of T, B, and natural killer (NK) cells in the peripheral blood prior to, during and after therapy.

III. To determine the kinetics of MRD following treatment with nemtabrutinib plus venetoclax.

IV. To determine whether nemtabrutinib primes cells toward apoptosis using BH3 profiling before treatment and prior to initiation of venetoclax.

OUTLINE:

Patients receive nemtabrutinib orally (PO) daily on days 1-28 of each cycle. Starting in cycle 3, patients also receive venetoclax PO daily on day 1-28 of each cycle. Cycles repeat every 28 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT), bone marrow aspiration and biopsy, and blood sample collection throughout the trial.

After completion of study treatment, patients are followed up every 12 weeks.

Inclusion Criteria:

• Confirmed diagnosis of CLL/SLL meeting criteria established in the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines

• Is an individual of any sex/gender, who is at least 18 years of age on the day of signing informed consent

• Participants must have treatment-naïve CLL/SLL. Palliative loco-regional radiotherapy, rituximab for autoimmune conditions, or corticosteroids for symptom control will not be considered prior therapy

• Participants must meet criteria for treatment as defined by 2018 iwCLL guidelines which includes at least one of the following criteria:

  • Massive (>= 6 cm below the costal margin), progressive or symptomatic splenomegaly

  • Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy

  • Progressive lymphocytosis with a lymphocyte doubling time < 6 months or an increase of >= 50% over a 2 month period

  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy

  • Symptomatic or functional extranodal involvement (e.g. skin, kidney, lung, spine)

  • Constitutional symptoms, which include any of the following:

    • Unintentional weight loss of 10% or more within 6 months
    • Significant fatigue
    • Fevers > 100.5 degrees Fahrenheit (F) for 2 weeks or more without evidence of infection
    • Night sweats >= 1 month without evidence of infection

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention

• Adequate bone marrow independent of growth factor support or infusion support at screening unless evidence shows that the cytopenia(s) is due to marrow involvement by CLL/SLL and/or disease-related immune thrombocytopenia, or anemia. If cytopenias are due to disease in the bone marrow any degree of cytopenias are allowed. Patients with active uncontrolled autoimmune cytopenias are excluded

• Absolute neutrophil count (ANC) >= 1000/mm^3

• Platelets >= 50,000/mm^3

• Hemoglobin >= 8 g/dL

• Willing and able to participate in all required evaluations and procedures in this study protocol

• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information

• Participants assigned male sex at birth: If capable of producing sperm, the participant agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:

  • Nemtabrutinib: 12 days

  • Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent OR

  • Uses contraception as detailed below unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel's review of the participant's medical records, medical examination, or medical history interview) as detailed below:

  • Uses a penile/external condom plus nonparticipant of childbearing potential who is not currently pregnant and should also be advised of the benefit for that partner to use an additional method of contraception, as a condom may break or leak.

    • Note: Participants capable of producing ejaculate whose partner is pregnant or breastfeeding must agree to use penile/external condom during each episode of sexual activity in which the partner is at risk of drug exposure via ejaculate.

  • Contraceptive use by participants capable of producing sperm should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed

• Participants assigned female sex at birth: A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies:

  • Is not a person of childbearing potential (POCBP) OR

  • Is a POCBP and:

    • Uses a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency, or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:

      • Nemtabrutinib: 1 month

    • The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.

    • Has a negative highly sensitive pregnancy test (urine or serum) as required by local regulations within 24 hours (for urine test) or 72 hours (for serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

    • Abstains from breastfeeding during the study intervention period and for at least 30 days after study intervention with nemtabrutinib.

    • Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy

• The ability to swallow and retain oral medication.

  • NOTE: Administration of nemtabrutinib is not permitted through a percutaneous endoscopic gastro-jejunostomy (J-PEG) tube

• Participants who are hepatitis B surface antigen (HbsAg) positive are eligible if they have received hepatitis B viral (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to screening.

  • Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. Hepatitis B screening tests, including HBsAg and anti-HBc (hepatitis B core), are required for all participants

• Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening.

  • Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization.

  • Hepatitis C screening tests are not required unless:

    • Known history of HCV infection
    • As mandated by local health authority

• Participants with human immunodeficiency virus (HIV) are eligible if they meet ALL of the following criteria:

  • The CD4 count is > 350 cells/ìL at screening

  • The HIV viral load is below the detectable level as per locally available testing

  • Are on a stable antiretroviral therapy (ART) regimen for at least 4 weeks prior to study entry

  • NOTE: ART includes drugs, which are NOT strong CYP3A4 inducers (participants receiving ART that are strong CYP3A4 inducers are not eligible to be included in the study).

  • HIV screening tests are not required unless:

    • Known history of HIV infection
    • As mandated by local health authority

  • Are compliant with their ART

  • NOTE: If the participant has had an acquired immunodeficiency syndrome (AIDS) defining opportunistic infection in the past 12 months prior to screening, they are not eligible to be included in the study

• Absolute neutrophil count (ANC) >= 1000/uL

  • Growth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if needed.
  • No lower limit if cytopenia is related to bone marrow involvement

• Platelets >= 50000/uL

  • Growth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if needed.
  • No lower limit if cytopenia is related to bone marrow involvement

• Hemoglobin >= 8 g/dL

  • Growth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if needed.
  • No lower limit if cytopenia is related to bone marrow involvement

• Creatinine clearance (CrCl) >= 30mL/min

• Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases)

• International normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants

Exclusion Criteria:

• Subject with other malignancies that are associated with a life expectancy of < 2 years or that would confound assessment of toxicity in this study.

  • NOTE: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder

• Clinically significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification. Note: Subjects with controlled atrial fibrillation can enroll on study

• Active HBV/HCV infection

• Inability to swallow oral medication or gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy)

• Diagnosis of Richter transformation

• Active central nervous system (CNS) involvement

• Active infection requiring systemic therapy, including intravenous (IV) antibiotics during screening. Participants may be rescreened followed completion of IV antibiotic course

• AIDS defining opportunistic infection in the past 12 months prior to screening

• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator

• Corrected QT (QTc) prolongation (defined as a Fridericia-corrected QT interval [QTcF] > 450 msecs) or other significant electrocardiogram (ECG) abnormalities including second degree atrioventricular (AV) block type II, third degree AV block, or bradycardia (ventricular rate less than 50 beats/min)

• Known allergy/sensitivity (>= grade 3) to nemtabrutinib or any of the excipients.

  • NOTE: Refer to the investigator brochure (IB) for details regarding excipients for nemtabrutinib

• History of severe bleeding disorders

• A POCBP who has a positive urine pregnancy test within 72 hours prior to enrollment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

  • Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication

• Prior CLL/SLL directed therapy

• Currently being treated with the following drugs:

  • P-glycoprotein (P-gp) substrates with a narrow therapeutic index
  • CYP3A strong inducers
  • CYP3A strong inhibitors
  • NOTE: A washout period of at least 5 times the half-life after the last dose of any of the above treatments is required for a participant to be eligible for study enrollment. A list of example in vivo substrates for specific CYP enzymes and P-gp is provided
  • NOTE: Refer to protocol regarding prohibited concomitant medications and potential drug interactions after participant randomization

• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks (if prior therapy was a monoclonal antibody) or 5 half-lives before randomization (whichever is longer)

• Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids

  • Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease, with a 1-week washout, is permitted

• Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.

  • Note: please refer to protocol for information on COVID-19 vaccines

• Is currently enrolled on another therapeutic clinical trial. Concurrent enrollment on another therapeutic clinical trial or any trial designed to impact the efficacy of anti-cancer therapy is prohibited

• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication

• Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid)

• Has an active infection requiring systemic therapy

• Has not adequately recovered after 4 weeks from major surgery or has ongoing surgical complications.

  • Note: Biopsy and placement of central venous access devices are not considered major surgery

• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial