The purpose of this clinical trial it to test the safety and tolerability of the study drugs mosunetuzumab in combination with pirtobrutinib in patients with relapsed or refractory Waldenstrom's Macroglobulinemia.

Inclusion Criteria:

• Subjects aged ≥ 18 years with documented diagnosis of WM with the definition of measurable disease

• Subjects who are able to comply with the study protocol.

• Subjects with relapsed or refractory WM who have received at least one prior line of therapy.

  • Must have received prior treatment with covalent BTK inhibitor or have declined such treatment.
  • Prior autologous stem cell transplant is permitted if completed ≥ 100 days prior to treatment.
  • Prior allogeneic transplants are not permitted.

• Subjects must have an indication for treatment per 2nd International Workshop on WM35

• ECOG Performance Status ≤ 2

  • Adequate organ function as defined as:

  • Hematologic:

    • Absolute neutrophil count ≥ 1000/mm3 independent of G-CSF support, unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case ANC of 750 cells/mm3 (0.75 x 10^9/L) is permissible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
    • Platelet count ≥75,000 cells/mm3 (≥75 x 10^9/L) independent of transfusion support unless there is documented bone marrow involvement in which case platelet count of 50,000 cells/mm3 (50 x 10^9/L) is permissible. Patients must be responsive to transfusion support if given for thrombocytopenia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
    • Hemoglobin of ≥ 8.5 g/dL (≥ 85 g/L) independent of transfusion support unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case hemoglobin of 7 g/dL (70 g/L) is permissible. Patients must be responsive to transfusion support if given for anemia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
    • Coagulation: Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN.

  • Hepatic:

    • Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN) or ≤3 x ULN with document liver involvement and/ or Gilbert's disease
    • AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN
    • Participants with liver metastases will be allowed to enroll with AST and ALT levels ≤ 5 x ULN.

  • Renal:

    • Estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula.

• Participants must adhere to the following sex and contraceptive/barrier requirements:

  • If participant is of childbearing potential, they must have a negative pregnancy test

  • For participants of non-childbearing potential: The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

  • < 50 years of age:

    • Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and

    • Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution

      --≥ 50 years of age:

    • Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or

    • Had radiation-induced menopause with last menses >1 year ago; or

    • Had chemotherapy-induced menopause with last menses >1 year ago

    • Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution

  • Participants of childbearing potential and participants with a sexual partner of childbearing potential must agree to use a highly effective method of contraception and lactation requirements as described in Sections 5.4.1 and 5.4.2.

• Able to swallow oral tablets.

• Clinically significant adverse effects from any prior oncologic treatment (e.g. prior surgery, radiotherapy, or other antineoplastic therapy) must have recovered to grade 1 or have been determined to be clinically stable per the Investigator.

• Subject or their legal representative is able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.

Exclusion Criteria:

• History of transformation of indolent disease to DLBCL

• Active or history of CNS lymphoma or leptomeningeal infiltration

• Prior treatment with a non-covalent BTK inhibitor

• Prior treatment with CD20-directed bispecific antibody therapy

• Receiving other investigational agents.

• Receipt of a live, attenuated vaccine within 4 weeks before first dose of study treatment or anticipation that such a live attenuated vaccine will be required during the study

  • Patients must not receive live, attenuated vaccines (e.g., FluMistâ) while receiving study treatment or after the last dose until B-cell recovery to the normal ranges.
  • Inactivated influenza vaccination should be given during the influenza season only.
  • An approved coronavirus disease 2019 (COVID-19) vaccine (messenger RNA [mRNA], inactivated virus, and replication deficient viral vector vaccines) is allowed, as these are not considered live vaccines.

• Receipt of systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) with the exception of corticosteroid treatment £ 10 mg/day prednisone or equivalent within 2 weeks prior to the first dose of mosunetuzumab

  • Patients who received acute, low-dose, systemic immunosuppressant medications (e.g., single dose of dexamethasone for nausea or B-symptoms) may be enrolled in the study if deemed appropriate by the investigator.
  • The use of inhaled corticosteroids is permitted.
  • The use of mineralocorticoids for management of orthostatic hypotension is permitted.
  • The use of physiologic doses of corticosteroids for management of adrenal insufficiency is permitted.

