Mantle Cell Lymphoma (MCL) Clinical Trials

• • Confirmed diagnosis of relapsed or refractory mantle cell lymphoma who meets institutional eligibility criteria to receive standard of care brexu-cel therapy

‣ Is an individual of any sex/gender, who are at least 18 years of age on the day of signing informed consent with confirmed diagnosis of R/R MCL will be enrolled in this study

⁃ The participant (or legally acceptable representative if applicable) has provided documented informed consent/assent for the trial

⁃ Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention

⁃ 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 virus 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 allocation

‣ \* 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

⁃ 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 allocation

∙ Hepatitis C screening tests are not required unless:

‣ Known history of HCV infection

⁃ As mandated by local health authority

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

‣ \* The CD4 count is ≥ 350 cells/uL at screening

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

∙ Are on a stable anti-retroviral therapy (ART) regimen for at least 4 weeks prior to study entry

∙ NOTE: ART includes drugs, which are NOT strong cytochrome P450 (CYP)3A4 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 or institutional standards

∙ Are compliant with their ART

⁃ Adequate organ function as defined. Specimens must be collected within 10 days prior to treatment initiation with nemtabrutinib in both pre-CAR and post-CAR T phase

⁃ Absolute neutrophil count (ANC) ≥ 500/uL (within 10 days prior to treatment initiation with nemtabrutinib in both pre-CAR and post-CAR T phase)

‣ \* Growth factor (granulocyte colony-stimulating factor \[GCSF\] and thyroid peroxidase \[TPO\] agonist) and/or transfusion support is permissible to stabilize participant at least 7 days before screening or planned start of nemtabrutinib

⁃ Platelets ≥ 25000/uL (within 10 days prior to treatment initiation with nemtabrutinib in both pre-CAR and post-CAR T phase)

‣ \* Growth factor (GCSF and TPO agonist) and/or transfusion support is permissible to stabilize participant at least 7 days before screening or planned start of nemtabrutinib

⁃ Hemoglobin ≥ 7 g/dL (within 10 days prior to treatment initiation with nemtabrutinib in both pre-CAR and post-CAR T phase)

‣ \* Growth factor (GCSF and TPO agonist) and/or transfusion support is permissible to stabilize participant at least 7 days before screening or planned start of nemtabrutinib

⁃ Creatinine ≤ 1.5 x upper limit of normal (ULN) (within 10 days prior to treatment initiation with nemtabrutinib in both pre-CAR and post-CAR T phase) OR measured or calculated creatinine clearance ≥ 30 mL/min for participant with creatinine levels \> 1.5 x institutional ULN (glomerular filtration rate \[GFR} can also be used in place of creatinine or creatinine clearance \[CrCl\])

‣ \* Creatinine clearance (CrCl) should be calculated per institutional standard

⁃ Total bilirubin ≤ 1.5 x ULN (within 10 days prior to treatment initiation with nemtabrutinib in both pre-CAR and post-CAR T phase) OR direct bilirubin ≤ ULN for participants with total bilirubin levels \> 1.5 x ULN

⁃ Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) ≤ 5 x ULN (within 10 days prior to treatment initiation with nemtabrutinib in both pre-CAR and post-CAR T phase)

⁃ International normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN (within 10 days prior to treatment initiation with nemtabrutinib in both pre-CAR and post-CAR T phase) unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

⁃ 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

∙ Cyclophosphamide: 4 months

∙ Fludarabine: 3 months

∙ 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

∙ Cyclophosphamide: 12 months

∙ Fludarabine: 6 months

⁃ 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 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 (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

⁃ 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