Epcoritamab Before and After CAR T-cell Therapy for the Treatment of Patients with Relapsed or Refractory Large B-cell Lymphomas

Inclusion Criteria

• Age > 18 years
• Subject must be able and willing to provide informed consent * In the case where the patient is incapacitated or not otherwise capable, a legally authorized representative (or decision maker when there is not an advanced directive in place) must be willing to provide informed consent on behalf of the patient
• Able to comply with the study protocol, in the investigator’s judgment
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 – 2
• Pathology report confirming eligible diagnosis, as noted below: * Diffuse large B-cell lymphoma, not otherwise specified (NOS) ** Morphological variants *** Centroblastic *** Immunoblastic *** Anaplastic *** Other rare variants ** Cell of origin subtypes *** Germinal center B-cell subtype *** Activated B-cell-like subtype * High grade B-cell lymphoma ** High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements ** High-grade B-cell lymphoma, NOS * High grade B-cell lymphoma, unclassifiable ** B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma * Large cell transformation of follicular lymphoma * Large cell transformation of marginal zone lymphoma * Follicular lymphoma, grade 3B
• Documented CD20+ tumor cells on most recent biopsy
• Patients will have failed to respond to frontline standard of care therapy containing an anthracycline and anti-CD20 antibody
• Patients will be eligible and consent to be treated with a “commercially available” anti-CD19, 4-1BB, CD3zeta CAR-T cell therapy or anti-CD19, CD28, CD3zeta CAR T cell therapy (for example, tisagenlecleucel, lisocabtagene maraleucel, or axicabtagene maraleucel)
• Patients must have a PET/CT scan (preferred), diagnostic CT scan, or MRI with at least one bi-dimensionally measurable lesion ( ≥ 1.5 cm for nodal lesions or ≥ 1 cm for extra-nodal lesions in largest dimension by low-dose computerized tomography [CT] scan with fluorodeoxyglucose [FDG]-uptake ≥ liver) * Imaging studies as listed above previously performed for standard of care (SOC) within 8 weeks of planned bispecific antibody (bsAb) start date without intervening therapy will be accepted for screening/inclusion imaging assessments
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal (ULN)
• Total bilirubin level ≤ 1.5 x ULN, or ≤ 5 x ULN for subjects with hepatic involvement of disease or of non-hepatic origin
• Subjects with a documented history of Gilbert syndrome may have total bilirubin levels > 1.5 x ULN, but direct bilirubin must be ≤ 2 x ULN and in whom total bilirubin elevations are accompanied by an isolated elevated indirect bilirubin are eligible
• Platelet count ≥ 50,000/mm^3 (transfusions permitted)
• Absolute neutrophil count (ANC) ≥ 1000/mm^3 (granulocyte colony stimulating factor [G-CSF] permitted)
• Hemoglobin ≥ 8.0 g/dL (transfusions permitted)
• Patients who do not meet criteria for hematologic function because of extensive marrow involvement by lymphoma and/or disease-related cytopenias, e.g., hypersplenism, may be enrolled into the study
• CD3 count ≥ 150/uL
• Serum creatinine < 2.0 mg/dL or estimated creatinine clearance (CrCl) ≥ 45 mL/min by Cockcroft-Gault method modified as needed for factors such as sex and race
• Resolution of toxicities from prior therapy to a grade that does not contraindicate trial participation in the opinion of the investigator
• Ability and willingness to take proper contraceptive precautions, defined as: * Before the first dose of epcoritamab, during the trial and for 12 months after last administration of epcoritamab, a person of child-bearing potential must be either: ** Not of childbearing potential as defined as: premenarchal; postmenopausal ( > 45 years of age with amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months and a serum follicle stimulating hormone [FSH] level > 40 IU/L or mIU/mL); permanently sterilized (e.g., bilateral tubal occlusion [which includes tubal ligation procedures as consistent with local regulations], hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy, OR ** Of childbearing potential and practicing a highly effective method of birth control (as defined by the European Union [EU] Clinical Trial Facilitation Group) consistent with local regulations regarding the use of birth control methods for patients participating in clinical trials: e.g., established use of oral, injected or implanted combined (estradiol and progesterone containing) hormonal contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS); male partner sterilization (the vasectomized partner should be the sole partner for that patient); true abstinence (when this is in line with the preferred and usual lifestyle of the patient) ** If the childbearing potential changes after start of the trial (e.g., woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) a woman must begin a highly effective method of birth control, as described above * A man who is sexually active with a person of childbearing potential must agree to use a barrier method of birth control (that is the use of condom) during the trial and for 12 months after receiving the last dose of epcoritamab * Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the trial and for 12 months after receiving the last dose of epcoritamab. Men must also not donate sperm during the trial and for 12 months after receiving the last dose of epcoritamab

