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