• History of solid organ transplantation

• History of severe allergic or anaphylactic reaction to humanized, chimeric or murine monoclonal antibodies (MAbs) or known sensitivity or allergy to murine products

• Known active bacterial, viral (including SARS-CoV-2), fungal, or other infection, or any major episode of infection requiring treatment with IV antibiotics within 4 weeks of Day 1 of Cycle 1

• Known or suspected chronic active Epstein-Barr virus (EBV) infection

• Known or suspected history of macrophage activation syndrome (MAS) / hemophagocytic lymphohistiocytosis (HLH)

• History of confirmed progressive multifocal leukoencephalopathy (PML)

• Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease

  • Patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 1 year and have no significant residual neurologic deficits as judged by the investigator are allowed.
  • Patients with a history of epilepsy who have had no seizures in the past 1 year while not receiving any anti-epileptic medications are allowed.

• Clinically significant active malabsorption syndrome or other conditions likely to affect gastrointestinal absorption of the study drug

• History of bleeding diathesis

• Major surgery 4 weeks prior to starting study therapy or participant has not fully recovered from major surgery.

• The diagnosis of another malignancy which, in the opinion of the Investigator, is likely to negatively impact the participant's safety or ability to participate in the study.

• Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:

  • Cardiovascular disorders:

    • Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious cardiac arrhythmias.
    • Unstable angina or acute coronary syndrome within 6 months prior to first dose of study therapy.
    • History of myocardial infarction within 6 months prior to first dose of study therapy
    • QTc prolongation defined as a QTcF > 470 ms.

  • Correction of suspected drug induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.

  • Correction for underlying bundle branch block (BBB) allowed.

  • Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker

    ---Left ventricular ejection fraction < 40% within 12 months prior to first dose of study therapy.

  • Any other condition that would, in the Investigator's judgment, contraindicate the participant's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, social/ psychological issues, etc.)

• Evidence of other clinically significant uncontrolled condition(s) or other clinically significant active disease process which, in the opinion of the investigator, is likely to pose a risk for patient participation.

• Known HIV infection.

• Clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis

  --Note: Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Participants with positive anti-HBc and negative HBV DNA should be on prophylactic nucleo(t)side analogue therapy to prevent reactivation with serial HBV DNA PCR monitoring Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

• Known active cytomegalovirus (CMV) infection.

• History of autoimmune disease, including, but not limited to myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis

  • Patients with a remote history of, or well-controlled, autoimmune disease with a treatment-free interval from immunosuppressive therapy for 12 months may be eligible to enroll if judged to be safe by the investigator.

  • Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone are eligible.

  • Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.

  • Patients with a history of disease-related immune thrombocytopenic purpura, or autoimmune hemolytic anemia may be eligible.

  • Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

    • Rash must cover 10% of body surface area
    • Disease is well controlled at baseline and requires only low-potency topical corticosteroids
    • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency oral corticosteroids within the previous 12 months.

• Positive SARS-CoV-2 test within 7 days prior to enrollment

• Substance abuse within 12 months prior to screening

• Medical, psychiatric, cognitive, or other conditions that may compromise the participant's ability to understand the participant information, give informed consent, comply with the study protocol or complete the study.

• Known prior severe hypersensitivity to investigational product or any component in its formulations (CTCAE v 6.0 Grade ≥ 3).

• Participants taking prohibited medications as described in Section 7.4.10.

• Subject has received prior standard or investigational anti cancer therapy as specified below:

  • Chimeric antigen receptor T-cell therapy within 60 days prior to Day 1 of Cycle 1.

  • Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1.

  • Prior treatment with monoclonal antibodies, chemotherapy, or antibody-drug conjugates within 4 weeks before first mosunetuzumab administration.

  • Treatment with any anticancer agent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to first dose of study treatment.

  • Radiotherapy

    • 14 days for local site radiation therapy
    • 6 weeks for prior radioisotope therapy
    • 12 weeks for 50% pelvic or total body irradiation