Exclusion Criteria

• Inability or unwillingness of the patient or legally authorized representative (or decision-maker when there is not an advanced directive in place) to provide informed consent
• Prior solid organ transplantation
• Primary central nervous system (CNS) lymphoma or active secondary CNS involvement by lymphoma at screening as confirmed by magnetic resonance imaging (MRI)/computed tomography (CT) scan (brain) or, if clinically indicated, by lumbar puncture
• History of autoimmune disease or other diseases resulting in permanent immunosuppression or requiring chronic immunosuppressive therapy, with the following exceptions: * Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone * Patients with a history of lymphoma-related immune thrombocytopenic purpura or autoimmune hemolytic anemia in remission may be eligible for this study if approved by the Regulatory Sponsor and Principal Investigator * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: ** Rash must cover < 10% of body surface area ** Disease is well controlled at baseline and requires only low-potency topical corticosteroid ** No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or corticosteroids ( > 20 mg/day prednisone or equivalent for > 2 weeks) within the previous 3 months * Rheumatoid arthritis or similar autoimmune/rheumatic conditions
• Systemic immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents). However, the following are permitted: * If receiving glucocorticoid treatment at screening, must be a maximum daily dose of prednisone 10 mg (or equivalent) and a total of no more than 140 mg over the last 14 days prior to the first dose of epcoritamab, unless for disease control * Patients who received a single dose of a systemic immunosuppressant medications (e.g., single dose of dexamethasone for nausea or B symptoms) may be enrolled * The use of inhaled corticosteroids is permitted * The use of mineralocorticoids for management of orthostatic hypotension is permitted * The use of physiologic doses of corticosteroids (< 20 mg/day of prednisone or equivalent) for uses such as management of adrenal insufficiency is permitted
• Known past or current malignancy, other than inclusion diagnoses, except for: * Cervical carcinoma of stage 1B or less * Adequately resected, non-metastatic basal cell or squamous cell skin carcinoma * Non-invasive, superficial bladder cancer * Prostate cancer with a current prostate specific antigen (PSA) level < 0.1 ng/mL * Patients with a malignancy that has been treated with curative intent will also be enrolled if that malignancy is in remission prior to first dose of epcoritamab
• Known clinically significant cardiovascular disease such as * New York Heart Association class III or IV cardiac disease * Myocardial infarction within the last 6 months * Unstable arrhythmias, or unstable angina * Hemorrhagic or ischemic stroke within the last 6 months * Left ventricular ejection fraction (LVEF) < 45%
• Patients with the following active infection(s) could have increased risks for toxicity if treated with bispecific antibody therapy, thus patient will be excluded if: * Positive serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection. Patients whose HBV infection status cannot be determined by serologic test results must be negative for HBV by PCR to be eligible for study participation. Patients with a history of hepatitis B who are negative for HBV by PCR, will not be excluded but will be placed on suppressive antiviral therapy * Acute or chronic hepatitis C virus (HCV) infection. Patients who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation. Patients with a history of hepatitis C who have been adequately treated (negative PCR) will not be excluded * Positive serologic or reverse transcriptase (RT)-PCR test results for HIV infection
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major documented infection requiring treatment with IV antibiotics or hospitalization within 2 weeks of enrollment. Empiric or prophylactic antibiotics administered during neutropenia or neutropenic fever without microbiologic evidence of infection do not exclude patients
• Clinically significant pulmonary disease (e.g., bronchospasm and/or obstructive pulmonary disease) that requires chronic oxygen or corticosteroid use > 20 mg mg/day prednisone or equivalent
• Uncontrolled seizure disorder
• Exposure to live or live attenuated vaccine within 4 weeks prior to signing informed consent form (ICF)
• Pregnancy or breast feeding
• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results