Outpatient Epcoritamab as 2L in NTE R/R DLBCL

Inclusion Criteria:

• Participants must have large B-cell lymphoma of one of the following histologicsubtypes by WHO criteria:

• Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS)

• High grade B-cell lymphoma (HGBCL) with rearrangements of MYC and BCL2 and/orBCL6

• HGBCL NOS

• EBV+ DLBCL

• Primary mediastinal B-cell lymphoma

• T-cell/histiocyte rich LBCL

• Grade 3B follicular lymphoma

• Large B-cell lymphoma transformed from underlying indolent NHL

• PET measurable disease per Lugano criteria.

• Relapsed or refractory disease treated with 1 prior systemic antineoplastic line oftherapy that includes an anti-CD20 monoclonal antibody and an anthracycline or analkylating agent. Patients who have received more than 1 prior systemicantineoplastic line of therapy are not eligible.

• Age ≥18 years.

• ECOG performance status 0-2.

• Not a candidate for high dose chemotherapy and autologous stem cell transplant perthe treating investigator, or patient refusal of high dose chemotherapy andautologous transplant.

• Participants must meet the following organ and marrow function as defined below:

• absolute neutrophil count ≥1,000/mcL (Growth factor support is permitted)

• platelets ≥75,000/mcL (>50,000 in the presence of bone marrow involvement orsplenomegaly; platelet transfusions are permitted)

• Hemoglobin ≥8 g/dL (>7 g/dL in the presence of bone marrow involvement; bloodtransfusions are permitted)

• Participants must have adequate organ function as defined below (unlessabnormalities are considered related to target organ involvement or compression bylymphoma):

• total bilirubin ≤ 1.5x institutional upper limit of normal (ULN) (Isolatedbilirubin ≤3.0x ULN is acceptable if considered secondary to Gilbert'ssyndrome)

• AST(SGOT) and ALT(SGPT) ≤3.0x institutional ULN

• Creatinine clearance ≥45 mL/min eGFR (Cockcroft-Gault or MDRD equation)

• PT within institutional normal range (unless on anticoagulation expected toaffect PT, in which case PT cut off does not apply)

• PTT within institutional normal range (unless on anticoagulation expected toaffect PTT, in which case PTT cut off does not apply)

• Ability to remain within 60 minutes of the administration site for 24 hoursfollowing cycle 1 day 15 dose of study drug.

• The effects of epcoritamab on the developing human fetus are unknown. Women ofchild-bearing potential must agree to use adequate contraception starting with thefirst dose of study drug, for the duration of study participation, and for at least 6 months after the last dose of study intervention. Women must also agree not todonate eggs (ova, oocytes) for the purpose of reproduction during this period.Should a woman become pregnant or suspect she is pregnant while she or her partneris participating in this study, she should inform her treating physicianimmediately. Adequate contraception methods:

• Male Partner Sterilization: When the appropriate post-vasectomy documentationof the absence of sperm in the ejaculate.

• Use of a combination of any two of the following (one from "a" and one from "b"):

1. Placement of an intrauterine device (IUD) or intrauterine system orestablished use of oral, injected, or implanted hormonal methods ofcontraception
2. Barrier methods of contraception: Male Condom or Occlusive cap (diaphragmor cervical/vault caps) with spermicidal foam/gel/film/cream/vaginalsuppository.

• True abstinence, defined as refraining from heterosexual intercourse when this is inline with the preferred and usual lifestyle of the subject.

• Nonchildbearing potential is defined as follows:

• ≥45 years of age and has not had menses for at least 12 consecutive months.

• Subjects who have been amenorrhoeic for <1 year must have, on at least twooccasions prior to first dose of study drug, a follicle stimulating hormonevalue greater than 40 IU/L; historical follicle stimulating hormone values areeligible

• Post-bilateral oophorectomy (with or without hysterectomy) or post-tuballigation at least six weeks prior to first dose of study drug. Documentedoophorectomy must be confirmed with medical records of the actual procedure orconfirmed by an ultrasound. Tubal ligation must be confirmed with medicalrecords of the actual procedure. In the case of oophorectomy alone,reproductive status must be confirmed by follicle stimulating hormone levelassessment as above.

• Women of childbearing potential (WOCBP) must have a negative highly sensitive serumpregnancy test at screening.

