Nemtabrutinib and Lisocabtagene Maraleucel for the Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Inclusion Criteria:

• Confirmed diagnosis of CLL/SLL per International Workshop on Chronic LymphocyticLeukemia (iwCLL) classification

• Measurable disease by imaging (lymph node [LN] > 1.5cm) or absolute lymphocyte count (ALC) (> 5000/μL) or marrow involvement of at least 30% by flow cytometry

• Eligible for lisocabtagene maraleucel (liso-cel) as standard-of-care per Food andDrug Administration (FDA) label for CLL/SLL

• At least 18 years of age at time of study enrollment

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

• The ability to swallow and retain oral medication

• NOTE: Administration of nemtabrutinib is not permitted through a percutaneousendoscopic gastro-jejunal (J PEG) tube

• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible ifthey have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeksand have undetectable HBV viral load prior to randomization

• Note: Participants should remain on anti-viral therapy throughout studyintervention and follow local guidelines for HBV anti-viral therapy postcompletion of study intervention. Hepatitis B screening tests should includeHBsAg and anti-HBV. Hepatitis B screening tests are not required unless:

• Known history of HBV infection,

• As mandated by local health authority

• Absolute neutrophil count (ANC) ≥ 500/µL

• Growth factor and/or transfusion support is permissible to stabilizeparticipant 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 stabilizeparticipant prior to study treatment if needed

• No lower limit if cytopenia is related to bone marrow involvement

• Platelets ≥ 25 000/µL

• Growth factor and/or transfusion support is permissible to stabilizeparticipant prior to study treatment if needed

• No lower limit if cytopenia is related to bone marrow involvement

• Creatinine ≤ 1.5 × upper limit of normal (ULN) OR measured or calculated creatinineclearance (glomerular filtration rate [GFR] can also be used in place of creatinineor CrCl) ≥ 30 mL/min for participant with creatinine levels > 1.5 × institutionalULN

• Creatinine clearance (CrCl) should be calculated per institutional standard

• Total bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for participants with totalbilirubin levels > 1.5 × ULN

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])and alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases)

• International normalized ratio (INR) OR prothrombin time (PT) ≤ 1.5 × ULN unlessparticipant is receiving anticoagulant therapy as long as PT or partialthromboplastin time (PTT) is within therapeutic range of intended use ofanticoagulants

• Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant isreceiving anticoagulant therapy as long as PT or PTT is within therapeutic range ofintended use of anticoagulants

• Cardiac (echocardiogram [Echo] or multi-gated acquisition scan [MUGA]) ejectionfraction ≥ 40%

Exclusion Criteria:

• Diagnosis of Richter Transformation

• Clinically significant (symptomatic) central nervous system (CNS) involvement attime of study enrollment. Previously treated CNS disease is allowed if theparticipant is asymptomatic. Incidental findings including positive cerebral spinalfluid (CSF) studies are not exclusionary

• Active infection and uncontrolled infection

• Active HBV/hepatitis C virus (HCV) infection

• Participants must have completed curative anti-viral therapy for HCV at least 4weeks prior to study enrollment

• Participants who are HBsAg positive are eligible if they have received HBVantiviral therapy for at least 4 weeks and have undetectable HBV viral loadprior to study enrollment

• Note: Participants should remain on anti-viral therapy throughout studyintervention and follow local guidelines for HBV anti-viral therapy postcompletion of study intervention

• HIV with a detectable viral load or a CD4 count ≤ 350 cells/µL at time of screening

• Participants with HIV who do not meet the above criteria are eligible if theyare on a stable antiretroviral therapy (ART) regimen (ART must not be strongCYP3A4 inducers) for at least 4 weeks prior to study entry and are compliantwith ART are eligible

• Patients with an AIDS defining opportunistic infection in the past 12 monthsprior to screening

• Gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypasssurgery, gastrectomy)

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

• Corrected QT interval (QTc) prolongation (defined as a QTc > 450 msecs) or othersignificant electrocardiogram (ECG) abnormalities including second degreeatrioventricular (AV) block type II, third degree AV block, or bradycardia (ventricular rate less than 50 beats/min)

• Known allergy/sensitivity to nemtabrutinib or any of the excipients

• Known prior progressive disease while on nemtabrutinib

• NOTE: Refer to the investigator's brochure (IB) for details regarding priorrecipients of nemtabrutinib

• History of severe bleeding disorder defined as an ongoing congenital or acquiredcondition that leads to an increased likelihood of bleeding

• History of a second malignancy

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

• A participant of childbearing potential (POCBP) who has a positive urine pregnancytest within 72 hours prior to study enrollment. If the urine test is positive orcannot be confirmed as negative, a serum pregnancy test will be required

• Note: In the event that 72 hours have elapsed between the screening pregnancytest and the first dose of study treatment, another pregnancy test (urine orserum) must be performed and must be negative in order for participant to startreceiving study medication

• Need or anticipation of need for additional bridging therapy in addition tonemtabrutinib

• Palliative radiation therapy for less than 2 weeks or the use of prednisone 30mg (or the prednisone equivalent) for a maximum of 5 days is allowed and isnot exclusionary

• Currently being treated with the following drugs:

• 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 ofany of the above treatments is required for a participant to be eligible forstudy enrollment

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

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

• Has received an investigational agent or has used an investigational device within 4weeks prior to study intervention administration

• Has not adequately recovered after 4 weeks from major surgery or has ongoingsurgical complications

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

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality or other circumstance that might confound the results of the study,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 theopinion of the treating investigator

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

• Any condition or history that the study investigator deems not in the best interestof the patient to participate