Nemtabrutinib, Bortezomib, and Rituximab for WM

Inclusion Criteria

• •Participants are eligible to be included in the study only if all of the following criteria apply:
• •1. Confirmed diagnosis of WM in accordance with the consensus panel of the IWWM (per local evaluation), and treatment naïve
• •2. Symptomatic disease meeting at least 1 of the recommendations from the IWWM for requiring treatment.
• •3. Measurable disease defined as serum monoclonal IgM \> 0.5g/dL.
• •4. Is an individual of any sex/gender, who are at least 19 years of age on the day of signing informed consent (ICF).
• •5. 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
• •* 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), as described in Appendix 3 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
• •* 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. Additional requirements for pregnancy testing during and after study intervention are in Section X.
• •* 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.
• •6. The participant (or legally acceptable representative if applicable) has provided documented informed consent/assent for the trial.
• •7. 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.
• •8. The ability to swallow and retain oral medication.
• •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 must have completed curative anti-viral therapy at least 4 weeks prior to randomization.
• •Hepatitis C screening tests are not required unless:
• •* Known history of HCV infection
• •* As mandated by local health authority
• •11. Adequate organ function as defined in the following table (Table 5.1.1). Specimens must be collected within 7 days prior to randomization.
• •Table 5.1.1 Adequate organ function System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥500/µL a, b Platelets ≥25 000/µL a, b Hemoglobin ≥8 g/dL a, b Renal Creatinine OR Measured or calculated c creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR
• •≥30 mL/min for participant with creatinine levels \>1.5 × institutional ULN Hepatic Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases) Coagulation International normalized ratio (INR) OR prothrombin time (PT) 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 ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.
• •aGrowth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if needed.
• •bNo lower limit if cytopenia is related to bone marrow involvement. cCreatinine clearance (CrCl) should be calculated per institutional standard. Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.