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

PRIMARY OBJECTIVES:

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 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 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).

TERTIARY 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, 1 or 2

- 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

- Platelet count >= 25 x 10^9/L

- Absolute neutrophil count >= 0.5 x 10^9/L

- 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

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

- 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) used for treatment of non-hematologic medical conditions

- 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 Sjogrens
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:

- 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