Duvelisib and Nivolumab in Treating Patients With Richter Syndrome or Transformed Follicular Lymphoma
Duvelisib and Nivolumab in Treating Patients With Richter Syndrome or Transformed Follicular Lymphoma
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