CC-486 and Nivolumab for the Treatment of Hodgkin Lymphoma Refractory to PD-1 Therapy or Relapsed

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 from a fresh core or excisional biopsy (performed as standard of care) of a tumor lesion prior to starting study therapy or from archival tissue of a biopsy that was performed after the most recent systemic therapy
• •* Exception may be granted by the principal investigator (PI) if a biopsy is not feasible and/or safe
• •Age: \>= 18 years
• •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
• •Refractory to PD-1/PD-L1 directed immunotherapy, defined as patients who had prior exposure to PD-1/PD-L1 immunotherapy and either:
• •* Achieved a best response of PD, or
• •* Achieved a best response of CR/PR but developed PD while on active PD-1/PD-L1 treatment or within 12 weeks of last dose of PD-1/PD-L1 treatment
• •Relapse must have been confirmed histologically (with hematopathology review at the participating institution)
• •* Exceptions may be granted with study PI approval
• •Patient must have received at least one prior systemic therapy and must not currently be candidate for stem cell transplantation
• •Measurable disease by computed tomography (CT) or positron emission tomography (PET)/CT scan with one or more sites of disease \>= 1.5 cm in longest dimension
• •Fully recovered from the acute toxic effects (except alopecia) to =\< Grade 1 to prior anti-cancer therapy
• •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 \>= 75,000/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
• •Total bilirubin =\< 1.5 x upper limit of normal (ULN) or =\< 3 x ULN if patient has Gilbert's disease OR direct bilirubin =\< ULN for subjects with total bilirubin levels \> 1.5 x ULN
• •Aspartate aminotransferase (AST) =\< 2.5 x ULN OR =\< 5 x ULN for subjects with liver involvement by lymphoma as the etiology of transaminase elevation
• •Alanine aminotransferase (ALT) =\< 2.5 x ULN OR =\< 5 x ULN for subjects with liver involvement by lymphoma as the etiology of transaminase elevation
• •Creatinine clearance of \>= 40 mL/min per 24 hour urine test or the Cockcroft-Gault formula
• •If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (PT) =\< 1.5 x ULN
• •* If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
• •If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) =\< 1.5 x ULN
• •* If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants
• •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 females and males 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 after the last dose of nivolumab and 6 months after the last dose of CC-486 for females, and 3 months after the last dose of CC-486 for males with female partners of reproductive potential
• •* Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)
• •Known active human immunodeficiency virus (HIV) infection. Subjects who have an undetectable or unquantifiable 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
• •Females only: Pregnant or breastfeeding
• •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)