This phase I trial studies the side effects and best dose of duvelisib when given together with nivolumab in treating patients with Richter syndrome or transformed follicular lymphoma. Duvelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving duvelisib and nivolumab may work better in treating patients with Richter syndrome or transformed follicular lymphoma compared to giving duvelisib or nivolumab alone.

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) of duvelisib in combination with nivolumab for patients with Richter?s syndrome or transformed follicular lymphoma.

SECONDARY OBJECTIVES:

I. To assess preliminary efficacy of duvelisib in combination with nivolumab in Richter?s syndrome and transformed follicular lymphoma (overall response rate, progression free survival, overall survival).

II. To determine the toxicity profile of duvelisib in combination with nivolumab.

EXPLORATORY OBJECTIVES:

I. To correlate response to duvelisib in combination with nivolumab with cytogenetic/fluorescence in-situ hybridization (FISH) abnormalities of the chronic lymphocytic leukemia (CLL) and lymphoma compartments (for patients with Richter?s syndrome) at baseline.

II. To correlate response to duvelisib in combination with nivolumab with baseline deoxyribonucleic acid (DNA) mutation of CLL and lymphoma as assessed in tumor samples and cell free DNA.

III. To determine changes in T, B, and natural killer (NK) cell number and function during duvelisib plus nivolumab therapy.

OUTLINE: This is a dose-escalation study of duvelisib.

Patients receive duvelisib orally (PO) twice daily (BID) on days 1-28 and nivolumab intravenously (IV) over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months thereafter.

Inclusion Criteria:

• Diagnosis of CLL or small lymphocytic lymphoma (SLL) meeting International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria AND biopsy proven transformation to diffuse large B cell lymphoma (DLBCL), clinically consistent with Richter?s syndrome (RS) OR histologically diagnosed relapsed or refractory DLBCL including transformed follicular lymphoma (tFL) ineligible for or refractory to platinum containing salvage therapy for the dose escalation portion of the study. For the dose expansion phase only patients with CLL with transformation to DLBCL or tFL will be eligible
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count (ANC) >= 500/uL
• Platelet count >= 30,000/uL (unless due to bone marrow involvement)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 ULN
• Total bilirubin =< 1.5 ULN (unless due to liver involvement, hemolysis, or Gilbert?s disease)
• Creatinine clearance >= 40 mL/min (Cockcroft-Gault estimated)
• Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug
• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) or urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study
• Patients must sign an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study

Exclusion Criteria:

• Documented infection with human immunodeficiency virus (HIV) or chronic, active hepatitis B or C infection
• Any chemotherapy or monoclonal antibodies within 14 days or kinase inhibitors (except BTKi) within 5 half-lives before cycle 1, day 1 (C1D1). BTK inhibitors may be continued until 2 days prior to C1D1. Steroids are allowed for palliation of symptoms due to lymphoma
• Toxicity from previous therapy which has not resolved to grade 1 (or patient?s previous baseline)
• Other active malignancies except those treated with curative intent with no active disease at the time of study entry or those felt to be at low risk of progression or recurrence over the next 2 years (such as low risk prostate cancer on active surveillance)
• New York Heart Association (NYHA) class III/IV heart disease or other significant medical condition or organ system dysfunction which could compromise the subject?s safety or put the study outcomes at undue risk
• Uncontrolled systemic infection
• Unable to swallow capsules or significant malabsorption syndrome, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction at the time of screening
• Patients who are pregnant or breastfeeding
• Patients with known central nervous system (CNS) involvement by CLL or lymphoma
• Patients who have underwent autologous or allogeneic stem cell transplant =< 4 weeks prior to C1D1 or have active graft-versus-host disease are excluded