Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Condition: B-Cell Chronic Lymphocytic Leukemia; B-Lymphocytic Leukemia, Chronic; Chronic Lymphocytic Leukemia; Leukemia, Chronic Lymphatic; Leukemia, Chronic Lymphocytic, B-Cell; Leukemia, Lymphocytic, Chronic; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytic Leukemia, Chronic, B Cell; Lymphocytic Leukemia, Chronic, B-Cell
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, B-Cell; Chronic Disease
Intervention: Ibrutinib; Fludarabine; Pembrolizumab
Intervention description: Ibrutinib will be administered daily by mouth starting cycle -3 at 420 mg until end study or disease progression or intolerable side effects occur.; Fludarabine will be administered intravenously only on cycle -2 at 25mg/m^2 x5 days.; Pembrolizumab will be administered intravenously every 3 weeks at 200 mg starting from cycle 1 through cycle 17 or 1 year of immunotherapy phase.
Intervention MeSH terms: Pembrolizumab; Fludarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Deletion 17p; TP53 Mutation; NOTCH1 mutation; Complex Cytogenetics; Bruton's Tyrosine Kinase (BTK) Inhibitor

Summary:

      Background:

      Chronic lymphocytic leukemia and small lymphocytic lymphoma (hereby referred as CLL) are
      tumors of B cells. A subset of patients categorized as high-risk CLL has a poor clinical
      outcome when treated with conventional chemotherapy. This single-arm, phase II study
      investigates the combination of ibrutinib, fludarabine and pembrolizumab for treatment of
      CLL. Ibrutinib is an orally administered therapy for CLL. Fludarabine is a well-tolerated
      drug that has been widely used to treat CLL. Also, fludarabine can modulate CLL cells as well
      as immune cells that support the growth of CLL cells. Pembrolizumab recruits immune cells to
      attack CLL cells. With this approach we hope to achieve a greater reduction in CLL cells than
      with single agent ibrutinib and to restore healthier immune system that could contribute to
      durable responses.

      Objective:

      To investigate the rate of complete response to ibrutinib, short course fludarabine and
      pembrolizumab.

      Eligibility:

      Patients with active CLL meeting treatment indications defined by 2008 International Workshop
      on CLL (IWCLL) consensus guideline.

      High-risk CLL defined by one of the following:

        -  Relapsed/refractory disease status, or

        -  Presence of high-risk mutations regardless of prior treatment status: deletion 17p, TP53
           mutation, NOTCH1 mutation, SF3B1 mutation, MYC aberration, or complex cytogenetics.

      Design:

      This is a single-arm, open-label phase II study.

      Timeline: Treatment on this study is given in cycles from cycle -3 to 17, then in months
      beyond cycle 17. Cycles -3 to -1 are 28-day cycles. Cycles 1 to 17 are 21-day cycles. After
      completion of 1 year of pembrolizumab, the time on study is by chronological months on study
      from starting pembrolizumab.

      Treatment plan:

        -  Ibrutinib is given starting from cycle -3 and continuously until disease progression or
           intolerable side effects occur.

        -  Fludarabine is given on D1-D5 on cycle -2 only

        -  Pembrolizumab is given every 3 weeks starting from cycle 1 for 1 year.

        -  Minimal residual disease will be measured at 2 years from cycle 1 to determine the need
           for long- term treatment with ibrutinib.

             -  Previously-untreated patients who achieve minimal residual disease negativity will
                stop ibrutinib.

             -  Patients who do not achieve minimal residual disease negativity or who has
                Relapsed/refractory CLL will continue ibrutinib.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Men and women with histologically confirmed CLL or SLL

          -  Active disease as defined by at least one of the following IWCLL consensus criteria:

               -  Weight loss greater than or equal to 10% within the previous 6 months.

               -  Extreme fatigue.

               -  Fevers of greater than 100.5 degrees F for greater than or equal to 2 weeks
                  without evidence of infection.

               -  Night sweats for more than one month without evidence of infection.

               -  Evidence of progressive marrow failure as manifested by the development of, or
                  worsening of, anemia and/or thrombocytopenia.

               -  Massive or progressive splenomegaly.

               -  Massive nodes or clusters or progressive lymphadenopathy.

