BELLWAVE MK1026-011 

An individual is eligible for inclusion in the study if the individual meets all of the following criteria: Type of Participant and Disease Characteristics

1. Confirmed diagnosis of CLL/SLL and active disease clearly documented to have a need 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 less than 10 g/dL or platelet counts less than 100 × 109/L are generally regarded as indication for treatment. However, in some participants, platelet counts less than 100 × 109/L may remain stable over a long period; this situation does not automatically require therapeutic intervention.

Massive (ie, more than or equal to 6 cm below the left costal margin) or progressive or symptomatic splenomegaly.

Massive nodes (ie, more than or equal to 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.

Progressive lymphocytosis with an increase of more than or equal to 50% over a 2-month period, or LDT less than 6months. LDT can be obtained by linear regression extrapolation of ALCs obtained at intervals of 2 weeks over an observation period of 2 to 3 months; participants with initial blood lymphocyte counts less than 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 extraࣘ nodal involvement (eg, skin, kidney, lung, spine).

Disease-related symptoms as defined by any of the following: Unintentional weight loss more than or equal to 10% within the previous 6 months. Significant fatigue (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 more than or equal to 1 month without evidence of infection.

2. 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 more than 1.5 cm in longest diameter when assessed by CT/MRI scan.

Absolute lymphocyte count more than 4 x 109/L-Platelet count less than 100 x 109/L-Hemoglobin less than 11 g/dL

3. Provision of peripheral blood, bone marrow aspirate, and/or a lymph node sample as specified in the SoA (Section 1.3.1) and Appendix 13 for determination of del(17p) status and TP53mutation status, both determined by central testing. This is required before randomization.-Del(17p) indeterminate is eligible only if TP53mutation is present.

TP53indeterminate is eligible only if del(17p) is detected.

4. An ECOG PS of 0 to 2 within 7 days before randomization.

5. The ability to swallow and retain oral medication. NOTE: Administration of nemtabrutinib is not permitted through a J-PEG tube.

6. 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, including HBsAg and anti-HBc, are required for all participants. See Appendix 7 for country-specific requirements.

7. 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)

8. Participants with HIV are eligible if they meet ALL of the following criteria:

The CD4 count is more than 350 cells/µL at screening

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

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 inducers are not eligible to be included in the study screening tests are not required unless: Known history of HIV infection As mandated by local health authority (see Appendix 7 for country-specific requirements)

Are compliant with their ART NOTE: If the participant has had an AIDS-defining opportunistic infection in the past 12months before screening, they are not eligible to be included in the study. See Appendix 7 for country-specific requirements.

9. Adequate organ function as defined in the following table (Table 3). Specimens must be collected within 7 days before randomization.

5.2 Exclusion Criteria

An individual must be excluded from the study if the individual meets any of the following criteria: Medical Conditions

1. Active HBV/HCV infection. See Inclusion Criteria 6(HBV) and 7(HCV) for requirements.

2. Gastrointestinal dysfunction that may affect drug absorption (eg, gastric bypass surgery, gastrectomy).

3. Diagnosis of Richter Transformation or active CNS involvement by CLL/SLL.

4. AIDS-defining opportunistic infection in the past 12 months before screening.

5. QTc prolongation (defined as a QTcF more than 450 msecs) or other significant ECG abnormalities including second degree AV block type II, third degree AV block, or bradycardia (ventricular rate less than 50 beats/min).

6. Hypersensitivity to nemtabrutinib or contraindication to ibrutinibor acalabrutinib (eg, Child-Pugh Class C hepatic impairment), or any of the excipients. NOTE: Refer to the IB for details regarding excipients for nemtabrutinib and the current prescribing information for ibrutinibor acalabrutinib.

7. History of severe bleeding disorder.

8. History of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. 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. Prior/Concomitant Therapy

9. Has received any systemic anti cancer therapy for CLL/SLL

10.Currently being treated with the following drugs: a. P-gp substrates with a narrow therapeutic index b. CYP3A strong inducers c. CYP3A stronginhibitors-CYP3A moderate inhibitors are not excluded, but coadministration with ibrutinib or acalabrutinib may require dose modifications. Consult the current version of the relevant prescribing information as stated in Section 6.6.2. 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. -Refer to Section 6.5 and Appendix 8 regarding prohibited concomitant medications and potential drug interactions after participant randomization.

11.Received prior radiotherapy within 2weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease is permitted. The last radiotherapy treatment must have been performed at least 7days before the first dose of study intervention.

12.Received a live or live-attenuated vaccine within 30days before the first dose of study intervention. Administration of killed vaccines are allowed. Refer to Section 6.5 for information on COVID-19 vaccines. Prior/Concurrent Clinical Study Experience

13.Has received an investigational agent or has used an investigational device within 4weeksprior to study intervention administration. Diagnostic Assessments

14.History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.

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

16.Active autoimmune disease that has required systemic treatment in the past 2years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid)is allowed.

17.Active infection requiring systemic therapy.

18.Known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.

Other Exclusions

19.Participants who have not adequately recovered from major surgery or have ongoing surgical complications.

20.Participating sites in EU region only: Participants who are incapacitated are not eligible for this study.

For country-specific requirements, see Appendix 7. 

Research Nurse: Hilary Thatcher

Administrator: research.oncology@mbht.nhs.uk