Safety and Efficacy of Epcoritamab With Gemcitabine, Dexamethasone, and Cisplatin (GDP) Salvage Chemotherapy in Relapsed Refractory Large B-cell Lymphoma

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal healthinformation prior to registration. NOTE: HIPAA authorization may be included in theinformed consent or obtained separately.

2. Age ≥ 18 years at the time of consent.

3. ECOG Performance Status of 0-2 within 28 days prior to registration.

4. Histological confirmed CD20+ relapsed large cell lymphoma according to the 5thedition of the WHO classification of the hematolymphoid tumors and the 2022international consensus classification of mature lymphoid neoplasms includingde-novo and transformed from prior indolent B-cell NHL such as follicular lymphoma,or marginal zone lymphoma (33, 34). NOTE: Subjects with high-grade B-cell lymphoma (HGBCL), NOS subtype, and high-grade B-cell lymphoma with c-MYC, Bcl2 and/or Bcl6rearrangements (double or triple hit lymphoma) are eligible. Patients with primarymediastinal B-cell lymphoma, and T-cell histiocyte-rich B-cell lymphoma, primarycutaneous diffuse large B-cell lymphoma, leg type, Intravascular large B-celllymphoma, Epstein-Barr virus-positive diffuse large B-cell lymphoma, NOS, Diffuselarge B-cell lymphoma associated with chronic inflammation, and ALK-positive largeB-cell lymphoma are eligible. Patients with Burkitt lymphoma or lymphoplasmacyticlymphoma are not eligible.

5. Positron emission tomography (PET) positive measurable disease with at least 1 nodehaving the longest diameter (LDi) greater than (>) 1.5 centimeter (cm) or 1extranodal lesion with LDi >1 cm (per the Lugano Criteria 2014).

6. Have received at least 1 prior line of systemic therapy for the treatment of largecell lymphoma. NOTE: Prior radiation therapy or systemic corticosteroids will not beconsidered a line of therapy.

7. Must have had relapsed or refractory disease following standard frontlinechemotherapy. Refractory disease is defined as large cell lymphoma not achievingcomplete remission, progressing or relapsing within 6 months after first-linechemotherapy based on PET/CT per the Lugano criteria. Relapsed disease is defined asdisease that recurs beyond 6 months after completion of initial chemotherapy basedon PET/CT per the Lugano criteria.

8. Patients must be deemed eligible to proceed with stem cell transplantation (autologous or allogeneic) or CAR T-cell therapy per treating physician discretion.Patients being considered for allogeneic stem cell transplant may be eligible.

9. Archival tissue obtained within 2 years of signing consent is required if availableand will be identified at screening and shipped prior to Cycle 2 Day 1. If archivaltissue is not available, fresh tissue from a standard of care biopsy is required. Ifa subject does not have archival tissue or is not undergoing a standard of carebiopsy, they are not eligible for the trial. NOTE: A pre-treatment fresh tissue coreor excisional biopsy at screening is preferred which should be considered standardof care.

10. Demonstrate adequate organ function. All screening labs to be obtained within 21days prior to registration. *Patients with bone marrow involvement will be eligibleto participate in the study but must meet hematologic parameters.

11. Life expectancy of ≥ 6 months, as determined by the enrolling physician or protocoldesignee.

12. Females subjects of childbearing potential must have a negative urine or serumpregnancy test within 24 hours prior to study treatment. If a urine test is done andit is positice ir cannot be confirmed as negative, a serum pregnancy test will berequired.

13. Female subjects of childbearing potential and male subjects must be willing toabstain from penile-vaginal intercourse or to use an effective method(s) ofcontraception.

14. As determined by the enrolling physician or protocol designee, ability of thesubject to understand and comply with study procedures for the entire length of thestudy.

Exclusion Criteria:

1. Previous treatment with gemcitabine, cisplatin, and epcoritamab or other bispecificT-cell engager antibody (BiTE) such aas glofitamab, mosunetuzumab, or odronextamab.

2. Known active central nervous system or meningeal involvement by large cell lymphomaat time of screening. Patients diagnosed with CNS disease who achieved andmaintained CNS CR at the time of relapse are eligible. Lumbar puncture must be donein this case prior to study entry to demonstrate CNS CR status. Tests to investigateCNS involvement are required otherwise only if clinically indicated (i.e. diseasesuspected on basis of symptoms or other findings).

3. Contraindication to any drug contained in the combination therapy regimen (GDP).

4. Known hypersensitivity or allergic reaction to epcoritamab or its' excipients.

5. Use of any standard or experimental anti-large cell lymphoma therapy (includingnonpalliative radiation, chemotherapy, immunotherapy, radio-immunotherapy, or anyother anticancer therapy) < 14 days prior to C1D1. NOTE: Prednisone up to 50 mg orequivalent for 5 days is permitted; palliative radiation is permitted only if onnon-target lesions).

6. Major surgery < 14 days of Cycle 1 Day 1.

7. Neuropathy Grade ≥ 2 (CTCAE v.5.0).

8. Patients with a history of other malignancies, except adequately treatednon-melanoma skin cancer, non-invasive superficial bladder cancer, curativelytreated in-situ cancer of the cervix, DCIS of the breast, localized low gradeprostate cancer (up to Gleason score 6), or other solid tumours curatively treatedwith no evidence of disease for at least 3 years.

9. Active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) requiring systemic treatment within 7days prior to the first dose of study treatment. Prophylactic antibacterial,antiviral, and antifungal agents are allowed.

10. Active HIV infection. NOTE: Testing for HIV antibody is required at the time ofscreening. Those with positive HIV antibody will require HIV viral load by PCRtesting. Patients with detectable viral load will not be eligible for the study.Those with positive antibody but undetectable viral load and CD4 >200 will beeligible.

11. Testing for hepatitis B (HBV) and hepatitis C virus (HCV) is required at screening.Hepatitis B testing will consist of Hepatitis B surface Antigen (HBsAg), Hepatitis BCore Antibody (HBcAb) and Hepatitis Surface Antibody (HBsAb). Hepatitis C testingwill consist of Hepatitis C Antibody (HCAb). Subjects with a history of chronichepatitis B virus (HBV) infection must have an undetectable HBV viral load onsuppressive therapy, if indicated. Subjects with evidence of prior HBV but who arePCR-negative are permitted in the trial but should receive prophylactic antiviraltherapy. Subjects with a history of hepatitis C virus (HCV) infection must have beentreated. For patients with HCV infection who are currently on treatment, the HCVviral load must be undetectable to be eligible for this trial. Subjects who receivedtreatment for HCV that was intended to eradicate the virus may participate ifhepatitis C RNA levels are undetectable.

12. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use whilethe mother is being treated on study).

13. Any life-threatening illness, medical condition, or organ system dysfunction which,in the Investigator's opinion, could compromise the subject's safety, or beingcompliant with the study procedures.