Mosunetuzumab and Polatuzumab Vedotin for the Treatment of Patients with Relapsed or Refractory Grade 1-3a Follicular Lymphoma

Inclusion Criteria:

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

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

• Be willing to provide tissue from a fresh core or excisional biopsy (performed asstandard of care) of a tumor lesion prior to starting study therapy or fromdiagnostic tumor biopsies

• If unavailable, exceptions may be granted with study principal investigator (PI) approval

• Age: ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) ≤ 2

• Histologically confirmed diagnosis of follicular lymphoma grade 1-3a according tothe World Health Organization (WHO) classification. Note: A history of diffuse largeB-cell lymphoma (DLBCL) and/or grade 3b follicular lymphoma is allowed (follicularlarge B-cell lymphoma in the WHO 5th classification of mature B-cell lymphoma) butthese cannot be present at the time of study enrollment. Enrollment of any suchcases on this study must receive prior approval by the study PI

• Relapsed/ refractory disease after at least one prior line of therapy. Relapse musthave been confirmed histologically

• Tumor must be positive for CD20 by immunohistochemistry or flow cytometry after themost recent therapy. Note: As a pan-B marker, CD79B+ is nearly always present and isnot a criterion for inclusion

• Active disease requiring treatment per treating physician's decision

• Radiographically measurable disease by Lugano criteria (e.g., one or more nodalsites of disease ≥ 1.5 cm and/or at least one extranodal site of disease ≥ 1.0 cm inlongest dimension)

• Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prioranti-cancer therapy

• WITHOUT BONE MARROW INVOLVEMENT BY LYMPHOMA: Absolute neutrophil count (ANC) ≥ 1,000/mm^3. NOTE: Growth factor is not permitted within 7 days of ANC assessmentunless cytopenia is secondary to disease involvement

• WITH BONE MARROW INVOLVEMENT BY LYMPHOMA AND/OR DISEASE-RELATED NEUTROPENIAS: ANC ≥ 500/mm^3. NOTE: Growth factor is not permitted within 7 days of ANC assessmentunless cytopenia is secondary to disease involvement

• WITHOUT BONE MARROW INVOLVEMENT BY LYMPHOMA: Platelets ≥ 75,000/mm^3. NOTE: Platelettransfusions are not permitted within 7 days of platelet assessment unless cytopeniais secondary to disease involvement

• WITH BONE MARROW INVOLVEMENT BY LYMPHOMA AND/OR DISEASE-RELATED CYTOPENIAS:Platelets ≥ 50,000/mm^3. NOTE: Platelet transfusions are not permitted within 7 daysof platelet assessment unless cytopenia is secondary to disease involvement

• Hemoglobin ≥ 8 g/dL. NOTE: Red blood cell transfusions are not permitted within 7days of hemoglobin assessment unless cytopenia is secondary to disease involvement

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN). If hepatic involvement bylymphoma, or Gilbert's disease: ≤ 3 x ULN

• Aspartate aminotransferase (AST) ≤ 2.5 x ULN. If hepatic involvement by lymphoma:AST ≤ 5 x ULN

• Alanine aminotransferase (ALT) ≤ 2.5 x ULN. If hepatic involvement by lymphoma: ALT ≤ 5 x ULN

• Creatinine clearance of ≥ 40 mL/min per 24 hour urine test or the Cockcroft-Gaultformula

• IF NOT RECEIVING ANTICOAGULANTS: International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN

• IF ON ANTICOAGULANT THERAPY: PT must be within therapeutic range of intended use ofanticoagulants

• IF NOT RECEIVING ANTICOAGULANTS: Activated partial thromboplastin time (aPTT) ≤ 1.5x ULN

• IF ON ANTICOAGULANT THERAPY: aPTT must be within therapeutic range of intended useof anticoagulants

• WOMEN OF CHILDBEARING POTENTIAL (WOCBP): Negative urine or serum pregnancy test. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required

• Agreement by females of childbearing potential to abstain from heterosexualintercourse or use two adequate method of birth control, including at least 1 methodwith a failure rate of < 1% per year, for at least 28 days prior to day 1 of cycle 1, during the treatment period (including periods of treatment interruption), until 3 months after the final dose mosunetuzumab, 3 months after the last dose ofpolatuzumab vedotin, and 3 months after the last dose of tocilizumab (ifapplicable). Women must refrain from donating eggs during this same period.Agreement by males to abstain from heterosexual intercourse or use a condom withfemale partners of childbearing potential or pregnant female partners during thetreatment period and until 5 months after the last dose of polatuzumab vedotin, and 2 months after the last dose of tocilizumab (if applicable). Men must refrain fromdonating sperm during this same period

• Childbearing potential defined as not being surgically sterilized (men andwomen) or have not been free from menses for > 1 year (women only) with noidentified cause other than menopause

• Examples of contraceptive methods with a failure rate of < 1% per year includebilateral tubal ligation, male sterilization, established proper use ofhormonal contraceptives that inhibit ovulation, hormone releasing intrauterinedevices, and copper intrauterine devices. The reliability of sexual abstinenceshould be evaluated in relation to the duration of the clinical trial and thepreferred and usual lifestyle of the patient. Periodic abstinence (e.g.,calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawalare not acceptable methods of contraception

Exclusion Criteria:

• Prior treatment with mosunetuzumab or other CD20-directed bispecific antibodies.Prior exposure to 2 or less doses without evidence of resistance is allowed

• Prior treatment with polatuzumab vedotin or with an antibody-drug conjugatecontaining monomethyl auristatin E (MMAE). Prior exposure to 2 or less doses withoutevidence of resistance is allowed

