Pembrolizumab Alone or With Idelalisib or Ibrutinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Other Low-Grade B-Cell Non-Hodgkin Lymphomas
Pembrolizumab Alone or With Idelalisib or Ibrutinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Other Low-Grade B-Cell Non-Hodgkin Lymphomas
This phase II trial studies how well pembrolizumab alone or with idelalisib or ibrutinib
 works in treating patients with chronic lymphocytic leukemia or other low-grade B-cell
 non-Hodgkin lymphomas that have returned after a period of improvement (relapsed) or have not
 responded to treatment (refractory). Immunotherapy with monoclonal antibodies, such as
 pembrolizumab, may help the body's immune system attack the cancer, and may interfere with
 the ability of tumor cells to grow and spread. Idelalisib and ibrutinib may stop the growth
 of cancer cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab
 alone or with idelalisib or ibrutinib may be an effective treatment in patients with chronic
 lymphocytic leukemia or other low-grade B-cell non-Hodgkin lymphomas.
PRIMARY OBJECTIVE:

 I. Test the efficacy (overall response rate) of single-agent MK-3475 (pembrolizumab) in
 relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (Arm A) other
 low grade B-cell non-Hodgkin lymphoma (B-NHL), and CLL with Richter's transformation (Arm C).

 SECONDARY OBJECTIVES:

 I. Test the safety of single-agent MK-3475 in relapsed CLL/SLL (Arm A), other low grade B-NHL
 (Arm B), and CLL with Richter's transformation (Arm C).

 II. Test the overall survival, progression free survival, treatment free survival, duration
 of response and time to next therapy of single-agent MK-3475 in relapsed CLL/SLL (Arm A),
 other low grade B-NHL (Arm B), and CLL with Richter's transformation (Arm C).

 III. Test the complete response rate of single MK-3475 in relapsed CLL/SLL (Arm A), other low
 grade B-NHL (Arm B), and CLL with Richter's transformation (Arm C).

 IV. Test the safety of MK-3475 in combination with the signal inhibitor (either idelalisib or
 ibrutinib) in relapsed CLL/SLL (Arm A) and CLL with Richter's transformation (Arm C).

 V. Test the progression-free survival, treatment-free survival, duration of response and time
 to next therapy, as well as overall survival of MK-3475 in combination with the signal
 inhibitor (either idelalisib or ibrutinib) in relapsed CLL/SLL (Arm A) and CLL with Richter's
 transformation (Arm C).

 VI. Test the overall and complete response rates of MK-3475 in combination with the signal
 inhibitor (either idelalisib or ibrutinib) in relapsed CLL/SLL (Arm A) and CLL with Richter's
 transformation (Arm C).

 CORRELATIVE RESEARCH OBJECTIVES:

 I. To assess the potential association between programmed cell death ligand 1
 (PD-L1)/programmed cell death 1 (PD-1)/PD-L2 expression on tumor and T cells and/or PD-L1
 soluble levels in plasma with clinical efficacy of PD-1 blockade.

 II. To investigate the effects of MK-3475 on selected markers of immune modulation and immune
 profiles in peripheral blood and tumor samples.

 III. Examine T-cell immune synapse function and expression/location of co-stimulatory and
 co-inhibitory molecules (including effector molecules) as potential biomarkers to response
 for anti-PD-1 immune checkpoint blockade immunotherapy.

 OUTLINE:

 ALL PATIENTS (ARMS A, B, and C): Patients receive pembrolizumab intravenously (IV) over 30
 minutes on day 1. Treatment repeats every 21 days for up to 12 months in the absence of
 disease progression or unacceptable toxicity. Patients receiving benefit may continue to
 receive treatment for an additional 12 months at the discretion of the investigator. Patients
 with CLL or CLL with Richter's transformation experiencing stable disease without partial
 remission or progressive disease at 3 months of treatment with pembrolizumab proceed to the
 treatment continuation phase.

