Diffuse Large B-Cell Lymphoma (DLBCL) Clinical Trials

• Previously untreated patients with CD20-positive DLBCL, including one of the following diagnoses by 2016 WHO classification of lymphoid neoplasms

‣ DLBCL, not otherwise specified (NOS)

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

⁃ Epstein-Barr virus-positive DLBCL, NOS

⁃ ALK-positive large B-cell lymphoma

⁃ HHV8-positive DLBCL, NOS

⁃ High-grade B-cell lymphoma (HGBCL), NOS

⁃ HGBCL with translocations of MYC and BCL-2, or MYC and BCL-6

• Availability of archival (within 90 days) or freshly collected tumor tissue before study enrollment. If archival tissue is unavailable or is determined to be inadequate, tumor tissue must be obtained from a biopsy performed at screening, unless an exception is given after consultation with the principal investigator.

• IPI score of 2-5

• ECOG Performance Status of 0, 1, or 2 (see Appendix A)

• Greater than or equal to 18 years at the time of signing informed consent

• Left ventricular ejection fraction (LVEF) ≥ 50% on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO)

• Adequate hematologic function (unless due to underlying disease, as established for example, by extensive bone marrow involvement or due to hypersplenism secondary to the involvement of the spleen by DLBCL per the investigator), defined as follows:

‣ Hemoglobin ≥ 9.0 g/dL without transfusion for 14 days before first treatment

⁃ ANC ≥ 1,000/μL

⁃ Platelet count ≥ 75,000/μL

• Participants must have adequate organ as defined below:

‣ Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) or \< 3 x ULN in participants with Gilbert's disease

⁃ PT or INR \> 1.5 the ULN in the absence of therapeutic anticoagulation or lupus anticoagulant

⁃ AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN

⁃ Adequate renal function defined by serum creatinine ≤1.5 x ULN or creatinine clearance (by Cockcroft-Gault) ≥ 40 ml/min

• At least one bi-dimensionally FDG-avid measurable lymphoma lesion on PET/CT scan, defined as \> 1.5 cm in its longest dimension on CT scan

• Women of childbearing potential (WOCBP) must agree to use effective contraception when sexually active. Women must remain abstinent or use methods of contraception, including at least one method with a failure rate of \<1% per year, during the treatment period and for 12 months after the final dose of pola-R-CHP, 2 months after the last dose of glofitamab, and 9 months after the last dose of polatuzumab whichever is longer. Examples of contraceptive methods with a failure rate of \<1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control. The use of condoms by male patients is required unless the female partner is permanently sterile.

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 12 months after the final dose of pola-R-CHP, 2 months after the last dose of glofitamab, and 9 months after the last dose of polatuzumab whichever is longer. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Male patients considering preservation of fertility should bank sperm before study treatment.

• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients must be willing to have monthly testing and antiviral therapy if indicated. Participants with a history of hepatitis C virus (HCV) infection must have undetectable viral load.

• Ability to understand and the willingness to sign a written informed consent document.