• Allogeneic stem cell transplant within 2 years prior to day 1 of protocol therapy,requires immunosuppression, or has evidence of active-versus-host-disease

• Patients who had an allogeneic transplant > 2 years prior to day 1 of protocoltherapy must additionally have been stable off immunosuppressive agents for ≥ 2months

• Autologous stem cell transplant within 100 days prior to day 1 of protocol therapy

• Chimeric antigen receptor (CAR)-T therapy within 30 days prior to day 1 of protocoltherapy

• Prior use of any anti-lymphoma treatment with monoclonal antibody,radioimmunoconjugate or antineoplastic drug conjugate (ADC) within 4 weeks prior today 1 of protocol therapy

• Treatment with any chemotherapeutic agent, or treatment with any other anti-canceragent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug,whichever is shorter, prior to day 1 of protocol therapy

• Treatment with radiotherapy within 2 weeks prior to day 1 of protocol therapy

• If patients have received radiotherapy within 4 weeks prior to prior to day 1of protocol therapy, patients must have at least one measurable lesion outsideof the radiation field. Patients who have only one measurable lesion that waspreviously irradiated but subsequently progressed are eligible

• Live vaccine within 30 days prior to day 1 of protocol therapy

• Systemic immunosuppressive therapy (including, but not limited to, cyclophosphamide,azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF]agents) with the exception of corticosteroid treatment for lymphoma symptom controlmust be tapered down to ≤ 10 mg/day prednisone or equivalent 14 days prior to day 1of protocol therapy. Exceptions are:

• Inhaled or topical steroids

• Use of mineralocorticoids for management of orthostatic hypotension

• Use of physiologic doses of corticosteroids for management of adrenalinsufficiency

• Use of 4 or less pulsed doses of steroids (i.e. dexamethasone) for urgentstabilization of lymphoma or symptom management

• Grade ≥ 2 peripheral neuropathy

• History of severe allergic or anaphylactic reaction to humanized, chimeric or murinemonoclonal antibodies (or recombinant antibody-related fusion proteins)

• History of solid organ transplantation

• History of progressive multifocal leukoencephalopathy (PML)

• Known or suspected history of hemophagocytic lymphohistiocytosis (HLH)

• Significant active pulmonary disease (e.g., bronchospasm and/or obstructivepulmonary disease)

• Pneumonitis or interstitial lung disease requiring ongoing corticosteroid orimmunosuppression and/or requirement for supplemental oxygen

• Patients with any other history of pneumonitis or interstitial lung disease maybe eligible after discussion with the study PI

• Positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen orpolymerase chain reaction (PCR) test within 7 days prior to day 1 of protocoltherapy

• 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 requiring treatment with IV antibiotics or hospitalization (relating tothe completion of the course of antibiotics) within 2 weeks prior to the first studytreatment administration

• Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Patientswith past HBV infection (defined as negative hepatitis B surface antigen [HBsAg] andpositive hepatitis B core antibody [HBcAb]) are eligible if HBV deoxyribonucleicacid (DNA) is undetectable. Patients who are positive for HCV antibody are eligibleif PCR is negative for HCV ribonucleic acid (RNA). Testing to be done only inpatients suspected of having infections or exposures

• Known active human immunodeficiency virus (HIV) infection. Subjects who have anundetectable or unquantifiable HIV viral load with CD4 > 200 and are on highlyactive antiretroviral therapy (HAART) medication are allowed. Testing to be doneonly in patients suspected of having infections or exposures

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

• Known active central nervous system (CNS) involvement by lymphoma, includingleptomeningeal involvement

• Previously treated CNS involvement including disease with leptomeningealinvolvement, is acceptable. Patients should be neurologically stable prior tostudy entry, and receiving a stable or decreasing corticosteroid dose

• History of CNS disease which was symptomatic or required treatment in the past 1year, such as stroke, epilepsy, CNS vasculitis or neurodegenerative disease

• Symptomatic cardiac disease such as New York Heart Association class III or IV (including symptomatic ventricular dysfunction, symptomatic coronary artery disease,and symptomatic arrhythmias), cerebrovascular event/stroke or myocardial infarctionwithin the past 6 months

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

• Active autoimmune disease requiring systemic treatment

• History of autoimmune disease, including, but not limited to, myasthenia gravis,myositis, autoimmune hepatitis, inflammatory bowel disease, vascular thrombosisassociated with antiphospholipid syndrome, Wegener granulomatosis, Guillain-Barrésyndrome, multiple sclerosis, vasculitis, or glomerulonephritis

• Patients with a history of autoimmune-related hypothyroidism on a stable doseof thyroid replacement hormone may be eligible

• Patients with controlled type 1 diabetes mellitus who are on an insulin regimenare eligible for the study

• Patients with a history of rheumatoid arthritis, Sjögren syndrome, systemiclupus erythematosus may be eligible after discussion with the study PI

• Patients with a history of disease-related immune thrombocytopenic purpura,autoimmune hemolytic anemia, or other stable autoimmune diseases may beeligible after discussion with the study PI

• Recent major surgery (within 4 weeks) prior to start of protocol therapy, other thanfor diagnosis

• History of another primary malignancy that has not been in remission for at least 2years, with the following exceptions:

• Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma insitu) without evidence of disease

• Adequately treated in situ carcinomas (e.g. cervical, esophageal) withoutevidence of disease

• Asymptomatic prostate cancer managed with a watch-and-wait strategy

• If the malignancy is expected to not require any treatment for at least 2 years (this exception should be discussed with the study PI)

• Concomitant investigational therapeutic therapy or within 7 days prior to initiationof study treatment

• FEMALES ONLY: Pregnant or breastfeeding

• 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)