 CONTINUATION PHASE (ARMS A and C): Patients receive pembrolizumab IV over 30 minutes on day
 1. Patients also receive idelalisib orally (PO) twice daily (BID) on days 1-21 OR ibrutinib
 PO once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 12 or 24 months in
 the absence of disease progression or unacceptable toxicity. Patients receiving benefit may
 continue to receive treatment for an additional 12 months at the discretion of the
 investigator.

 After completion of study treatment, patients are followed up every 3 months for 1 year.
Inclusion Criteria:

 -  CLL/SLL PATIENTS (ARM A) ONLY

 -  Diagnosis of CLL according to the National Cancer Institute (NCI) criteria or SLL
 according to the World Health Organization (WHO) criteria; this includes previous
 documentation of:

 -  Biopsy-proven small lymphocytic lymphoma or

 -  Diagnosis of CLL according to NCI working group criteria as evidenced by all of
 the following:

 -  Peripheral blood B cell count of > 5 x 10^9/L consisting of small to
 moderate size lymphocytes

 -  Immunophenotyping consistent with CLL defined as:

 -  The predominant population of lymphocytes share both B-cell antigens
 (cluster of differentiation [CD]19, CD20 [typically dim expression] or
 CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3,
 CD2, etc.)

 -  Clonality as evidenced by kappa or lambda light chain expression
 (typically dim immunoglobulin expression) or other genetic method (e.g.
 immunoglobulin heavy chain variable [IGHV] analysis)

 -  NOTE: splenomegaly, hepatomegaly, or lymphadenopathy are not required
 for the diagnosis of CLL

 -  Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by
 demonstrating a negative fluorescent in situ hybridization (FISH) analysis
 for t(11;14) (immunoglobulin H [IgH]/cyclin D1 [CCND1]) on peripheral blood
 or tissue biopsy or negative immunohistochemical stains for cyclin D1 on
 involved tissue biopsy

 -  Patients must be previously treated with at least one prior line of therapy;
 EXCEPTION: CLL patients with Richter's transformation or Hodgkin transformation do not
 need prior therapy to enroll

 -  NOTE:

 -  Prior chemotherapy or biologic novel therapy or anti-cancer monoclonal
 antibody based therapy for treatment of CLL will be considered prior
 therapy; nutraceutical treatments with no established benefit in CLL (such
 as epigallocatechin gallate or EGCG, found in green tea or other herbal
 treatments) will not be considered "prior treatment"

 -  Prior oral corticosteroid therapy for an indication other than CLL will not
 be considered "prior treatment"

 -  Previous use of corticosteroids in the combination with other therapy for
 treatment of autoimmune complications of CLL does constitute prior therapy
 for CLL

 -  CLL/SLL patients must have progressive disease with any one of the following
 characteristics based on standard criteria for treatment as defined by the NCI-Working
 Group (WG) 1996

 -  Symptomatic CLL characterized by any one of the following:

 -  Weight loss >= 10% within the previous 6 months

 -  Extreme fatigue attributed to CLL

 -  Fevers >= 100.5 degree Fahrenheit (F) for 2 weeks without evidence of
 infection

 -  Drenching night sweats without evidence of infection

 -  Evidence of progressive bone marrow failure with hemoglobin =< 11 g/dL or
 platelet count =< 100 x 10^9/L

 -  Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly

 -  Note: marked hypogammaglobulinemia or the development of a monoclonal protein in
 the absence of any of the above criteria for active disease are not sufficient
 for protocol therapy OR biopsy proven Richter's transformation or Hodgkin
 transformation of the CLL; NOTE: both untreated and previously treated patients
 in this category can be enrolled; they do not need to meet the progressive
 disease criteria in first bullet as long as measurable disease can be detected by
 positron emission tomography (PET)/computed tomography (CT) or CT (>= 1.5 cm in
 diameter)

 -  LOW GRADE B-NHL PATIENTS ONLY

 -  Histologically confirmed relapsed (response to last treatment >= 6 months duration) or
 refractory (no response to last treatment or response duration < 6 months)
 indolent/low grade B cell NHL; NOTE: if patient has received previous anti-PD-1 or
 anti-PDL-1 consult with study chair

 -  Follicular lymphoma, grades 1, 2 and 3

 -  Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
 (MALT) type

 -  Splenic and nodal marginal zone lymphoma

 -  Lymphoplasmacytic lymphoma including Waldenstrom macroglobulinemia

 -  Measurable disease (at least 1 lesion of >= 1.5 cm in diameter) as detected by CT or
 the CT images of the PET/CT; NOTE: patients with Waldenstrom macroglobulinemia are not
 required to have measurable disease by CT or PET/CT if monoclonal protein is
 detectable by serum protein electrophoresis and/or immunoglobulin M (IgM) level is at
 least 2 times upper limit of normal

 -  CLL WITH RICHTER's TRANSFORMATION (ARM C) ONLY

 -  CLL diagnosis confirmed as have biopsy-proven Richter's transformation; NOTE: both
 untreated and previously treated patients in this category can be enrolled as long as
 measurable disease can be detected by PET/CT or CT (>= 1.5 cm in diameter)

 -  ALL PATIENTS

 -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

 -  Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance >= 60 mL/min
 for subject with creatinine levels > 1.5 x institutional ULN (obtained =< 14 days
 prior to registration)

 -  Platelet count >= 25 x 10^9/L (obtained =< 14 days prior to registration)

 -  Absolute neutrophil count >= 0.5 x 10^9/L (obtained =< 14 days prior to registration)

 -  Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's disease;
 if total bilirubin is > 1.5 x ULN, a direct bilirubin should be performed and must be
 =< upper limit of normal (obtained =< 14 days prior to registration)

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or
 alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
 ULN (obtained =< 14 days prior to registration)

 -  Negative pregnancy test done =< 7 days prior to registration, for women of
 childbearing potential only

 -  Provide informed written consent

 -  Willing to return to enrolling institution for follow-up (during the Active Monitoring
 Phase of the study)

 -  Note: During the Active Monitoring Phase of a study (i.e., active treatment and
 observation), participants must be willing to return to the consenting
 institution for follow-up

 -  Willing to provide bone marrow, tissue, and blood samples for correlative research
 purposes

 -  Must have failed or be unable to tolerate or refused other available Food and Drug
 Administration (FDA) approved effective therapies; NOTE: patients should not have
 other treatment options considered curative

 Exclusion Criteria:

 -  Currently participating in or has participated in a study of an investigational agent
 or using an investigational device =< 28 days prior to registration

 -  Receiving systemic steroid therapy or any other form of systemic immunosuppressive
 therapy =< 7 days prior to registration; EXCEPTIONS:

 -  Low doses of steroids (=< 20 mg of prednisone or equivalent dose of other
 steroid/day)

 -  Previous use of corticosteroids is allowed

 -  After initiation of MK-3475 therapy, steroid can be used for management of
 potential immune mediated adverse events (AE) for less than 8 weeks of therapy

 -  Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
 (with minimal systemic absorption) are permitted

 -  Prior anti-cancer monoclonal antibody =< 28 days prior to registration or who has not
 recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents
 administered more than 4 weeks earlier

 -  Prior chemotherapy or radiation therapy =< 14 days prior to registration or who has
 not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a
 previously administered agent

 -  Note: subjects with =< grade 2 neuropathy are an exception to this criterion and
 may qualify for the study

 -  Note: if subject received major surgery, they must have recovered adequately from
 the toxicity and/or complications from the intervention prior to starting therapy

 -  Known additional malignancy that is progressing or requires active treatment;
 EXCEPTIONS (these following exceptions are permitted to enroll in this trial):

 -  Basal cell carcinoma or squamous cell carcinoma or melanoma of the skin that has
 undergone or will undergo potentially curative therapy

 -  In situ cervical cancer that has undergone or will undergo potentially curative
 therapy

 -  Active autoimmune disease requiring systemic treatment within the past 3 months or a
 documented history of clinically severe autoimmune disease/syndrome difficult to
 control in the past; EXCEPTIONS:

 -  Subjects with vitiligo or resolved childhood asthma/atopy would be an exception
 to this rule

 -  Subjects that require intermittent use of bronchodilators or local steroid
 injections would not be excluded from the study

 -  Subjects with hypothyroidism stable on hormone replacement, diabetes or Sjogren's
 syndrome are permitted for the study

 -  Patients who have a positive Coombs test but no evidence of hemolysis are
 permitted for participation

 -  Patients with psoriasis not requiring systemic treatment are permitted for
 participation

 -  Conditions not expected to recur in the absence of an external trigger are
 permitted to enroll

 -  Evidence of interstitial lung disease or active, non-infectious pneumonitis

 -  Active infection requiring systemic therapy; NOTE: when the infection is controlled,
 patients are permitted for this study

 -  Known psychiatric or substance abuse disorders that would interfere with cooperation
 with the requirements of the trial

 -  Any of the following because this study involves an investigational agent whose
 genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are
 unknown:

 -  Pregnant women

 -  Nursing women

 -  Men or women of childbearing potential who are unwilling to employ adequate
 contraception starting with the pre-screening or screening visit through 120 days
 after the last dose of trial treatment

 -  Known to be human immunodeficiency virus (HIV) positive

 -  Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
 hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
 detected); NOTE: patients with active hepatitis B defined by hepatitis B surface
 antigen positivity or core antibody positivity in the presence of hepatitis B
 deoxyribonucleic acid (DNA) are not eligible for this study; patients with a positive
 hepatitis B core antibody but with negative hepatitis B DNA may participate, but must
 have hepatitis serologies and hepatitis B DNA monitored periodically by the treating
 physician

 -  NOTE: intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B
 serology; if patients receiving routine IVIG have core antibody or surface
 antigen positivity without evidence of active viremia (negative hepatitis B DNA)
 they may still participate in the study, but should have hepatitis serologies and
 hepatitis B DNA monitored periodically by the treating physician

 -  Received a live vaccine =< 30 days prior to registration

 -  New York Heart Association classification III or IV cardiovascular disease or recent
 myocardial infarction or unstable angina pectoris or cardiac arrhythmia (< 30 days)

 -  Active central nervous system (CNS) lymphoma or cerebrospinal fluid involvement with
 malignant lymphoma cells that requires therapy

 -  Has a clinically significant coagulopathy per investigator's assessment

 -  Has received an allogeneic stem cell transplant

 -  CLL ARMS (ARM A and ARM C) FOR COMBINATION THERAPY INCLUDING IBRUTINIB or IDELALISIB:

 -  Is chronically taking a strong cytochrome P450, family 3, subfamily A, polypeptide 4
 (CYP3A) inhibitor or inducer and cannot be switched to an alternative agent at least 7
 days prior to idelalisib or ibrutinib initiation that in the opinion of
 investigator/treating physicians precludes utilization of either Ibrutinib or
 Idelalisib; caution is recommended for patients taking moderate inhibitors of CYP3A

 -  CLL ARMS (ARM A and ARM C) FOR COMBINATION THERAPY INCLUDING IDELALISIB ARM:

 -  Is chronically taking a sensitive CYP3A substrate or a CYP3A substrate with a narrow
 therapeutic index and cannot be switched to an alternative agent at least 7 days prior
 to study initiation that in the opinion of investigator/treating physicians precludes
 utilization of idelalisib

 -  A history of chronic diarrhea, colitis, or intestinal perforation that in the opinion
 of the investigator precludes utilization of idelalisib