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

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.

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.

Eligibility 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

   -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. Absolute neutrophil count (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 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.
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:

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.