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
Condition: Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Lymphoplasmacytic Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Nodal Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent Splenic Marginal Zone Lymphoma; Recurrent Waldenstrom Macroglobulinemia; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Refractory Follicular Lymphoma; Refractory Lymphoplasmacytic Lymphoma; Refractory Nodal Marginal Zone Lymphoma; Refractory Small Lymphocytic Lymphoma; Refractory Splenic Marginal Zone Lymphoma; Refractory Waldenstrom Macroglobulinemia; Richter Syndrome; Waldenstrom Macroglobulinemia
MeSH terms: Lymphoma; Leukemia; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, B-Cell; Waldenstrom Macroglobulinemia; Recurrence
Intervention: Ibrutinib; Idelalisib; Laboratory Biomarker Analysis; Pembrolizumab
Intervention description: Given PO; Given PO; Correlative studies; Given IV
Intervention MeSH terms: Pembrolizumab; Idelalisib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 65.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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