CLINICAL TRIAL / NCT04561206

Inclusion Criteria: - Documented informed consent of the participant and/or legally authorized representative - Assent, when appropriate, will be obtained per institutional guidelines - Be willing to provide tissue (either from a fresh core or excisional biopsy performed as standard of care, or from archival tissue) of a biopsy that was performed after frontline systemic therapy, and prior to starting protocol therapy - If unavailable, exceptions may be granted with study principal investigator (PI) approval - Eastern Cooperative Oncology Group (ECOG) =< 2 - Histologically confirmed diagnosis of classical Hodgkin lymphoma (excluding nodular lymphocyte predominant Hodgkin lymphoma) according to the World Health Organization (WHO) classification, with hematopathology review at the participating institution - Relapsed or refractory disease after no more than 1 line of prior therapy (not counting radiotherapy). However, a maximum of 5 patients with primary refractory disease may be enrolled in this study. Note: Patients who received BV or an anti-PD-1/PD-L1 agent as part of frontline therapy are eligible if they achieved a CMR with frontline therapy and have not relapsed within 6 months from the end of frontline therapy Relapse must have been confirmed histologically (with hematopathology review at the participating institution) - Not a candidate for ASCT, based on age, co-morbidities, or patient preference. The reason for ASCT non-candidacy must be documented in the Case Report Form and verified by the site PI - Measurable disease (at least one non-bony fludeoxyglucose F-18 [FDG]-avid lesion >= 1.5 cm in long axis) - Absolute neutrophil count (ANC) >= 1,000/mm^3 - NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement - Platelets >= 50,000/mm^3 - NOTE: Platelet transfusions are not permitted within 7 days of platelet assessment unless cytopenia is secondary to disease involvement - Hemoglobin >= 8 g/dL (no transfusion allowed within 3 days prior to screening) - Total bilirubin =< 1.5 x upper limit of normal (ULN) or direct bilirubin =< 1.5 x ULN for patients with Gilbert's disease - Aspartate aminotransferase (AST) =< 2.5 x ULN - Alanine aminotransferase (ALT) =< 2.5 x ULN - Creatinine clearance of >= 40 mL/min per 24 hour urine test or the Cockcroft-Gault formula - Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required - Agreement by women and men of childbearing potential* to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 5 months (women) or 7 months (men) after the last dose of protocol therapy - Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only) Exclusion Criteria: - Concomitant investigational therapy - Live vaccine within 30 days prior to day 1 of protocol therapy (e.g. measles, mumps, rubella, varicella, yellow fever, rabies, bacillus Calmette-Guerin [BCG], oral polio vaccine, and oral typhoid) - Grade >= 2 peripheral neuropathy - History of prior >= grade 3 hypersensitivity to either brentuximab vedotin or nivolumab - Known active central nervous system (CNS) involvement by lymphoma, including parenchymal and/or lymphomatous meningitis - History of another primary malignancy that has not been in remission for at least 3 years, with the following exceptions: - Non-melanoma skin cancer treated with curative intent - In situ cervical cancer - If the malignancy is expected to not require any treatment for at least 2 years (this exception should be discussed with the study PI) - Condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration. Exceptions are: - Inhaled or topical steroids and - Adrenal replacement doses > 10 mg daily prednisone equivalents in the absence of active autoimmune disease - History of progressive multifocal leukoencephalopathy (PML) - Prior diagnosis of inherited or acquired immunodeficiency - Active pneumonitis or interstitial lung disease - Active, known or suspected autoimmune disease. The following are exceptions: - Vitiligo - Psoriasis not requiring systemic treatment - Hemolytic anemia associated with the lymphoma - Type I diabetes mellitus, if adequately controlled with therapy - Thyroid disease, if adequately controlled with therapy - Conditions not expected to recur in the absence of an external trigger (such exceptions should be discussed with the study PI) - Active history of: - Hepatitis B (hepatitis B virus [HBV]) or C (hepatitis C virus [HCV]) infection. Patients with past HBV infection (defined as negative hepatitis B surface antigen [HBsAg] and positive hepatitis B core antibody [HBcAb]) are eligible if HBV DNA is undetectable. Patients who are positive for HCV antibody are eligible if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA) - Human immunodeficiency virus (HIV) infection. Subjects who have an undetectable or unquantifiable human immunodeficiency virus (HIV) viral load with CD4 >= 200 and are on highly active antiretroviral therapy (HAART) medication are allowed. Testing to be done only in patients suspected of having infections or exposures - History of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association class III-IV within 6 months prior to day 1 of protocol therapy - Pregnant or breastfeeding - Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures - Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)