A Study of Subcutaneously Injected Epcoritamab Plus Oral Lenalidomide Tablets Compared to Intravenously (IV) Infused Rituximab Plus IV Infused Gemcitabine and IV Infused Oxaliplatin in Adult Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

B-cell Lymphoma is an aggressive and rare cancer of a type of immune cells (a white blood cell responsible for fighting infections). This study will assess how safe and effective epcoritamab plus lenalidomide (E-Len) is compared to rituximab plus gemcitabine and oxaliplatin (R-GemOx) )in treating adult participants with relapsed or refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL). Adverse events and change in disease condition will be assessed.

Epcoritamab is an investigational drug being developed for the treatment of DLBCL. Study doctors put the participants in 1 of 2 groups, called treatment arms. Each group receives a different treatment. Around 320 adult participants with R/R DLBCL will be enrolled in approximately 165 sites across the world.

Participants in arm A will receive subcutaneous (SC) injections of epcoritamab plus oral lenalidomide capsules (E-Len) for up to 12 cycles (each cycle is 28 days). Participants "in arm B will receive intrav... (IV) infused R-GemOx for up to 4 cycles (each cycle is 28 days)

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.


Eligibility Criteria:
Inclusion Criteria:

* Eastern Cooperative Oncology Group Performance status score of 0 to 2.
* Histologically confirmed CD20+ Diffuse Large B-Cell Lymphoma (DLBCL) and documented in the most recent and representative pathology report, inclusive of the following according to the World Health Organization (WHO) 2022 as per the protocol.
* Must have relapsed or refractory (R/R) disease and have been previously treated with at least 1 line of systemic antineoplastic therapy including anti-CD20 mAb-containing combination chemotherapy since DLBCL diagnosis.
* . Participant must meet at least 1 of the following criteria:

  * Failed prior autologous stem cell transplant (ASCT), defined as relapsed after ASCT or been refractory to ASCT.
  * Not be considered a candidate for ASCT due to age, performance status, comorbidities and/or insufficient response to prior treatment, or have refused ASCT.
  * Be ineligible for or unable to receive chimeric antigen receptor T-cell (CAR-T) meeting at least 1 of the following criteria:

    * Unable to receive CAR-T therapy due to fitness and/or comorbidity.
    * Lymphocyte apheresis failure.
    * Unwilling to receive CAR-T therapy.
    * Unable to receive CAR-T therapy due to financial, geographic, insurance, access, and/or manufacturing constraints.
    * Relapsed/progressed after having achieved at least a Partial Response (PR) or Complete Response (CR) while on prior CAR-T therapy.
* Must have measurable disease.
* Life expectancy \> 3 months on standard of care treatment at the time of enrolling in the study

Exclusion Criteria:

* Current evidence of primary central nervous system (CNS) lymphoma or known CNS involvement by lymphoma including leptomeningeal disease, at screening.
* History of prior treatment with a bispecific antibody targeting CD3 and CD20 or prior treatment with rituximab plus gemcitabine and oxaliplatin (R-GemOx) or gemcitabine and oxaliplatin (GemOx).
* Documented refractoriness to lenalidomide.