Nivolumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or High-Risk Untreated Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Richter Transformation
Nivolumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or High-Risk Untreated Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Richter Transformation
This phase II trial studies how well nivolumab and ibrutinib work when given together in
 treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or Richter
 transformation that has come back after a period of improvement (relapsed), does not respond
 to treatment (refractory), or is at high risk of spreading and has not been treated.
 Immunotherapy with monoclonal antibodies, such as niolumab, may help the body's immune system
 attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
 Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell
 growth. Giving nivolumab together with ibrutinib may kill more cancer cells.
PRIMARY OBJECTIVES:

 I. To determine the efficacy (response rate) of nivolumab in combination with ibrutinib in
 patients with relapsed/refractory or high-risk untreated chronic lymphocytic leukemia (CLL).

 II. Determine the response rate (complete response [CR]/complete response with incomplete
 marrow recovery [CRi]) by 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL)
 criteria. (Cohort I) III. Determine the conversion rate from partial response (PR) to CR/CRi
 by 2008 IWCLL criteria. (Cohort II) IV. Determine the response rate (CR/CRi). (Cohort III)

 SECONDARY OBJECTIVES:

 I. To determine the safety of nivolumab in combination with ibrutinib in patients with
 relapsed, refractory or high-risk untreated CLL/Richter transformation (RT).

 II. To determine the progression-free survival of patients with relapsed, refractory or
 high-risk untreated CLL/RT treated with nivolumab in combination with ibrutinib.

 III. To determine the overall survival of patients with relapsed, refractory or high-risk
 untreated CLL/RT treated with nivolumab in combination with ibrutinib.

 EXPLORATORY OBJECTIVES:

 I. To study immunological and molecular changes in peripheral blood, lymph node, and bone
 marrow in response to nivolumab and ibrutinib therapy.

 OUTLINE: Patients are assigned to 1 of 3 treatment cohorts.

 COHORT I (NO CURRENT IBRUTINIB TREATMENT): Patients receive nivolumab intravenously (IV) over
 1 hour on days 1 and 15 and ibrutinib orally (PO) once daily (QD) on days 1-28 of courses
 2-24. Treatment repeats every 28 days for up to 24 courses in the absence of disease
 progression or unacceptable toxicity.

 COHORT II (IBRUTINIB TREATMENT > 9 MONTHS): Patients receive nivolumab as in Cohort I and
 continue previous ibrutinib treatment.

 COHORT III (RICHTER TRANSFORMATION): Patients receive nivolumab and ibrutinib as in cohort I.
 Ibrutinib may be given earlier than course 2 in case of worsening disease after discussion
 with study principal investigator. Treatment repeats every 28 days for up to 24 courses in
 the absence of disease progression or unacceptable toxicity

 * Note: After 3 cycles of treatment, nivolumab administration may be decreased to once every
 4 weeks in all cohorts, in consultation with the study principal investigator.

 After completion of study treatment, patients are followed up monthly for 1 year.
Inclusion Criteria:

 -  Patients will have a diagnosis of CLL or small lymphocytic lymphoma (SLL), refractory
 to or relapsed after at least one prior standard therapy or untreated with deletion
 (del)(17p) by fluorescence in-situ hybridization (FISH) (high-risk cytogenetics) and
 have an indication for treatment by IWCLL 2008 criteria (Cohort 1) OR have been on
 ibrutinib for at least 9 months with measurable persistent disease (absolute
 lymphocyte count [ALC] > 4 K/muL, any lymph node > 1.5 cm by computed tomography [CT]
 scan, or > 30% lymphocytes on bone marrow aspirate differential) (Cohort 2), OR
 patients will have a diagnosis of RT, refractory to and/or relapsed after at least one
 prior standard therapy or untreated with del(17p) by FISH (high-risk cytogenetics)
 (Cohort 3)

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

 -  Total bilirubin =< 1.5 x upper limit of normal (ULN); for patients with Gilbert's
 disease, total bilirubin up to =< 3 x ULN is allowed provided normal direct bilirubin

