BELLWAVE-010

Adults ≥18 with R/R CLL/SLL (not refractory to venetoclax), ≥1 prior therapy, active disease, ECOG 0–2, measurable disease burden, adequate organ function.

Type of Participant and Disease Characteristics 1. Confirmed diagnosis of CLL/SLL and active disease clearly documented to initiate therapy. At least 1 of the following criteria should be met: • Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. Cutoff levels of Hb <10g/dL or platelet counts <100 x 109/L are generally regarded as indication for treatment; however, in some patients, platelet counts <100 x 109/L may remain stable over a long period; this situation does not automatically require therapeutic intervention. • Massive (ie, ≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly. • Massive nodes (ie, ≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy. • Progressive lymphocytosis with an increase of ≥50% over a 2-month period, or LDT, <6 months. LDT can be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; participants with initial blood lymphocyte counts <30 × 109/L may require a longer observation period to determine the LDT. Factors contributing to lymphocytosis other than CLL (eg, infections, steroid administration) should be excluded. • Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids, as deemed by the investigator. • Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, spine). • Disease-related symptoms as defined by any of the following: - Unintentional weight loss ≥10% within the previous 6 months. - Significant fatigue (ie, up to ECOG performance status 2; cannot work or unable to perform usual activities). - Fever of 100.5°F or 38.0°C for 2 or more weeks without evidence of infection. - Night sweats for ≥1 month without evidence of infection. 2. Del(17p) status, TP53 mutation status, and IGHV mutation status results required before randomization for Part 2 participants only as determined by central testing: • Del(17p) status, TP53 mutation status, IGHV mutation status. For accurate prognostic stratification, each patient must have a known result for IGHV, del(17p), and TP53. In cases where del(17p) or TP53 results are indeterminate, eligibility may be determined with sponsor consultation and approval as follows: participants with an indeterminate del(17p) result are eligible only if a TP53 mutation is confirmed, and participants with an indeterminate TP53 result are eligible only if del(17p) is confirmed. • Provision of peripheral blood sample (at screening for CLL participants). For SLL participants, peripheral blood and a bone marrow aspirate are required, and if available/preferrable a lymph node sample (if obtained up to 1 year before central laboratory submission if there was no intervening therapy). Further information is provided in Appendix 14. NOTE: Tissue collection and submission to the central laboratory should only be performed once all other eligibility criteria have been collected and reviewed. 3. Relapsed or refractory to at least 1 prior available therapy. NOTE: Participants refractory to venetoclax are excluded. NOTE: There is no limit on the number of prior therapies. NOTE: The definition of relapsed/refractory disease follows the iwCLL definition (see Appendix 10). Relapse is defined as evidence of disease progression in a patient who has previously achieved a CR or PR for ≥6 months. Refractory disease is defined as treatment failure (including SD, nonresponse, disease progression) or as progression within 6 months from the last dose of therapy. 4. Have at least 1 of the following markers of disease burden: • Malignant lymph nodes attributable to CLL/SLL which are clearly and reproducibly measurable in 2 dimensions in the axial plane, and measure ≥1.5 cm in longest diameter when assessed by CT/MRI scan • Absolute lymphocyte count >4 x 109/L • Platelet count <100 x 109/L • Hemoglobin <11 g/dL 5. An ECOG performance status of 0 to 2 within 7 days before randomization. 6. A life expectancy of at least 3 months, based on the investigator assessment. 7. The ability to swallow and retain oral medication. NOTE: Administration of nemtabrutinib and venetoclax is not permitted through a J-PEG tube. 8. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV DNA viral load before randomization. NOTE: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention. Hepatitis B screening tests should include HBsAg and anti-HBc. 9. Participants with history of HCV infection are eligible if HCV RNA viral load is undetectable at screening. NOTE: Participants must have completed curative antiviral therapy at least 4 weeks before randomization. Hepatitis C screening tests are not required unless: • Known history of HCV infection • As mandated by local health authority (see Appendix 7 for country-specific requirements) 10. Participants with HIV are eligible if they meet ALL the following criteria: • The CD4 count is ≥350 cells/µL at screening • Achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening • Are on a stable ART regimen for at least 4 weeks before study entry NOTE: ART must include drugs that are not strong CYP3A4 inducers (participants receiving ART that are strong CYP3A4 inhibitors are not eligible to be included in the study). • Are compliant with their ART NOTE: If the participant has had an AIDS-defining opportunistic infection in the past 12 months before screening, they are not eligible to be included in the study. HIV screening will follow local regulations. See Appendix 7 for country-specific requirements. 11. Adequate organ function as defined in Table 6. Specimens must be collected within 7 days before the start of study intervention. [Hematological: ANC ≥1,000 µL; Platelets ≥50,000/µL regardless of bone marrow involvement; Hgb ≥8.0 g/dL (stable ≥1 week, except AIHA for CLL/SLL) | Renal: CrCl ≥30 mL/min (Cockcroft-Gault or 24-hr urine) | Hepatic: Total bilirubin ≤1.5× ULN or direct bilirubin ≤ULN if total >1.5× ULN (≤3× ULN if Gilbert's/liver mets); AST/ALT ≤2.5× ULN (≤5× ULN with liver mets) | Coagulation: INR or PT ≤1.5× ULN; aPTT ≤1.5× ULN (unless on therapeutic anticoagulation)] Demographics 12. Is an individual of any sex/gender and aged at least 18 years at the time of providing documented informed consent. Participants Assigned Male Sex at Birth 13. 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. - Venetoclax: 1 month (30 days). - Rituximab (rituximab biosimilar [see Appendix 13]): not applicable. • 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): - Uses a penile/external condom when having penile-vaginal intercourse with a 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 a 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 14. 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 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), as described in Appendix 5 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 (30 days). ◦ Venetoclax: 1 month (30 days). ◦ Rituximab (or rituximab biosimilar [see Appendix 13]): 12 months (See Appendix 7 for country-specific requirements). ◦ The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCPBs 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 (eg, 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. Additional requirements for pregnancy testing during and after study intervention are in Section 8.3.7. - Abstains from breastfeeding during the study intervention period and for at least 30 days after study intervention with nemtabrutinib, 1 month (30 days) after the last dose of venetoclax, and 6 months after the last dose of rituximab (or rituximab biosimilar [see Appendix 13]). - Medical history, menstrual history, and recent sexual activity have been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy. Informed Consent 15. The participant (or legally acceptable representative) has provided documented informed consent for the study and the participant has provided documented assent, when applicable, for the study. The participant may also provide consent for FBR; however, the participant may participate in the study without participating in FBR. 16. Criterion was modified and moved to Section 10.7.11 EEA Appendix. See Appendix 7 for EU-specific consenting requirements for participants who require a legally designated representative for consenting purposes.

