Polatuzumab Vedotin and Combination Chemotherapy With or Without Glofitamab for the Treatment of Untreated Aggressive Large B-cell Lymphoma

Inclusion Criteria:

• Untreated aggressive B-cell large-B cell lymphoma (non-Hodgkin lymphoma) withadverse features that may predict sub-optimal response torituximab-cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), prednisone (R-CHOP) and in the opinion of the investigator would betreated with DA-EPOCH-R as standard of care. Subjects must be planned to receivefull course (6 cycles) chemoimmunotherapy as per clinical standard of care.Composite lymphomas are not excluded provided that the subject has not receive priorsystemic therapy for the indolent component and would receive DA-EPOCH-R as thestandard of care regimen for the aggressive component. Eligible histologies based on 2016 World Health Organization (WHO) classification include:

• High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 translocations

• High grade B-cell lymphoma, not otherwise specified (NOS)

• Diffuse large B-cell lymphoma (DLBCL) NOS

• Primary mediastinal B-cell lymphoma

• T-cell/histiocyte-rich large-B-cell lymphoma

• Epstein-Barr virus (EBV) + DLBCL, NOS

• ALK+ large B-cell lymphoma (must be CD20+)

• B-cell lymphoma, unclassifiable, with features intermediate between DLBCL andclassical Hodgkin lymphoma

• Be willing and able to provide written informed consent for the trial

• Be >= 18 years of age on day of signing informed consent

• Have measurable disease, including at least 1 nodal site measuring 1.5 cm or 1extranodal site measuring 1.0 cm in longest dimension on computed tomography (CT) orfluorodeoxyglucose-positron emission tomography (FDG-PET)

• Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG)performance scale (PS)

• Left ventricular ejection fraction (LVEF) >= 50% on cardiac multiple-gatedacquisition (MUGA) scan or cardiac echocardiogram (ECHO)

• Absolute neutrophil count (ANC) >= 1,000/uL except in cases of marrow infiltrationby lymphoma

• Platelets >= 75,000 / mcL except in cases of marrow infiltration by lymphoma orhypersplenism

• Hemoglobin >= 8 g/dL except in cases of marrow infiltration by lymphoma without redblood cell (RBC) transfusion within 14 days of first treatment

• Measured or calculated creatinine clearance (Glomerular filtration rate [GFR] canalso be used in place of creatinine or creatinine clearance [CrCl]) >= 40 mL/min.

• Creatinine clearance should be calculated per institutional standard

• Serum total bilirubin =< 1.5 X upper limit of normal (ULN) (Patients with documentedGilbert disease may be enrolled if total bilirubin =< 3.0 x ULN)

• Direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver involvement

• International Normalized Ratio (INR) or Prothrombin Time (PT) =< 1.5 X ULN unlesssubject is receiving anticoagulant therapy as long as PT or partial thromboplastintime (PTT) is within therapeutic range of intended use of anticoagulants

• Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject isreceiving anticoagulant therapy as long as PT or PTT is within therapeutic range ofintended use of anticoagulants, or subject is shown to have an antiphospholipidantibody on workup

• For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive methods that result in a failure rateof =< 1% per year during the treatment period and for at least 12 months after thelast dose of EPCH-R, 9 months after the last dose of polatuzumab, 2 months after thelast dose of glofitamab (Arm B participants), or 3 months after the last dose oftocilizumab (if applicable), whichever is longer. Women must refrain from donatingeggs during this same period. A woman is considered to be of childbearing potentialif she is post-menarcheal, has not reached a postmenopausal state (=<12 continuousmonths of amenorrhea with no identified cause other than menopause), and has notundergone surgical sterilization (removal of ovaries and/or uterus). The definitionof childbearing potential may be adapted for alignment with local guidelines orrequirements. Examples of contraceptive methods with a failure rate of =<1% per yearinclude bilateral tubal ligation, male sterilization, hormonal contraceptives thatinhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterinedevices. The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of the patient.Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulationmethods) and withdrawal are not acceptable methods of contraception

• For women of childbearing potential, a negative serum pregnancy test result duringscreening period. Women who are considered not to be of childbearing potential arenot required to have a pregnancy test

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse a condom, and agreement to refrain from donating sperm, as defined below: Withfemale partners of childbearing potential or pregnant female partners, men mustremain abstinent or use a condom during the treatment period and for at least 6months after the last dose of EPCH-R or polatuzumab, 2 months after the last dose ofglofitamab (Arm B participants), or 2 months after the last dose of tocilizumab (ifapplicable), whichever is longer. Men must refrain from donating sperm during thissame period. The reliability of sexual abstinence should be evaluated in relation tothe duration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not acceptable methods of preventing drugexposure. Male patients considering preservation of fertility should bank spermbefore study treatment

• ARM B ONLY: Negative SARS-CoV-2 antigen or PCR test within 7 days prior toenrollment

Exclusion Criteria:

• Contraindication to any of the individual components of glofitamab, tocilizumab orEPCH-R, including prior receipt of anthracyclines, or history of severe allergic oranaphylactic reactions to humanized or murine monoclonal antibodies, or knownsensitivity or allergy to murine products

• Prior systemic treatment for lymphoma with the exception of corticosteroids. Priorradiotherapy is allowed provided that this site is not used as a measurable site toassess response.

• Richter's transformation from chronic lymphocytic leukemia/small lymphocyticlymphoma is not allowed. Transformation from follicular or other indolent lymphomasis allowed provided that the subject has not received prior systemic therapy fortheir lymphoma and the aggressive component meets one of the criteria listed ininclusion criterion 1

• Diagnosis of Burkitt lymphoma

• Prior organ transplantation

• Current Grade > 1 peripheral neuropathy by clinical examination or demyelinatingform of Charcot-Marie-Tooth disease

• Prior systemic therapy for indolent lymphoma

• Prior use of any monoclonal antibody within 3 months of the start of cycle 1; anyinvestigational therapy within 28 days prior to the start of cycle 1; vaccinationwith live vaccines within 28 days prior the start of cycle 1 and at any time duringthe study treatment period

• Prior therapy for large B-cell lymphoma except for patients who require lymphomasymptom control during screening may receive steroids in the following manner: Up to 30 mg/day of prednisone or equivalent may be used for lymphoma symptom controlduring screening, including prior to finalization of staging (not included as partof pre-phase treatment) If glucocorticoid treatment is urgently required at higherdoses for lymphoma symptom control prior to the start of study treatment, tumorassessments must be completed prior to initiation of > 30-100 mg/day of prednisoneor equivalent. Prednisone > 30-100 mg/day or equivalent may be given for a maximumof 7 days as a pre-phase treatment. If patients exceed the allowed dosing ofcorticosteroids, patients may still be eligible for the study provided that baselineimaging is performed (or repeated) after completion of the course of higher dose ofsteroids. Allowed corticosteroid dosing resets from the point of imaging forward andpatients who do not exceed the allowed corticosteroid dosing from the point ofimaging until initiation of study treatment may enroll

• History of other malignancy that could affect compliance with the protocol orinterpretation of results except with permission of the principal investigator. Thefollowing are eligible without a specific waiver:

• Patients with a history of curatively treated basal or squamous cell carcinomaor melanoma of the skin or in situ carcinoma of the cervix at any time prior tothe study are eligible

• Patients with any malignancy appropriately treated with curative intent and themalignancy has been in remission without treatment for >= 2 years prior toenrollment are eligible

• Patients with low-grade, early-stage prostate cancer (Gleason score 6 or below,Stage 1 or 2) with no requirement for therapy at any time prior to study areeligible

• Evidence of significant, uncontrolled, concomitant diseases that could affectcompliance with the protocol or interpretation of results, including significantcardiovascular disease (such as New York Heart Association Class III or IV cardiacdisease, myocardial infarction within the last 6 months, unstable arrhythmias, orunstable angina) or pulmonary disease (including obstructive pulmonary disease andhistory of bronchospasm)

• Recent major surgery (within 4 weeks prior to the start of cycle 1), other than fordiagnosis

• History or presence of an abnormal electrocardiogram (ECG) that is clinicallysignificant in the investigator's opinion, including complete left bundle branchblock, second- or third-degree heart block, or evidence of prior myocardialinfarction

• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) which requires systemic treatment.Patients may proceed with screening during treatment for infection, but systemictreatment must be completed by cycle 1 day 1

• Positive test results for chronic hepatitis B infection (defined as positivehepatitis B surface antigen [HBsAg] serology):

• Patients with occult or prior hepatitis B infection (defined as positive totalhepatitis B core antibody and negative HBsAg) may be included if hepatitis B virus (HBV) DNA is undetectable at the time of screening. These patients must be willingto undergo monthly DNA testing and appropriate antiviral therapy as indicated byinstitutional standard

• Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serologytesting)

• Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

• History of uncontrolled human immunodeficiency virus (HIV)

• Patients with known diagnosis of HIV must have undetectable viral load, have a CD4count ≥ 200/μL, and be on anti-retroviral therapy. HIV positive patients should bemonitored per local/institutional standards while receiving study treatment

• Patients with a history of progressive multifocal leukoencephalopathy

• Pregnancy or lactation or intending to become pregnant during study

• ARM B ONLY: Known or suspected history of hemophagocytic lymphohistiocytosis (HLH)

• ARM B ONLY: Known or suspected chronic active Epstein-Barr virus infection

• ARM B ONLY: Current or past history of Waldenström macroglobulinemia

• ARM B ONLY: Current or past history of central nervous system (CNS) disease, such asstroke, epilepsy, CNS vasculitis, CNS lymphoma or neurodegenerative disease

• ARM B ONLY: Participants with a history of stroke who have not experienced a strokeor transient ischemic attack in the past 2 years and have no residual neurologicaldeficits, as judged by the investigator, are allowed

• ARM B ONLY: Active autoimmune disease which is not well controlled by therapy

• ARM B ONLY: Participants with a history of autoimmune-related hypothyroidism on astable dose of thyroid-replacement hormone may be eligible

• ARM B ONLY: Participants with controlled type 1 diabetes mellitus who are on aninsulin regimen are eligible for the study

• ARM B ONLY: Participants with active autoimmune disease with dermatologicmanifestations are eligible for the study

• ARM B ONLY: Participants with a history of autoimmune hepatitis, systemic lupuserythematosus, inflammatory bowel disease, vascular thrombosis associated withantiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, multiplesclerosis, or glomerulonephritis will be excluded

• ARM B ONLY: Participants with a history of immune thrombocytopenic purpura,autoimmune hemolytic anemia, Guillain-Barré syndrome, myasthenia gravis, myositis,rheumatoid arthritis, vasculitis, or other autoimmune disease will be excludedunless they have not required systemic therapy in the last 12 months

• ARM B ONLY: Clinically significant liver disease, including active viral or otherhepatitis, current alcohol abuse, or cirrhosis

• ARM B ONLY: Suspected active or latent tuberculosis (as confirmed by a positiveinterferon-gamma release assay)

• ARM B ONLY: Grade 3 infection within 4 weeks of treatment initiation