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

Updated on 23 November 2020
chronic lymphocytic leukemia
neutrophil count
night sweats



  • Chronic lymphocytic leukemia (CLL) is a cancer of white blood cells. It is also called small lymphocytic lymphoma (SLL). It causes tiredness, night sweats, weight loss, swollen lymph nodes, easy bruising or bleeding, and frequent infections. Researchers want to test if a drug combination is effective and safe for people with CLL/SLL.


  • To test how safe and effective a combination of ibrutinib, short-course fludarabine, and pembrolizumab is for people with chronic lymphocytic leukemia (CLL), also known as small lymphocytic lymphoma (SLL).


  • Adults at least 18 years old who have CLL or SLL, with certain genetic changes.


  • Participants will be screened with:
    • Medical history
    • Physical exam
    • Heart tests
    • Blood and lab tests
    • Small lymph node sample removed by needle
    • Sample of bone marrow taken by needle in the hipbone. The area will be numbed.
    • CT or PET scan. They will lie in a machine that takes pictures. They may have a radioactive sugar injected before the scan.
    • Pregnancy test
  • Phase 1 will be 12 weeks. Participants will take ibrutinib by mouth once a day. For weeks 5 and 9 they will also take fludarabine. It will be infused in a vein for half an hour each day for 5 days in a row.
  • Phase 2 will be 2 years. Participants will take ibrutinib by mouth once a day. They will also get pembrolizumab by vein for half an hour once every 3 weeks.
  • After that, the study team will decide if participants should continue therapy.
  • During the study, participants will have regular visits. They will repeat some or all screening tests.

Please visit our Patient Recruitment Page for more information.




  • 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.
  • This study investigates the combination of ibrutinib, fludarabine and pembrolizumab for treatment of CLL. Fludarabine is a well-tolerated drug that has been used widely to treat CLL. Also, fludarabine can kill both malignant B cells and T cells that support the growth of leukemia cells. Pembrolizumab targets immune checkpoint molecules and enhances the cell-killing activity of T 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.


  • 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.


  • 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 daily 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.


Please visit our Patient Recruitment Page for more information.

Condition CLL, Fevers Higher Than 100.5 Degress F or 38.0 Degrees C for 2 or More Weeks, Progressive Marrow Failure, Night Sweats for More Than 1 Month Without Evidence of Infection, SLL, Chronic Lymphocytic Leukemia, Weight Loss of 10% or More Within the Previous 6 Months, SmallLymphocytic Lymphoma
Clinical Study IdentifierTX218206
Last Modified on23 November 2020


Yes No Not Sure

Inclusion Criteria

Men and women with histologically confirmed CLL or SLL as defined by the following
CLL: clonal B lymphocytosis 2: greater than or equal to 5,000
SLL: lymphadenopathy with the tissue morphology of CLL but are not leukemic (< 5,000 circulating clonal B lymphocytes/microliter)
Immunophenotypic profile or immunohistochemistry read by an expert pathologist as consistent with CLL. This will include CD5, CD19, and CD20 expression by the CLL cells typically also with CD23 expression, but CD23 negative cases may be included if there is an absence of t(11;14)
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 below
Summary of adequate organ function for eligibility: System/Laboratory Value
Absolute neutrophil count (ANC): greater than or equal to 750/microliter
Platelets: greater than or equal to 50,000/microliter
Hemoglobin: greater than or equal to 9 g/dL or greater than or equal to 5.6 mmol/L without EPO dependency (within 7 days of assessment). Post-transfusion hemoglobin is accepted
Measured or calculated GFR: GFR greater than or equal to 30ml/min/1.73m^2 based on CKD-EPI
Serum total bilirubin: less than or equal to 1.5 X ULN OR Direct bilirubin less than or equal to ULN for subjects with total bilirubin levels greater than or equal to 1.5 ULN due to Gilbert's disease
AST (SGOT) and ALT (SGPT): less than or equal to 2.5 X ULN
International Normalized Ratio (INR) or Prothrombin Time (PT): less than or equal to 1.5 X ULN unless subject is receiving anticoagulant therapy; as long as PT or PTT is within therapeutic range of intended use of anticoagulants
Activated Partial Thromboplastin Time (aPTT): less than or equal to 1.5 X ULN unless subject is receiving anticoagulant therapy; as long as PT or PTT is within therapeutic range of intended use of anticoagulants
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
Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for greater than or equal to 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy)
Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry
Male and female subjects who agree to use both a highly effective methods of birth control (i.e., implants, injectables, combined oral contraceptives, some intrauterine devices, complete abstinence, or sterilized partner) and a barrier method (i.e., condoms, vaginal ring, sponge, etc) during the period of therapy and for 90 days after the last dose of study drug
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 (in accordance with national and local subject privacy regulations)
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 (i.e., less than or equal to Grade 1 or at baseline) from non-hematologic adverse events due to a previously administered agent
Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to CTCAE, v4.03, grade 0 or 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
Major surgery within 4 weeks of first dose of study drug
Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
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
Note: Prior therapy with fludarabine is not excluded
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
Note: Exceptions include basal cell carcinoma of skin, squamous cell carcinoma of skin, and in situ cervical cancer that has undergone potentially curative therapy. Exceptions include other cancers from which the subject has been disease-free for greater than or equal to 2 years or which will not limit survival to < 2 years
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 (i.e., HIV 1 and 2 antibodies)
Active hepatitis B (i.e., HBsAg reactive) or hepatitis C (i.e. HCV RNA is detected by a qualitative test) 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
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Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

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If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

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Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

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