Participants in this study will have diffuse large B-cell lymphoma (DLBCL) that has come back or not gotten better with treatment. The trial will study whether brentuximab vedotin plus two drugs works better to treat this type of cancer than the two drugs alone.

Participants will be randomly assigned to get either brentuximab vedotin or placebo. The placebo will look like brentuximab vedotin, but has no medicine in it. Since the study is "blinded," participants and their doctors will not know whether a participant gets brentuximab vedotin or placebo. All participants in the study will get rituximab and lenalidomide. These are drugs that can be used to treat DLBCL.

Inclusion Criteria:

• Participants with relapsed or refractory diffuse and transformed large B-cell lymphoma (R/R DLBCL). DLBCL and cell of origin (GCB versus non-GCB) will be histologically determined by local pathology assessment for the purposes of study eligibility and stratification.

• Participants must have R/R disease following 2 or more lines of prior systemic therapy.

  • For participants with transformed DLBCL, at least the last systemic therapy used must have been for DLBCL

• Participants must be HSCT or CAR-T ineligible according to the investigator and must meet at least one of the following criteria:

  1. One or more co-morbidities, including cardiac, pulmonary, renal or hepatic dysfunction that in the opinion of the Investigator make the participant medically unfit to received HSCT or CAR-T therapy
  2. Active disease following induction and salvage chemotherapy
  3. Inadequate stem cell mobilization (for HSCT)
  4. Relapse following prior HSCT or CAR-T
  5. Unable to receive CAR-T therapy due to financial, geographic, insurance, or manufacturing issues

• Participants must have tumor tissue submitted to the central pathology lab. The tumor tissue submitted should be from the most recent biopsy that contains DLBCL.

• An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2

• Participants must have fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) and bidimensional measurable disease of at least 1.5 cm by computed tomography (CT), as assessed by the site radiologist within 28 days of Day 1.

Exclusion Criteria:

• History of another malignancy within 2 years before the first dose of study drug or any evidence of residual disease from a previously diagnosed malignancy

• History of progressive multifocal leukoencephalopathy (PML)

• Active cerebral/meningeal disease related to the underlying malignancy. Participants with a history of cerebral/meningeal disease related to the underlying malignancy are allowed if prior CNS disease has been effectively treated and without progression for at least 3 months.

• Any uncontrolled Grade 3 or higher (per NCI CTCAE version 5.0) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study drug. Routine antimicrobial prophylaxis is permitted

• Chemotherapy, radiotherapy, biologics, and/or other antitumor treatment with immunotherapy that is not completed 3 weeks prior to first dose of study drug, unless underlying disease has progressed on treatment

• Previous treatment with brentuximab vedotin or lenalidomide.

  • Previous treatment with other vedotin-based ADCs is permitted if the last dose is at least 6 months prior to Day 1.

• Current therapy with immunosuppressive medications (including steroids), other systemic anti-neoplastic, or investigational agents

  a) Prednisone (or equivalent) ≤10 mg/day may be used for non-lymphomatous purposes

• Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III-IV within 6 months prior to the first dose of study drugs

• Congestive heart failure, Class III or IV, by the NYHA criteria

• Grade 2 or higher peripheral sensory or motor neuropathy at baseline

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.