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

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Macroglobulinemia and in IgM-MGUS Vaccine Therapy in Treating Patients With Lymphoplasmacytic Lymphoma Ofatumumab and Bortezomib in Treating Patients With Previously Untreated Waldenstrom Macroglobulinemia Perifosine in Patients With Relapsed/Refractory Waldenstrom’s Macroglobulinemia Randomised Trial in Waldenstrom’s Macroglobulinaemia A Study of Ibrutinib (PCI-32765) in Chinese Participants With Relapse or Refractory Waldenstrom’s Macroglobulinemia (WM) Pomalidomide, Dexamethasone and Rituximab in Waldenstrom’s Macroglobulinemia Study of the Combination of Bortezomib, Dexamethasone, and Rituximab in Patients With Waldenstroms Macroglobulinemia Study of Epratuzumab (hLL2) in Patients With Waldenstrom’s Macroglobulinemia A Study for Patients That Have Been Previously Been Treated in Waldenstrom’s Macroglobulinemia or Multiple Myeloma Ibrutinib With Rituximab in Adults With Waldenström’s Macroglobulinemia Oblimersen in Treating Patients With Relapsed or Refractory Waldenstrom’s Macroglobulinemia Investigating the Safety and Efficacy of Rituximab and Pembrolizumab in Relapsed/Refractory Waldenström’s Macroglobulinaemia An Open-label, Phase 2 Study of Acalabrutinib in Subjects With Waldenström Macroglobulinemia Simvastatin in Waldenstrom’s Macroglobulinemia Ibrutinib (PCI-32765) in Waldenstrom’s Macroglobulinemia Carfilzomib, Rituximab and Dexamethasone in Waldenstrom’s Macroglobulinemia Thalidomide and Rituximab in Waldenstrom’s Macroglobulinemia Comparison of ASCT and Conventional Chemotherapy in High Risk Waldenström Macroglobulinemia Fase II Study With BRB for Non-Hodgkin Lymphoplasmacytic Lymphoma/Waldenstrom Macroglobulinemia’s Study of Lenalidomide in Relapse/Refractory Waldenstrom Macroglobulinemia Efficacy of Bortezomib (Velcade(R)) in Patients With Advanced Waldenström Macroglobulinemia A Study of Daratumumab in Patients With Relapsed or Refractory Waldenström Macroglobulinemia A Study of Ulocuplumab And Ibrutinib in Symptomatic Patients With Mutated CXCR4 Waldenstrom’s Macroglobulinemia Study of Phosphatidylinositol-3-kinase (PI3K) Inhibitor Idelalisib (GS-1101) in Waldenström Macroglobulinemia Trial of Ixazomib, Dexamethasone and Rituximab in Patients With Untreated Waldenstrom’s Macroglobulinemia Study of Ibrutinib in Patients With Symptomatic, Previously Untreated Waldenstrom’s Macroglobulinemia, and Impact on Tumor Genomic Evolution Using Whole Genome Sequencing LBH589 in Relapsed or Relapsed and Refractory Waldenstrom’s Macroglobulinemia Everolimus, Bortezomib and/or Rituximab in Patients With Relapsed/Refractory Waldenstrom’s Macroglobulinemia A Phase II Trial of Ofatumumab in Subjects With Waldenstrom’s Macroglobulinemia Study of ABT-199 (GDC-199) In Patients With Relapsed Or Refractory Waldenström Macroglobulinemia Expression of Ku70/XRCC6 in Waldenström’s Macroglobulinemia Anti-Angiogenesis Therapy Using Thalidomide in Patients With Waldenstrom’s Macroglobulinemia Study of VTD in Waldenstrom’s Macroglobulinemia Dasatinib In Waldenström Macroglobulinemia The Comparison of RCD Versus BCD in Newly Diagnosed Waldenström Macroglobulinemia CC-5013 (Lenalidomide) and Rituximab in Waldenstrom’s Macroglobulinemia Combination Bortezomib and Rituximab in Patients With Waldenstrom’s Macroglobulinemia R-VRD Followed by Lenalidomide Maintenance in Patients With Waldenstrom’s Macroglobulinemia Phase 1/2 Dose Escalation Study in Patients With Relapsed or Refractory Waldenstrom’s Macroglobulinemia Antineoplaston Therapy in Treating Patients With Recurrent or Refractory Waldenstrom’s Macroglobulinemia Efficacy of First Line B-RI for Treatment Naive Waldenström’s Macroglobulinemia Sildenafil Citrate in Waldenstrom’s Macroglobulinemia Bortezomib (Velcade) in Waldenstrom’s Macroglobulinemia Phase II Study of Campath-1H Antibody to Treat Waldenstrom’s Macroglobulinemia

Brief Title

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

Official Title

A Phase II Study of Anti-PD-1 Antibody (MK-3475) in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) and Other Low Grade B Cell Non-Hodgkin Lymphoma (NHL)

Brief 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.
    

Detailed Description

      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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Proportion of patients who achieve a confirmed response

Secondary Outcome

 Progression-free survival of patients treated with single pembrolizumab

Condition

Recurrent B-Cell Non-Hodgkin Lymphoma

Intervention

Ibrutinib

Study Arms / Comparison Groups

 Treatment (pembrolizumab, idelalisib, or ibrutinib)
Description:  Patients receive pembrolizumab 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: Patients receive pembrolizumab IV over 30 minutes on day 1. Patients also receive idelalisib PO BID on days 1-21 OR ibrutinib PO 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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

68

Start Date

February 19, 2015

Completion Date

January 15, 2023

Primary Completion Date

January 5, 2022

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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Wei Ding, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02332980

Organization ID

MC1485

Secondary IDs

NCI-2014-02561

Responsible Party

Sponsor

Study Sponsor

Mayo Clinic

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

Wei Ding, Principal Investigator, Mayo Clinic in Rochester


Verification Date

November 2020