Nemtabrutinib With Rituximab for the Treatment of Patients With Mantle Cell Lymphoma

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorizedrepresentative.

• Assent, when appropriate, will be obtained per institutional guidelines

• Age: ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) ≤ 2

• Diagnosis of MCL established by histologic assessment including one of thefollowing:

• Immunohistochemistry of the biopsy

• Flow cytometry of the biopsy

• Requiring treatment for MCL, and for which no prior systemic anticancer therapieshave been received

• Local radiotherapy not exceeding a total dose of 20 gray (Gy) at least 2 weeksprior the first dose of study therapy is allowed

• Laboratory, radiographic, physical exam findings and/or symptoms attributable toMCL.

• Asymptomatic patients with blastoid or pleomorphic variant can be enrolled

• Radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (asdefined by Lugano Classification for non hodgkin's lymphoma [NHL])

• Without bone marrow involvement: absolute neutrophil count (ANC) ≥ 1,000/mm^3, withbone marrow involvement: ANC ≥ 500/mm^3

• NOTE: Growth factor is not permitted within 7 days of ANC assessment unlesscytopenia is secondary to disease involvement

• Without bone marrow involvement: platelets ≥ 75,000/mm^3 with bone marrowinvolvement: platelets ≥ 30,000/mm^3

• NOTE: Platelet transfusions are not permitted within 7 days of plateletassessment unless cytopenia is secondary to disease involvement

• Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN forparticipants with total bilirubin levels > 1.5 × ULN

• Aspartate aminotransferase (AST) ≤ 2.5 x ULN

• Alanine aminotransferase (ALT) ≤ 2.5 x ULN

• Serum creatinine ≤ 1.5 × ULN OR creatinine clearance of ≥ 30 mL/min per 24 hoururine test or the Cockcroft-Gault formula

• If not receiving anticoagulants: International normalized ratio (INR) OR prothrombintime (PT) ≤ 1.5 × ULN, if on anticoagulant therapy: PT must be within therapeuticrange of intended use of anticoagulants

• If not receiving anticoagulants: activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN, if on anticoagulant therapy: aPTT must be within therapeutic range ofintended use of anticoagulants

• Seronegative for hepatitis C virus (HCV), hepatitis B virus (HBV) (surface antigennegative) OR

• If seropositive for HBV or HCV, nucleic acid quantitation must be performed.Viral load must be undetectable. Patients with occult or prior HBV infection (defined as negative hepatitis B surface antigen [HBsAg] and positive hepatitisB core antibody [HBcAb]) may be included if HBV deoxyribonucleic acid (DNA) isundetectable, if they are willing to undergo DNA testing on day 1 of everycycle and every three months for at least 12 months after the last cycle ofstudy treatment

• Participants with HIV are eligible if they meet ALL the following:

• CD4 count > 350 cells/uL at screening

• The HIV viral load is below the detectable level as per locally availabletesting

• Are on a stable antiretroviral therapy (ART) regimen for at least 4 weeks priorto study entry

• NOTE: ART includes drugs, which are NOT strong CYP3A4 inducers (participants receiving ART that are strong CYP3A4 inducers are noteligible to be included in the study).

• HIV screening tests are not required unless:

• Known history of HIV infection

• As mandated by local health authority

• Are compliant with their ART NOTE: If the participant has had an AIDS definingopportunistic infection in the past 12 months prior to screening, they are noteligible to be included in the study

• Person of childbearing potential (POCBP): negative urine or serum pregnancy test. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required

• 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

• Rituximab: 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'sreview of the participant's medical records, medical examination, or medical historyinterview) as detailed below:

• Uses a penile/external condom plus nonparticipant of childbearing potential who isnot currently pregnant and should also be advised of the benefit for that partner touse an additional method of contraception, as a condom may break or leak.

• Note: Participants capable of producing ejaculate whose partner is pregnant orbreastfeeding must agree to use penile/external condom during each episode ofsexual activity in which the partner is at risk of drug exposure via ejaculate.

