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A Phase II Study Using Ibrutinib and Short-Course Fludarabine in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: CLL (Chronic Lymphocytic Leukemia); SLL (Small Lymphocytic Lymphoma)

Intervention: Ibrutinib (Drug); Fludarabine (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: National Heart, Lung, and Blood Institute (NHLBI)

Official(s) and/or principal investigator(s):
Inhye Ahn, M.D., Principal Investigator, Affiliation: National Cancer Institute (NCI)

Overall contact:
Inhye Ahn, M.D., Phone: (301) 451-4572, Email: inhye.ahn@nih.gov

Summary

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.

Clinical Details

Official title: A Phase II Study Using Ibrutinib and Short-Course Fludarabine in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: 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)

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, 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.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

- 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 4. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2 5. ANC > 750/uL, platelets > 50,000/uL 6. Agreement to use acceptable methods of contraception during the study and for 30 days after the last dose of study drug if sexually active and able to bear or beget children 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:

- Prior anti-CLL therapy

- 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

- 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

- Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,

congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or left ventricular ejection fraction (LVEF) less than or equal to 40%

- Requires treatment with strong and moderate CYP3A4/5 and/or strong CYP3A4/5

inhibitors.

Locations and Contacts

Inhye Ahn, M.D., Phone: (301) 451-4572, Email: inhye.ahn@nih.gov

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting
For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL), Phone: 800-411-1222, Ext: TTY8664111010, Email: prpl@mail.cc.nih.gov
Additional Information

NIH Clinical Center Detailed Web Page

Starting date: July 2015
Last updated: August 4, 2015

Page last updated: August 23, 2015

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