 -  Serum creatinine =< 1.5 x ULN

 -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN

 -  Females of childbearing potential must have a negative serum or urine beta human
 chorionic gonadotrophin (beta-hCG) pregnancy test result within 24 hours prior to the
 first dose of treatment and must agree to use an effective contraception method during
 the study and for 23 weeks following the last dose of the study drugs; females of
 non-childbearing potential are those who are postmenopausal greater than 1 year or who
 have had a bilateral tubal ligation or hysterectomy; males who have partners of
 childbearing potential must agree to use an effective contraceptive method during the
 study and for 31 weeks following the last dose of study drugs

 -  Patients or their legally authorized representative must provide written informed
 consent

 Exclusion Criteria:

 -  History of another primary invasive malignancy that has not been definitively treated
 or in remission for at least 2 years; patients with non-melanoma skin cancers or with
 carcinomas in situ are eligible regardless of the time from diagnosis (including
 concomitant diagnoses); if patients have another malignancy that was treated within
 the last 2 years, such patients may be enrolled if the likelihood of requiring
 systemic therapy for this other malignancy within 2 years is less than 10%, as
 determined by an expert in that particular malignancy at MD Anderson Cancer Center and
 after consultation with the principal investigator

 -  Any major surgery, radiotherapy, cytotoxic chemotherapy, biologic therapy,
 immunotherapy, immunomodulatory drugs, experimental therapy within 4 weeks prior to
 the first dose of the study drugs; Note: prior therapy with anti cluster of
 differentiation (CD)20 monoclonal antibody, anti CD52 monoclonal antibody, and
 lenalidomide are allowed; for oral targeted therapies (such as idelalisib,
 venetoclax), a washout of 3 days is allowed

 -  Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
 congestive heart failure, or myocardial infarction within 2 months of screening, or
 any class 3 or 4 cardiac disease as defined by the New York Heart Association
 functional classification

 -  History of stroke or cerebral hemorrhage within 2 month

 -  Patients who have uncontrolled hypertension (defined as sustained systolic blood
 pressure >= 160 mmHg or diastolic >= 100 mmHg)

 -  Known evidence of active cerebral/meningeal CLL; patients may have history of central
 nervous system (CNS) leukemic involvement if definitively treated with prior therapy
 and no evidence of active disease at the time of registration

 -  Active, uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring
 steroid therapy

 -  Patients with autoimmune diseases are excluded: patients with a history of
 inflammatory bowel disease (including Crohn's disease and ulcerative colitis) are
 excluded from this study as are patients with a history of autoimmune disease (e.g.,
 rheumatoid arthritis, systemic progressive sclerosis, systemic lupus erythematosus,
 Wegener's granulomatosis)

 -  Patients with previous allogeneic stem cell transplant (SCT) within 6 months or with
 active acute or chronic graft-versus host disease are excluded; patients must be off
 immunosuppression for graft-versus host disease (GVHD) for at least 30 days before
 cycle 1 day 1

 -  Patients with organ allografts (such as renal transplant) are excluded

 -  History of interstitial lung disease or pneumonitis

 -  Patients who are on high dose steroid (> 10 mg daily of prednisone or equivalent) or
 immune suppression medications; Note: patients on high-dose steroids (doses > 10mg/day
 of prednisone or equivalent) or immune suppression medications are eligible provided
 these drugs are discontinued at least 3 days prior to starting on the study drugs

 -  Patients with uncontrolled active infection (viral, bacterial, and fungal) are not
 eligible

 -  Current or chronic hepatitis B or C infection, or known seropositivity for human
 immunodeficiency virus (HIV)

 -  Patient is pregnant or breast-feeding

 -  Concurrent use of investigational therapeutic agent

 -  Malabsorption syndrome or other condition that precludes enteral route of
 administration

 -  Concomitant use of warfarin or other vitamin K antagonists

 -  Requires treatment with a strong cytochrome P450 (CYP) family 3, subfamily A (3A)
 inhibitor

 -  Other severe acute or chronic medical or psychiatric condition or laboratory
 abnormality that in the opinion of the investigator may increase the risk associated
 with study participation or investigational product administration or may interfere
 with the interpretation of study results and/or would make the patient inappropriate
 for enrollment into this study