A Phase II Study Using Ibrutinib and Short-Course Fludarabine in Treatment-Naive CLL

Sponsor
National Heart, Lung, and Blood Institute (NHLBI) (NIH)
Overall Status
Active, not recruiting
CT.gov ID
NCT02514083
Collaborator
(none)
29
Enrollment
1
Location
1
Arm
94.5
Anticipated Duration (Months)
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a pilot phase 2 study investigating the safety and efficacy of ibrutinib combined with short-course fludarabine in previously untreated CLL patients. Ibrutinib will be given daily until disease progression or intolerable side effects occur. Fludarabine will be given in cycles 3 and 4. The primary efficacy endpoint is the rate of complete response after 6 cycles or 24 weeks. The primary safety endpoint is the rate of treatment discontinuation after 6 cycles or 24 weeks.

Detailed Description

Chronic lymphocytic leukemia (CLL) and/or small lymphocytic lymphoma (SLL) are tumors of B cells that often affect elderly patients. 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 reduced with 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 patients with 17p deletion and for those who had at least one prior therapy. However, single-agent ibrutinib has limitations; the drug does not eliminate all the tumor cells, and, with time, the tumor cells may become resistant. Therefore, a combination of ibrutinib with other drugs could be beneficial. Here we chose fludarabine because it 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. With this approach, we hope to restore a healthier immune system.

This study will investigate the safety and efficacy of ibrutinib combined with fludarabine. This protocol is intended for previously untreated CLL patients. Ibrutinib will be given daily until disease progression or intolerable side effects occur. Fludarabine will be given only in cycles 3 and 4.

Study Design

Study Type:
Interventional
Actual Enrollment :
29 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Pilot Phase II Study Using Ibrutinib and Short-Course Fludarabine in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
Actual Study Start Date :
Dec 9, 2015
Actual Primary Completion Date :
Oct 2, 2019
Anticipated Study Completion Date :
Oct 23, 2023

Arms and Interventions

ArmIntervention/Treatment
Experimental: Ibrutinib and short-course fludarabine

Ibrutinib 420 mg PO daily for the duration of the study Fludarabine 25 mg/m2/day IV on days 1-5 of cycles 3 and 4

Drug: Ibrutinib
Ibrutinib 420mg PO daily for the duration of the study.
Other Names:
  • Imbruvica
  • Drug: Fludarabine
    Fludarabine 25 mg/m2/day IV on days 1-5 of cycles 3 and 4
    Other Names:
  • Fludara
  • Outcome Measures

    Primary Outcome Measures

    1. Rate of Complete Response at 24 Weeks [24 weeks]

      Rate of complete response at 24 weeks or after 6 cycles. Response assessment was conducted according to the guidelines from the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL).

    2. Rate of Treatment Discontinuation Within the First 24 Weeks [24 weeks]

      Rate of treatment discontinuation within the first 24 weeks or 6 cycles due to intolerable side effects from study therapy

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    INCLUSION CRITERIA:
    1. Men and women with histologically confirmed disease as defined by the following:
    • CLL: clonal B-lymphocytosis greater than or equal to 5,000 cells/microL .

    • SLL: lymphadenopathy with the tissue morphology of CLL but that are not leukemic, < 5,000 cells/microL.

    • 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).

    1. 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 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

    1. Treatment naive CLL/SLL patients

    -Treatment-naive CLL indicates no prior anti-CLL therapy. Anti-CLL therapy includes chemotherapies, monoclonal antibodies, and targeted agents with known or reasonably expected anti-leukemic activity.

    1. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2

    2. Absolute neutrophil count (ANC) > 750/microL, platelets > 50,000/microL

    3. 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 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 method of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices, complete abstinence, or sterilized partner) and a barrier method (e.g. condoms, vaginal ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study drug.

    4. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty

    5. 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)

    EXCLUSION CRITERIA:
    1. Transformed CLL, including Hodgkin and non-Hodgkin lymphoma

    2. Active autoimmune hemolytic anemia or thrombocytopenia

    3. Known bleeding disorders

    4. Impaired hepatic function: Total bilirubin greater than or equal to 1.5 times upper limit of normal unless due to Gilbert's disease, aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than or equal to 2.5 times institutional upper limit of normal unless due to infiltration of liver, Child-Pugh class B or C

    5. Impaired renal function: estimated glomerular filtration rate (GFR) < 30ml/min/1.73m(2) based on CKD-EPI

    6. Life-threatening illness, medical condition or organ system dysfunction which, in the investigators 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

    7. Concomitant immunomodulatory therapy, chemotherapy, radiotherapy or experimental therapy

    8. Active Hepatitis B or Hepatitis C infection

    9. HIV infection

    10. 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.

    11. Psychiatric illness/social situations that would limit the patient's ability to tolerate and/or comply with study requirements.

