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

Confirmed diagnosis of CLL/SLL per International Workshop on Chronic Lymphocytic Leukemia (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 and Drug 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 percutaneous endoscopic gastro-jejunal (J PEG) tube

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

• 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 should include HBsAg 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 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

Platelets ≥ 25 000/µL

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

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

Total bilirubin ≤ 1.5 × 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 pyruvate transaminase [SGPT]) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases)

International normalized ratio (INR) OR prothrombin time (PT) ≤ 1.5 × 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

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

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

Diagnosis of Richter Transformation

Clinically significant (symptomatic) central nervous system (CNS) involvement at time of study enrollment. Previously treated CNS disease is allowed if the participant is asymptomatic. Incidental findings including positive cerebral spinal fluid (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 4 weeks prior to study enrollment
• Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to study enrollment
• 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

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 they are on a stable antiretroviral therapy (ART) regimen (ART must not be strong CYP3A4 inducers) for at least 4 weeks prior to study entry and are compliant with ART are eligible
• Patients with an AIDS defining opportunistic infection in the past 12 months prior to screening

Gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy)

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 interval (QTc) prolongation (defined as a QTc > 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 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 prior recipients of nemtabrutinib

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

History of a second malignancy

• 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

A participant of childbearing potential (POCBP) who has a positive urine pregnancy test within 72 hours prior to study 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 participant to start receiving study medication

Need or anticipation of need for additional bridging therapy in addition to nemtabrutinib

• 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 is not 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 of any of the above treatments is required for a participant to be eligible for study enrollment

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

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

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

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 a history or current evidence of any condition, therapy, or laboratory abnormality 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 the opinion of the treating investigator

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

Any condition or history that the study investigator deems not in the best interest of the patient to participate