The purpose of this clinical trial is to assess the safety and tolerability of ration therapy followed by receiving epcoritamab or glofitamab in patients with relapsed/refractory diffuse large B-cell lymphoma.

Inclusion Criteria:

• Participant aged ≥ 18 years

• Disease criteria:

  • Histologically confirmed large b-cell lymphoma (LBCL), including DLBCL not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma with:
  • Relapsed or refractory disease with at least 2 prior systemic therapies

• Must be a candidate for radiation therapy up to 20 Gy. Radiation therapy to up to 3 lesions will be permitted.

• Must have at minimum two sites of evaluable disease per Lugano 2014, including one site that will not be irradiated as part of this study and has not received radiation therapy in the past.

• ECOG Performance Status ≤ 3

• Adequate organ function as defined as

  --Hematologic:

  • Absolute neutrophil count ≥ 1000/mm3 (Note: Use of G-CSF is permitted)

  • Platelet count ≥ 50,000/mm3 (Note: Use of platelet transfusions is permitted)

  • Hemoglobin ≥ 7 g/dL, (Note: Blood transfusions are permitted)

    --Hepatic:

  • Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)

  • 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 ≥ 40 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-child bearing 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.

• Clinically significant adverse effects from any prior oncologic treatment (e.g. prior surgery, radiotherapy, or other antineoplastic therapy) must have resolved or have been determined to be clinically stable per the Investigator.

• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.

Exclusion Criteria:

• Currently receiving any other approved or investigational therapy considered as a treatment for lymphoma with the exception of corticosteroids.

• Progressive disease on prior CD20 x CD3 bispecific antibody

  --Note: Prior therapy with CD20 x CD3 bispecific antibody is allowed.

• Prior systemic anti-cancer therapy which may have delayed treatment effects (e.g. immunotherapy) ≤ 14 days or within five half-lives prior to starting study treatment, whichever is shorter.

• 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.

• Known brain metastases or cranial epidural disease.

  --Note: Brain metastases or cranial epidural disease adequately treated with radiotherapy and/or surgery and stable for at least 4 weeks before the first dose of study treatment will be allowed on trial. Participants must be neurologically stable and receiving a stable or decreasing corticosteroid dose at the time of study entry

• Significant medical diseases or other conditions, as assessed by the investigator, that would substantially increase the risk-to-benefit ratio of participating in the study.

• Active systemic bacterial, viral, fungal or other infection requiring systemic treatment at time of screening.

• Known HIV infection with a detectable viral load within 6 months of the anticipated start of treatment.

  --Note: Participants on effective antiretroviral therapy with an undetectable viral load within 6 months of the anticipated start of treatment are eligible for this trial.

• Hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C.

  --Note: Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

• Medical, psychiatric, cognitive, or other conditions that may compromise the participant's ability to understand the participant information, give informed consent, comply with the study protocol or complete the study.

• Unable to tolerate corticosteroids

• Participants taking prohibited medications as described in Section 6.6.1.