    12. Unable to understand the investigational nature of the study or give informed consent.

    13. Individuals < 18 years old

    14. Known hypersensitivity to any component of ibrutinib or fludarabine

    15. Requires concomitant anticoagulation with Coumadin (warfarin) or other vitamin K antagonists.

    16. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer 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

    17. 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

    18. History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug

    19. Major surgery within 4 weeks of first dose of study drug

    20. Currently active, clinically significant cardiovascular disease such as 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 or unstable angina, or acute coronary syndrome within 6 months of screening.

    21. 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.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1National Institutes of Health Clinical CenterBethesdaMarylandUnited States20892

    Sponsors and Collaborators

    • National Heart, Lung, and Blood Institute (NHLBI)

    Investigators

    • Principal Investigator: Andy Itsara, M.D., National Heart, Lung, and Blood Institute (NHLBI)

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    National Heart, Lung, and Blood Institute (NHLBI)
    ClinicalTrials.gov Identifier:
    NCT02514083
    Other Study ID Numbers:
    • 150172
    • 15-H-0172
    First Posted:
    Aug 3, 2015
    Last Update Posted:
    Mar 22, 2022
    Last Verified:
    Mar 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Keywords provided by National Heart, Lung, and Blood Institute (NHLBI)
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleIbrutinib With Fludarabine in Patients With CLL or SLL
    Arm/Group DescriptionOpen-label study of ibrutinib and a short-course fludarabine in previously untreated participants with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Ibrutinib is administered orally, 420 mg daily for duration of study. Fludarabine dose is 25 mg/m2/day on days 1-5 of cycles 3 and 4.
    Period Title: Overall Study
    STARTED29
    COMPLETED28
    NOT COMPLETED1

    Baseline Characteristics

    Arm/Group TitleIbrutinib With Fludarabine in Patients With CLL or SLL
    Arm/Group DescriptionOpen-label study of ibrutinib and a short-course fludarabine in previously untreated participants with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Ibrutinib is administered orally, 420 mg daily for duration of study. Fludarabine dose is 25 mg/m2/day on days 1-5 of cycles 3 and 4.
    Overall Participants29
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    14
    48.3%
    >=65 years
    15
    51.7%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    62.4
    (10.7)
    Sex: Female, Male (Count of Participants)
    Female
    10
    34.5%
    Male
    19
    65.5%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    Not Hispanic or Latino
    29
    100%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    1
    3.4%
    White
    28
    96.6%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%

    Outcome Measures

    1. Primary Outcome
    TitleRate of Complete Response at 24 Weeks
    DescriptionRate of complete response at 24 weeks or after 6 cycles. Response assessment was conducted according to the guidelines from the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL).
    Time Frame24 weeks

    Outcome Measure Data

    Analysis Population Description
    Treatment-naive CLL or SLL patients
    Arm/Group TitleIbrutinib With Fludarabine in Patients With CLL or SLL
    Arm/Group DescriptionOpen-label study of ibrutinib and a short-course fludarabine in previously untreated participants with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Ibrutinib is administered orally, 420 mg daily for duration of study. Fludarabine dose is 25 mg/m2/day on days 1-5 of cycles 3 and 4.
    Measure Participants28
    Complete response
    6
    20.7%
    Partial response with or without lymphocytosis
    21
    72.4%
    Stable disease
    1
    3.4%
    2. Primary Outcome
    TitleRate of Treatment Discontinuation Within the First 24 Weeks
    DescriptionRate of treatment discontinuation within the first 24 weeks or 6 cycles due to intolerable side effects from study therapy
    Time Frame24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleIbrutinib With Fludarabine in Patients With CLL or SLL
    Arm/Group DescriptionOpen-label study of ibrutinib and a short-course fludarabine in previously untreated participants with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Ibrutinib is administered orally, 420 mg daily for duration of study. Fludarabine dose is 25 mg/m2/day on days 1-5 of cycles 3 and 4.
    Measure Participants29
    Treatment discontinued within 24 weeks
    1
    3.4%
    Treatment continued for 24+ weeks
    28
    96.6%