• Contraceptive use by participants capable of producing sperm should be consistentwith local regulations regarding the methods of contraception for thoseparticipating in clinical studies. If the contraception requirements in the locallabel for any of the study interventions are more stringent than the requirementsabove, 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-vaginalintercourse as their preferred and usual lifestyle (abstinent on a long-termand persistent basis), during the intervention period and for at least the timeneeded to eliminate each study intervention after the last dose of studyintervention. The length of time required to continue contraception for eachstudy intervention is:

• Nemtabrutinib: 1 month

• Rituximab: 12 months

• The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose ofstudy intervention. Contraceptive use by POCBPs should be consistent with localregulations regarding the methods of contraception for those participating inclinical studies. If the contraception requirements in the local label for anyof the study interventions are more stringent than the requirements above, thelocal label requirements are to be followed.

• Has a negative highly sensitive pregnancy test (urine or serum) as required by localregulations within 24 hours (for urine test) or 72 hours (for serum test) before thefirst dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, theparticipant must be excluded from participation if the serum pregnancy result ispositive.

• Abstains from breastfeeding during the study intervention period and for at least 30days after study intervention with nemtabrutinib.

• Medical history, menstrual history, and recent sexual activity has been reviewed bythe investigator to decrease the risk for inclusion of a POCBP with an earlyundetected pregnancy

Exclusion Criteria:

• Chronic systemic corticosteroid use > 20 mg/day of prednisone or equivalent.Patients who received corticosteroid treatment with ≤ 20 mg/day of prednisone orequivalent must be documented to be on a stable dose of at least 4 weeks' durationprior to day 1 of cycle 1. Patients may have received a brief (≤ 14 days) course ofsystemic steroids (≤ 100 mg prednisone equivalent per day) prior to initiation ofstudy therapy for control of lymphoma-related symptoms

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

• Unstable cardiac disease as defined by one of the following:

• Acute myocardial infarction (MI) within the past 6 months

• NYHA (New York Heart Association) heart failure class III-IV

• Unstable angina (angina symptoms at rest) or new-onset angina (begun within thelast 3 months)

• Corrected QT (QTc) prolongation (defined as a Fridericia's corrected QT interval [QTcF] > 450 msecs) or other significant electrocardiogram (ECG) abnormalitiesincluding second degree atrioventricular (AV) block type II, third degree AV block,or bradycardia (ventricular rate less than 50 beats/min)

• Positive for hepatitis C virus (HCV) virus by polymerase chain raction (PCR) atscreening. Testing only required if the hepatitis (hep) C antibody is positive

• AIDS-defining opportunistic infection in the past 12 months prior to screening

• Known allergy/sensitivity (≥ grade 3) to nemtabrutinib or any of the excipients;history of allergic reactions attributed to compounds of similar chemical orbiologic composition to study agents

• Clinically significant uncontrolled illness

• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episodeof infection (as evaluated by the investigator) within 4 weeks prior to the firststudy treatment

• Primary or secondary central nervous system (CNS) lymphoma at the time ofrecruitment or history of CNS lymphoma

• Other active malignancy. Exceptions include malignancy treated with curative intentand no known active disease present for ≥ 2 years prior to initiation of protocoltherapy; adequately treated non-melanoma skin cancer or lentigo maligna (melanoma insitu) without evidence of disease; adequately treated in situ carcinomas (e.g.,cervical, esophageal, etc.) without evidence of disease; asymptomatic prostatecancer managed with "watch and wait" strategy

• POCBP: Pregnant or breastfeeding

• Patients with gastrointestinal dysfunction and/or clinically significant medicalcondition of malabsorption, inflammatory bowel disease, chronic conditions whichmanifest with diarrhea, refractory nausea, vomiting or any other condition that willinterfere significantly with drug absorption (e.g., gastric bypass surgery,gastrectomy)

• Any other condition that would, in the investigator's judgment, contraindicate thepatient's participation in the clinical study due to safety concerns with clinicalstudy procedures

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)