               -  Progressive lymphocytosis with an increase of >50% over a 2-month period, or an
                  anticipated doubling time of less than 6 months.

          -  High-risk disease defined by meeting at least one of the following three criteria:

               -  Relapsed and/or refractory CLL/SLL.

               -  Presence of high-risk mutations detected by FISH or targeted sequencing,
                  regardless of prior treatments status.

                    -  FISH: deletion 17p (or TP53), complex cytogenetics (3 or more abnormalities)

                    -  Targeted sequencing: TP53 mutations, SF3B1 mutations, or NOTCH1 mutation.
                       Pathologic mutations occurring at the coding regions are accepted as
                       relevant mutations.

                    -  MYC aberration. Aberration includes rearrangement, amplification, and tissue
                       expression by immunohistochemistry

               -  CLL or SLL with disease transformation with Hodgkin-like cells regardless of
                  prior treatment status.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to
             1.

          -  Adequate organ function as defined by the study protocol.

          -  Agreement to use acceptable methods of contraception during the study and for 90 days
             after the last dose of study drug if sexually active and able to bear or beget
             children.

          -  Willing and able to participate in all required evaluations and procedures in this
             study protocol including swallowing capsules without difficulty.

          -  Ability to understand the purpose and risks of the study and provide signed and dated
             informed consent and authorization to use protected health information.

          -  Individuals greater than or equal to 18 years old

        EXCLUSION CRITERIA:

          -  Transformation of CLL into lymphomas other than those with Hodgkin-like cells.

          -  Currently receiving or previously participated to receive an investigational agent
             within 4 weeks prior to study treatment.

          -  Currently receiving or previously received monoclonal antibodies, immunomodulatory
             therapy, chemotherapy, radiation, or radioimmunotherapy within 4 weeks prior to study
             treatment, or has not recovered from non-hematologic adverse events due to a
             previously administered agent.

          -  Major surgery within 4 weeks of first dose of study drug

          -  Currently receiving systemic steroid therapy (i.e. prednisone) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

          -  Prior therapy with BTK inhibitor, anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

          -  Active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g.., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

          -  Known additional malignancy that is progressing or requires active treatment.

          -  Known history of, or any evidence of active, non-infectious pneumonitis that required
             steroids.

          -  Known bleeding disorders (i.e., von Willebrand s disease or hemophilia).

          -  Known HIV infection

          -  Active hepatitis B or hepatitis C infection.

          -  Recent known active infection requiring systemic therapy that was completed less than
             or equal to 14 days before the first dose of study drug.

          -  Known history of active tuberculosis.

          -  Any uncontrolled active systemic infection.

          -  Known hypersensitivity to ibrutinib, fludarabine, or pembrolizumab.

          -  Requires concomitant anticoagulation with Coumadin (warfarin) or other vitamin K
             antagonists.

          -  Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
             resection of the stomach or small bowel or ulcerative colitis, symptomatic
             inflammatory bowel disease, or partial or complete bowel obstruction

          -  History of stroke or intracranial hemorrhage within 6 months before the first dose of
             study drug

          -  Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior
             to the first dose of ibrutinib or subjects who require continuous treatment with a
             strong CYP3A inhibitor

          -  Currently active, clinically significant cardiovascular disease including uncontrolled
             or symptomatic arrhythmias, Class 3 or 4 congestive heart failure as defined by New
             York Heart Association Functional Classification, or a history of myocardial
             infarction, unstable angina or acute coronary syndrome within 6 months of screening.

          -  Life-threatening illness, medical condition or organ system dysfunction which, in the
             investigator's opinion, could compromise the subject's safety, interfere with the
             absorption or metabolism of ibrutinib and fludarabine, or put the study outcomes at
             undue risk

          -  Female patients who are currently in pregnancy, or unwilling to use acceptable methods
             of contraception or refrain from pregnancy if of childbearing potential or currently
             breastfeeding. Male patients who are unwilling to follow the contraception
             requirements described in this protocol.

          -  Psychiatric illness/social situations that would limit the patient s ability to
             tolerate and/or comply with study requirements.

          -  Unable to understand the investigational nature of the study or give informed consent.

          -  Currently active, clinically significant hepatic impairment Child-Pugh class B or C
             according to the Child Pugh classification.

          -  Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.