Testing the Combination of Nivolumab and ASTX727 for Relapsed or Refractory B-Cell Lymphoma

PRIMARY OBJECTIVE: I. To evaluate the safety and tolerability of the combination of oral deoxyribonucleic acid (DNA) methyltransferase (DNMT) inhibition and checkpoint inhibition in relapsed or refractory B cell lymphoma (dose escalation) and diffuse large B-cell lymphoma (DLBCL) (dose expansion) or Hodgkin lymphoma (dose expansion). SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To evaluate the response rate (overall response \[ORR\], complete response \[CR\], and partial response \[PR\]), and the progression free survival (PFS) and overall survival (OS) in patients with relapsed or refractory DLBCL treated with the combination of oral DNMT inhibition and checkpoint inhibition. III. To evaluate the duration of response (DOR) and PFS in patients deriving clinical benefit (stable disease \[SD\], PR, CR) who continue therapy for an additional 12 months (24 total months). CORRELATIVE OBJECTIVES: I. To evaluate the changes in systemic immune activation, exhaustion, and T cell phenotypes in patients before and during treatment, and to compare these activation profiles between responding and progressing patients. II. To profile the tumor microenvironment pre-treatment and monitor T cell dynamics and T-cell receptor (TCR) clonality by single-cell approaches before and during treatment, and compare these profiles between responding and progressing patients. III. To determine lymphoma mutational profiles in peripheral blood circulating tumor DNA (ctDNA) and to compare changes in ctDNA levels and mutational profiling between responding and progressing patients. IV. To evaluate DNA methylation (cytosine hydroxymethylation and cytosine methylation) status in cell free (cf)DNA at global level and to compare changes in cfDNA DNA methylation levels between responding and progressing patients. OUTLINE: Patients receive decitabine and cedazuridine orally (PO) once daily (QD) on days 1-3 or 1-5 of each cycle and nivolumab intravenously (IV) over 30 minutes on day 15 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients with CR, PR, or SD after 12 cycles receive decitabine and cedazuridine for an additional 12 months. Patients also undergo positron emission tomography (PET)/computed tomography (CT) and collection of blood samples throughout the trial. After completion of study treatment, patients are followed up every 3 months for 2 years.