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

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