• Fertile men, defined as all males physiologically capable of conceiving offspringwho are sexually active with a female partner of childbearing potential, must agreeto use adequate contraception starting with the first dose of study drug, for theduration of study participation, and 3 months after completion of administration.Men must also agree not to donate sperm during this period. Men may agree to remainabstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term or persistent basis) OR agree to use a male condom, andtheir female partner must use an additional highly effective contraceptive methodwith a failure rate of <1% per year when having sexual intercourse if they are aWOCBP (including pregnant females).

• Ability to understand and the willingness to sign a written informed consentdocument by the participant or a legally authorized representative.

Exclusion Criteria:

• Participant must not have used an investigational drug or approved systemic lymphomatherapy within 28 days preceding the first dose of study drug. Steroids for lymphomadisease control are permitted but must be stopped at least 7 days prior to the firstdose of study drug.

• Participants must not have received prior CD20/CD3 bispecific antibody.

• Participants must not have received prior autologous or allogeneic stem celltransplant.

• Participants must not have received prior anti-CD19 CAR T-cell therapy.

• Participants who have not recovered from adverse events due to prior anti-cancertherapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia.At the discretion of the overall PI, participants with residual toxicities > Grade 1may be considered eligible if in the opinion of the overall PI the residual toxicityis not likely to interfere with the safety or efficacy assessment of theinvestigational regimen. For residual hematologic toxicities greater than Grade 1.

• Participants must not have known central nervous system involvement by lymphoma.

• Participants must not have a current life-threatening illness, medical condition, ororgan system dysfunction (other than the disease under study) which, in theInvestigator's opinion, could compromise the subject's safety or put the study atrisk. Patients that have mild cognitive impairment or dementia are eligible perinvestigators' opinion.

• Participants must not have an uncontrolled active infection. Localized fungalinfection of skin or nails are permitted.

• Participants must not have active uncontrolled autoimmune disease. Autoimmunedisease under control with chronic systemic corticosteroids at a dose of 10 mg/dayof prednisone or less, or equivalent corticosteroid, are eligible.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to epcoritamab. A history of an infusion reaction toCD20-directed therapy is not considered an allergic reaction.

• Women who are pregnant are excluded from this study because it is unknown ifepcoritamab can cause embryo-fetal harm when administered to a pregnant woman.Because there is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with epcoritamab, breastfeeding should bediscontinued if the mother is treated with epcoritamab on study.

• Participant must not have active uncontrolled HIV infection. Participants with HIVare eligible if disease is adequately controlled on an antiretroviral regimen thatis in accordance with the current international AIDS Society guidelines, withadequate control defined by presence of both an undetectable viral load, a CD4 count >350, no evidence of AIDS-defining illness (with the exception of a lymphomadiagnosis), and no active opportunistic infections (infections controlled onappropriate anti-infective therapy are permitted).

• Participant must not have active hepatitis B infection. Participants with positiveHBV core antibody or HBV surface antigen at screening are eligible if HBV viral loadis negative by PCR and they are on appropriate antiviral therapy.

• Participant must not have active hepatitis C infection. Participants with positiveHepatitis C antibody due to prior resolved disease can be enrolled, only if aconfirmatory negative Hepatitis C RNA test is obtained. Note: Participants withnegative Hepatitis C antibody test are not required to also undergo Hepatitis C RNAtesting.

• Subject has no known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. If a subject has signs/symptoms suggestive of SARS-CoV-2infection or has had recent known exposure to someone with SARS-CoV-2 infection, thesubject must have a negative molecular (e.g., PCR) test, or 2 negative antigen testresults at least 24 hours apart, to rule out SARS-CoV-2 infection. Note: SARS-CoV-2diagnostic tests should be applied following local requirements/recommendations.Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screenfailed and may only rescreen after they meet the following SARS-CoV-2 infectionviral clearance criteria: No signs/symptoms suggestive of active SARS-CoV-2infection AND negative testing (molecular (e.g., PCR) result or 2 negative antigentest results at least 24 hours).

• Participants must not have received a live virus vaccine within 28 days of firstdose of study drug.

• Participants must not have any known past or current malignancy other than inclusiondiagnosis, except for:

1. Cervical carcinoma of Stage 1B or less.

2. Non-invasive basal cell or squamous cell skin carcinoma.

3. Non-invasive, superficial bladder cancer.

4. Prostate cancer with a current PSA level <0.1 ng/mL.

5. Any curable cancer with a complete response (CR) of >2 years duration