Mosunetuzumab in Combination With Pirtobrutinib in Patients With Relapsed or Refractory Waldenstrom Macroglobulinemia (MPOWER)

Exclusion Criteria

• •* 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.
• •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.