Expired Study
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Bethesda, Maryland 20892


Background: - Chronic lymphocytic leukemia (CLL) and/or small lymphocytic lymphoma (SLL) are tumors of abnormal B cells that often affect elderly patients. Studies have identified critical factors required for the growth of CLL cells. First, CLL cells survive because they receive signals through the B-cell receptor. Second, CLL cells benefit from interactions with other cells, especially T cells. - Survival signals through the B-cell receptor can be reduced with ibrutinib, which is a pill taken daily by mouth. Ibrutinib has been approved by the U.S. Food and Drug Administration to treat CLL patients. - T cells that interact with CLL cells can be removed by fludarabine, which is a drug given by vein and has been widely used to treat CLL. By adding a short course of fludarabine, we hope to complement the action of ibrutinib and restore a healthier immune system. Objectives: - To determine if ibrutinib and a short course of fludarabine can be used safely and effectively to treat CLL or SLL. Eligibility: - Diagnosed with CLL or SLL requiring treatment - No prior treatment for CLL or SLL - Age greater than or equal to 18 years - Not pregnant or breast-feeding women - Adequate kidney and liver function Study Design: - This is a phase II study of 32 patients. - Participants will be screened with blood tests and physical exam for eligibility. - Eligible participants will be treated with ibrutinib and a short course of fludarabine; - Treatment is given in cycles. Each cycle is defined as 28 days. Treatment continues as long as it is effective and safe for participants. - Ibrutinib is taken by mouth starting on the first day of cycle 1. Ibrutinib is continued daily. - Fludarabine is given through vein on the first five days of cycle 3 and 4 only. Each infusion takes approximately 30 minutes. - Participants will also take drugs that prevent infections and other complications. - Participants under treatment will have clinic visits with tests including: - Medical history - Physical exam - Blood and urine tests - CT and PET scans: They will lie in a machine that uses a computer to take serial images of the body. - For the PET scan, a radioactive sugar is injected into a vein for clear visualization of the body. - EKG: To assess heart rhythm. - Bone marrow and lymph node biopsies - Participants should avoid grapefruit, Seville oranges, and grapefruit juice during the study. They also should avoid any live vaccines.

Study summary:

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, 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 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.


-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). 2. 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 3. 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. 4. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2 5. ANC > 750/microL, platelets > 50,000/microL 6. 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 (ie, 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 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 - Complete abstinence is a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 7. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty 8. 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: - Transformed CLL, including Hodgkin and non-Hodgkin lymphoma - Active autoimmune hemolytic anemia or thrombocytopenia - Known bleeding disorders - Impaired hepatic function: Total bilirubin greater than or equal to 1.5 times upper limit of normal unless due to Gilbert s disease, AST/ 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 - Impaired renal function: estimated GFR < 30ml/min/1.73m(2) based on CKD-EPI - 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 - Concomitant immunomodulatory therapy, chemotherapy, radiotherapy or experimental therapy - Active Hepatitis B or Hepatitis C infection - HIV infection - 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. - Individuals < 18 years old - Known hypersensitivity to any component of ibrutinib or fludarabine - Requires concomitant anticoagulation with Coumadin (warfarin) or other vitamin K antagonists. - 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 - 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 - Major surgery within 4 weeks of first dose of study drug - 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. - 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.

Study is Available At:

Original ID:




Secondary ID:


Study Acronym:

Brief Title:

A Phase II Study Using Ibrutinib and Short-Course Fludarabine in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lym

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)

Overall Status:

Active, not recruiting

Study Phase:

Phase 2



Minimum Age:

18 Years

Maximum Age:


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

National Institutes of Health Clinical Center (CC)

Oversight Authority:

United States: Federal Government

Reasons Why Stopped:

Study Type:


Study Design:

Number of Arms:


Number of Groups:


Total Enrollment:


Enrollment Type:


Overall Contact Information

Official Name:Inhye Ahn, M.D.
Principal Investigator
National Heart, Lung, and Blood Institute (NHLBI)

Study Dates

Start Date:December 9, 2015
Completion Date:July 1, 2021
Completion Type:Anticipated
Primary Completion Date:February 4, 2021
Primary Completion Type:Anticipated
Verification Date:October 23, 2019
Last Changed Date:October 31, 2019
First Received Date:July 31, 2015

Study Outcomes

Outcome Type:Primary Outcome
Measure:Safety and efficacy of ibrutinib-based therapy combined with a short-course fludarabine in previously untreated patients with chronic lymphocytic leukemia (CLL) and/or small lymphocytic leukemia (SLL)
Time Frame:2 yrs
Safety Issues:False
Description:Primary efficacy endpoint is the rate of complete response at 24 weeks or after 6 cycles. Primary safety endpoint is the rate of treatment discontinuation within the first 24 weeks or 6 cycles due to intolerable side effects.

Study Interventions

Intervention Type:Drug
Arm Name:1
Intervention Type:Drug
Arm Name:1

Study Arms

Study Arm Type:Experimental
Arm Name:1

Study Agencies

Agency Class:NIH
Agency Type:Lead Sponsor
Agency Name:National Heart, Lung, and Blood Institute (NHLBI)

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: January 21, 2020

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