Excludes Richter's transformation, CNS involvement, prior venetoclax refractoriness or BCL2i <12 months, active infection, significant CV disease, recent anticancer/investigational therapy.

Medical Conditions 1. Active HBV/HCV infection. See Inclusion Criteria 8 (HBV) and 9 (HCV) for requirements. 2. GI dysfunction that may affect drug absorption (eg, gastric bypass surgery, gastrectomy). 3. Known additional malignancy that is progressing or has required active treatment within the past 2 years. NOTE: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potential curative therapy are not excluded. Participants with low risk, early-stage prostate cancer (T1-T2a, Gleason score ≤6, and prostate-specific antigen <10 ng/mL) either treated with definitive intent or untreated in active surveillance with SD are not excluded. 4. Diagnosis of Richter Transformation or active CNS involvement by CLL/SLL. 5. Active infection requiring systemic therapy, such as IV antibiotics, during screening. NOTE: Participants may be rescreened following completion of IV antibiotic course. 6. HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease and/or AIDS-defining opportunistic infection in the past 12 months before screening. 7. 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. 8. Clinically significant cardiovascular disease, including the following: • Myocardial infarction within 6 months before screening. • Unstable angina within 6 months before screening. • New York Heart Association Class III or IV congestive heart failure. • History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsade's de pointes). • QTcF >470 msecs based on Fridericia's formula (NOTE: QTcF value may be calculated as the numerical average of up to 3 separate readings for eligibility). • History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place. • Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure >170 mm Hg and diastolic blood pressure >105 mm Hg at screening. 9. Known allergy/sensitivity (≥Grade 3) to nemtabrutinib or contraindication to venetoclax/rituximab (or rituximab biosimilar [see Appendix 13]), or any of the excipients. NOTE: Refer to the IB for details regarding excipients for nemtabrutinib and the current prescribing information for venetoclax/rituximab (or rituximab biosimilar [see Appendix 13]). 10. History of severe bleeding disorders (eg, hemophilia). Prior/Concomitant Therapy 11. Received prior systemic anticancer therapy within 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibody) before randomization. 12. Received prior: • BCL2i within <12 months before randomization. • Prior radiotherapy within 2 weeks of start of study intervention, or radiation related toxicities, requiring corticosteroids. NOTE: Participants refractory to venetoclax are excluded. NOTE: Two weeks or fewer of palliative radiotherapy for non-CNS disease is permitted. The last radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention. 13. Currently being treated with the following therapies: • P-gp substrates with a narrow therapeutic index. • CYP3A strong or moderate 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 examples of in vivo CYP3A strong inhibitors, CYP3A strong or moderate inducers, and P-gp substrates with narrow therapeutic index is provided in Appendix 8. 14. Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention. Refer to Section 6.5.1 for information on COVID-19 vaccines. Prior/Concurrent Clinical Study Experience 15. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. Diagnostic Assessments 16. Known psychiatric or substance use disorder that would interfere with the participant's ability to cooperate with the requirements of the study. Other Exclusions 17. Participants who have not adequately recovered from major surgery or have ongoing surgical complications. 18. Participating Sites in EU Region only: Participants who are incapacitated are not eligible for this study. See Appendix 7 for country-specific requirements.