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

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ClinicalTrials.gov Identifier: NCT03204188
Recruitment Status : Recruiting
First Posted : June 29, 2017
Last Update Posted : December 6, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Brief 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 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.

Condition or disease Intervention/treatment Phase
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 Drug: Ibrutinib Drug: Fludarabine Drug: Pembrolizumab Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : September 22, 2017
Estimated Primary Completion Date : December 31, 2027
Estimated Study Completion Date : December 31, 2030


Arm Intervention/treatment
Experimental: Single Arm
IFP
Drug: Ibrutinib
Ibrutinib

Drug: Fludarabine
Fludarabine

Drug: Pembrolizumab
Pembrolizumab




Primary Outcome Measures :
  1. Rate of complete response (CR) after 12 months on pembrolizumab [ Time Frame: 1 year ]
    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 :
  1. Tolerability, response and best response, survival [ Time Frame: 2 years ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03204188


Contacts
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Contact: Pia Nierman, R.N. (301) 827-1094 pia.nierman@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Inhye Ahn, M.D. National Heart, Lung, and Blood Institute (NHLBI)

Additional Information:
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Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT03204188     History of Changes
Other Study ID Numbers: 170118
17-H-0118
First Posted: June 29, 2017    Key Record Dates
Last Update Posted: December 6, 2019
Last Verified: May 31, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
Deletion 17p
Bruton's Tyrosine Kinase Inhibitor
TP53 Mutation
NOTCH1 mutation
Complex Cytogenics
Additional relevant MeSH terms:
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Pembrolizumab
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Weight Loss
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia
Leukemia, B-Cell
Body Weight Changes
Body Weight
Signs and Symptoms
Vidarabine
Fludarabine
Fludarabine phosphate
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents