Clinical Trials /

Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCT03204188

Description:

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 andto 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 (except patients with deletion 13q AND mutated IgHV), or - Presence of high-risk mutations regardless of prior treatment status: deletion 17p, TP53 mutation, NOTCH1 mutation, 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 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.

Related Conditions:
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • Official Title: A Phase II Study Of Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Clinical Trial IDs

  • ORG STUDY ID: 170118
  • SECONDARY ID: 17-H-0118
  • NCT ID: NCT03204188

Conditions

  • Progressive Marrow Failure
  • Night Sweats for More Than 1 Month Without Evidence of Infection
  • Weight Loss of 10% or More Within the Previous 6 Months
  • Fevers Higher Than 100.5 Degress F or 38.0 Degrees C for 2 or More Weeks

Interventions

DrugSynonymsArms
IbrutinibSingle Arm
FludarabineSingle Arm
PembrolizumabSingle Arm

Purpose

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 andto 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 (except patients with deletion 13q AND mutated IgHV), or - Presence of high-risk mutations regardless of prior treatment status: deletion 17p, TP53 mutation, NOTCH1 mutation, 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 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.

Detailed Description

      Background:

      This study investigates the combination of ibrutinib, fludarabine and pembrolizumab for
      treatment of CLL. 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. High-risk CLL is defined
      by relapsed/refractory disease status, or the presence of high-risk mutations, such as
      deletion 17p, TP53, and NOTCH1. While the cause of CLL is still unclear, studies have
      indicated critical factors required for the tumor cells. First, CLL cells grow and survive
      because they receive signals through the B-cell receptor (BCR); and second, CLL cells benefit
      from interactions with other cells, especially T cells.

      The stimulation through the BCR can be blocked by ibrutinib, which is an oral drug that
      selectively inhibits Bruton s tyrosine kinase (BTK). In clinical trials, ibrutinib
      demonstrated safety and high response rates in patients with high-risk disease. Ibrutinib has
      gained FDA approval as a treatment for CLL regardless of prior treatment or cytogenetic
      status. However, single-agent ibrutinib has limitations; the drug does not eliminate all
      tumor cells and, with time, the tumor cells may become resistant. Therefore, combination of
      ibrutinib with other drugs could be beneficial.

      Objectives:

      -To investigate the rate of complete response to ibrutinib, short course fludarabine and

      pembrolizumab.

      Key eligibility criteria:

      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 (except patients with deletion 13q AND mutated IgHV), or

      Presence of high-risk mutations regardless of prior treatment status: deletion 17p, TP53

      mutation, NOTCH1 mutation, or complex cytogenetics.
    

Trial Arms

NameTypeDescriptionInterventions
Single ArmExperimentalIFP
  • Ibrutinib
  • Fludarabine
  • Pembrolizumab

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. Exceptions are patients with mutated IGHV and
                  isolated 13q deletion. These patients are not considered to be high-risk by prior
                  treatment history alone, and will be excluded from the trial.

               -  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, or NOTCH1 mutation. Pathologic mutations
                       occurring at the coding regions are accepted as relevant mutations.

               -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of complete response (CR) after 12 months on pembrolizumab
Time Frame:1 year
Safety Issue:
Description:To test the rate of CR defined by the IWCLL criteria after completion of 1 year of pembrolizumab combined with ibrutinib and a short-course fludarabine.

Secondary Outcome Measures

Measure:Tolerability, response and best response, survival
Time Frame:2 years
Safety Issue:
Description:Tolerability of the combination regimen, Overall response rate (ORR), Duration of response (DOR), Best response, Minimal residual disease (MRD) status, Progression-free survival (PFS), Overall survival (OS), To explore the biologic effects on B- and T-cell subsets and function, To identify predictors of clinical response.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Heart, Lung, and Blood Institute (NHLBI)

Trial Keywords

  • Deletion 17p
  • Bruton's Tyrosine Kinase Inhibitor
  • TP53 Mutation
  • NOTCH1 mutation
  • Complex Cytogenics

Last Updated

February 12, 2020