    Adverse Events

    Time FrameFrom treatment initiation until the last follow-up on study or death, whichever occurred first, assessed up to 4 years
    Adverse Event Reporting Description The AE reporting period for this study begins when the participant takes the first dose of study drug and continues until the last follow-up on the study. Participants will continue on study until disease progression or intolerable side effects occur.
    Arm/Group TitleIbrutinib With Fludarabine in Patients With CLL or SLL
    Arm/Group DescriptionOpen-label study of ibrutinib and a short-course fludarabine in previously untreated participants with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Ibrutinib is administered orally, 420 mg daily for days 1-28 from Cycle 1 up to Cycle 27. Fludarabine dose is 25 mg/m2/day on days 1-5 of cycles 3 and 4.
    All Cause Mortality
    Ibrutinib With Fludarabine in Patients With CLL or SLL
    Affected / at Risk (%)# Events
    Total1/29 (3.4%)
    Serious Adverse Events
    Ibrutinib With Fludarabine in Patients With CLL or SLL
    Affected / at Risk (%)# Events
    Total14/29 (48.3%)
    Cardiac disorders
    Heart Failure1/29 (3.4%) 1
    Palpitations1/29 (3.4%) 1
    Ventricular arrhythmia1/29 (3.4%) 1
    Gastrointestinal disorders
    Vomiting1/29 (3.4%) 1
    Pancreatitis1/29 (3.4%) 1
    General disorders
    Death NOS1/29 (3.4%) 1
    Non-cardiac chest pain1/29 (3.4%) 1
    Hepatobiliary disorders
    Cholecystitis1/29 (3.4%) 1
    Infections and infestations
    Appendicitis1/29 (3.4%) 1
    Lung infection2/29 (6.9%) 4
    Sepsis1/29 (3.4%) 1
    Urinary tract infection1/29 (3.4%) 1
    Injury, poisoning and procedural complications
    Post-operative Hemorrhage (Epistaxis)1/29 (3.4%) 1
    Investigations
    Alanine aminotransferase increased2/29 (6.9%) 2
    Aspartate aminotransferase increased2/29 (6.9%) 2
    Metabolism and nutrition disorders
    Hyponatremia1/29 (3.4%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Vulvar intraepithelial neoplasm1/29 (3.4%) 1
    Squamous cell carcinoma4/29 (13.8%) 4
    Prostate Cancer1/29 (3.4%) 1
    Triple negative Breast Cancer1/29 (3.4%) 1
    Papillary Thyroid Cancer1/29 (3.4%) 1
    Vascular disorders
    Thromboembolic event1/29 (3.4%) 1
    Other (Not Including Serious) Adverse Events
    Ibrutinib With Fludarabine in Patients With CLL or SLL
    Affected / at Risk (%)# Events
    Total29/29 (100%)
    Blood and lymphatic system disorders
    Leukocytosis14/29 (48.3%) 14
    Anemia4/29 (13.8%) 4
    Hematoma2/29 (6.9%) 2
    Gastrointestinal disorders
    Diarrhea13/29 (44.8%) 13
    Nausea5/29 (17.2%) 5
    Vomiting3/29 (10.3%) 3
    Gastroesophageal reflux disease2/29 (6.9%) 2
    General disorders
    Fatigue9/29 (31%) 9
    Pain7/29 (24.1%) 7
    Peripheral edema7/29 (24.1%) 7
    Flu like symptoms2/29 (6.9%) 2
    Infections and infestations
    Shingles5/29 (17.2%) 5
    Lung infection2/29 (6.9%) 2
    Infections and infestations: other2/29 (6.9%) 2
    Productive cough2/29 (6.9%) 2
    Sinusitis2/29 (6.9%) 2
    Injury, poisoning and procedural complications
    Bruising19/29 (65.5%) 19
    Investigations
    White blood cell decreased19/29 (65.5%) 19
    Platelet count decresaed14/29 (48.3%) 14
    Neutrophil count decresaed12/29 (41.4%) 12
    Alanine or aspartate aminotransferase increased4/29 (13.8%) 4
    Lymphocyte count decreased14/29 (48.3%) 14
    Lymphocyte count increased8/29 (27.6%) 8
    Creatinine increased4/29 (13.8%) 4
    Weight gain2/29 (6.9%) 2
    Metabolism and nutrition disorders
    Hyponatremia2/29 (6.9%) 2
    Hyperuricemia4/29 (13.8%) 4
    Hypocalcemia4/29 (13.8%) 4
    Hypophosphatemia2/29 (6.9%) 2
    Musculoskeletal and connective tissue disorders
    Arthralgia11/29 (37.9%) 11
    Myalgia12/29 (41.4%) 12
    Nervous system disorders
    Headache4/29 (13.8%) 4
    Dizziness3/29 (10.3%) 3
    Renal and urinary disorders
    Hematuria2/29 (6.9%) 2
    Urinary tract infection2/29 (6.9%) 2
    Respiratory, thoracic and mediastinal disorders
    Epistaxis5/29 (17.2%) 5
    Cough3/29 (10.3%) 3
    Skin and subcutaneous tissue disorders
    Brittle nails8/29 (27.6%) 8
    Petechiae6/29 (20.7%) 6
    Maculopapular rash5/29 (17.2%) 5
    Vascular disorders
    Hypertension9/29 (31%) 9

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleInhye Ahn, M.D.
    OrganizationNational Heart Lung and Blood Institute (NHLBI)
    Phone301-827-1203
    Emailinhye.ahn@nih.gov
    Responsible Party:
    National Heart, Lung, and Blood Institute (NHLBI)
    ClinicalTrials.gov Identifier:
    NCT02514083
    Other Study ID Numbers:
    • 150172
    • 15-H-0172
    First Posted:
    Aug 3, 2015
    Last Update Posted:
    Mar 22, 2022
    Last Verified:
    Mar 1, 2022