A Study of Polatuzumab Vedotin, Rituximab and Dose Attenuated CHP in Older Patients with DLBCL

Inclusion Criteria:

• Voluntary written informed consent before performance of any study-specificprocedure not part of routine medical care, with the understanding that consent maybe withdrawn by the subject at any time without prejudice to future medical care.Subjects must be able to understand and be willing to sign the written informedconsent form.

• Men and women aged greater than or equal to 75 years of age

• ECOG performance status of 0-3

• Histologically-confirmed DLBCL, NOS, NOS, high grade B-cell lymphoma with MYC, BCL2and/or BCL6 rearrangements, high grade B-cell lymphoma, NOS, and grade 3b follicularlymphoma by 2016 WHO classification by site hematopathologist

• Histologic transformation (HT) will be included on the study. This must beconfirmed with a biopsy. Patients with HT may have received prior treatment forindolent lymphoma including chemoimmunotherapy, but must not have received ananthracycline-containing regimen in the past. Patients with Richter'stransformation will be eligible.

• Composite and discordant lymphomas containing both indolent and large cellfeatures will be included

• Has received no prior therapy for aggressive B-cell lymphoma or HT with thefollowing exceptions:

• A course of corticosteroids given for lymphoma related symptoms.

• A course of cyclophosphamide or vincristine with or without steroids given forlymphoma related symptoms.

• One cycle of anthracycline containing chemotherapy such as R-CHOP or R-miniCHOPgiven urgently for aggressive disease.

Patient is not felt to be a candidate for standard dose R-CHOP due to age or comorbidities, per the site investigator.

• Ejection fraction of ≥ 45% on echocardiogram or MUGA

• Patient has a platelet count of ≥75,000/μL within 14 days before enrollment unlessinadequate function is due to bone marrow infiltration with aggressive B-celllymphoma

• Patient has an absolute neutrophil count of ≥1,500/ μL within 14 days beforeenrollment unless inadequate function is due to bone marrow infiltration withaggressive B-cell lymphoma

• Patient has a calculated or measured creatinine clearance of >30 mL/minute within 14days before enrollment.

• Total bilirubin must be less than 1.5 times the upper limit of normal (ULN) unlessthe elevation is known to be due to Gilbert syndrome or hepatic involvement withaggressive B-cell lymphoma in which case it can be ≤ 3.0 times the ULN.

• ALT or AST must be ≤ 2.5 times the ULN.

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse a condom, and agreement to refrain from donating sperm, as defined below:

• With female partners of childbearing potential or pregnant female partners, menmust remain abstinent or use a condom during the treatment period and for atleast 5 months after the last dose of polatuzumab vedotin to avoid exposing theembryo or fetus for the duration of the pregnancy. Men must refrain fromdonating sperm during this same period.

• The reliability of sexual abstinence should be evaluated in relation to theduration 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 preventingdrug exposure. Male patients considering preservation of fertility should banksperm before study treatment.

Exclusion Criteria:

• History of, or clinically apparent central nervous system (CNS) lymphoma

• Primary mediastinal B-cell lymphoma or EBV positive DLBCL

• Patient is receiving peritoneal dialysis or hemodialysis

• Patient has > Grade 1 peripheral neuropathy.

• New York Heart Association class III heart failure or EF <45%

• Patient has received other investigational drugs with 14 days before enrollment

• Prior exposure to anthracycline except for one cycle of therapy given urgently forlymphoma.

• Patient has concomitant active malignancy that the treating physician or PI feelsmay interfere with the ability to measure the primary or secondary outcomes

• Patients with stage 1 cancers are eligible after definitive treatment.

• Patients with low grade prostate cancer who are managed with observation areeligible.

• Patients with other malignancies that have been treated with curative intentwill be included if they are in documented remission without treatment for ≥ 3years prior to enrollment.

• Patient is known to be HIV positive (test result not required for enrollment).

• Patient has active hepatitis B with a positive surface antigen or viral load.Carriers of hepatitis B virus should be closely monitored for clinical andlaboratory signs of active HBV infection and for signs of hepatitis throughout studyparticipation according to national and local guidelines. Those at high risk ofreactivation should be placed on appropriate antiviral therapy as per nationalguidelines.

• History of solid organ transplantation, or post-transplant lymphoproliferativedisorder

• Patient has history of allogeneic stem cell transplantation.

• Serious medical or psychiatric illness likely to interfere with participation inthis clinical study.

• Any clinically significant abnormality in screening blood chemistry, hematology, orurinalysis results that, in the judgment of the investigator, would impede adequateevaluation of adverse