A Phase II Study of Ibrutinib Plus FCR in Previously Untreated, Younger Patients With Chronic Lymphocytic Leukemia
A Phase II Study of Ibrutinib Plus FCR in Previously Untreated, Younger Patients With Chronic Lymphocytic Leukemia
This research study is evaluating a new drug called ibrutinib in combination with the
 standard drugs fludarabine, cyclophosphamide, and rituximab (FCR) as a possible treatment for
 Chronic Lymphocytic Leukemia (CLL).
Ibrutinib is a type of drug called a kinase inhibitor. It is believed to block a protein
 called Bruton's tyrosine kinase (BTK) that helps CLL cells live and grow. By blocking this,
 it is possible that the study drug will kill cancer cells or stop them from growing.
 Ibrutinib has been FDA approved for the treatment of CLL patients who have received at least
 one prior treatment; however, the FDA has not yet approved ibrutinib as the first treatment
 for previously untreated CLL. Therefore, ibrutinib is still considered to be study drug,
 which means it is still being studied.

 Fludarabine, cyclophosphamide, and rituximab (FCR) are intravenous chemotherapy and antibody
 drugs that together are a standard chemotherapy regimen used for younger patients with CLL.
 Although FCR is highly effective, it does not typically lead to cure.

 In this research study, the investigators are combining a new treatment for CLL, ibrutinib,
 with a standard chemotherapy regimen for CLL, FCR, to determine whether this combination
 (iFCR) is safe and effective for patients with previously untreated CLL.
Inclusion Criteria:

 -  Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic
 lymphoma. as per IW-CLL 2008 criteria. Patients must also require therapy for that
 diagnosis, based on meeting at least one of the following criteria:

 -  evidence of progressive marrow failure as manifested by the development of, or
 worsening of, anemia (hemoglobin <11.0 g/L) and/or thrombocytopenia (platelets <100 x
 10^9/L)

 -  massive (≥ 6 cm below the left costal margin), progressive, or symptomatic
 splenomegaly

 -  massive nodes (at least 10 cm longest diameter), progressive, or symptomatic
 lymphadenopathy

 -  progressive lymphocytosis with an increase of more than 50% over a 2-month period or
 LDT of <6 months. Lymphocyte doubling time may be obtained by linear regression
 extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an
 observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts
 of <30 x 10^9/L, LDT should not be used as a single parameter to define indication for
 treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other
 than CLL (eg, infections) should be excluded

 -  autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids
 or other standard therapy

 -  documented constitutional symptoms, defined as 1 or more of the following
 disease-related symptoms or signs:

 -  unintentional weight loss >10% within 6 months prior to screening

 -  significant fatigue (inability to work or perform usual activities)

 -  fevers >100.5° F or 38.0° C for 2 or more weeks prior to screening without
 evidence of infection

 -  night sweats for more than 1 month prior to screening without evidence of
 infection

 -  No prior CLL-directed therapy that was instituted due to patient previously
 meeting IW-CLL 2008 criteria for treatment

 -  Age greater than or equal to 18 years and less than or equal to 65. Because
 CLL is extremely rare in persons <18 years of age, children are excluded
 from this study. Because iFCR is an aggressive therapy that is likely to be
 less well-tolerated even in fit elderly subjects, persons > 65 years of age
 are excluded

 -  ECOG performance status ≤ 1

 -  Adequate hematologic function independent of growth factor support for at
 least 7 days prior to screening and randomization, with the exception of
 pegylated G-CSF (pegfilgrastim) and darbepoetin which cannot be administered
 within 14 days of screening.

 -  Patients must meet the following hematologic criteria at screening:

 -  Absolute neutrophil count ≥ 750 cells/mm3 (0.75 x 109/L).

 -  Platelet count ≥ 50,000 cells/mm3 (50 x 109/L).

 -  Hemoglobin ≥ 8 g/L - Adequate hepatic and renal function defined as:

 -  Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper limit
 of normal (ULN)

 -  Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
 non-hepatic origin)

 -  Adequate renal function defined by serum creatinine >1.5 x ULN

 -  PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN.

 -  The effects of ibrutinib on the developing human fetus are unknown. For this
 reason and because similar agents are known to be teratogenic, women of
 child-bearing potential and men must agree to use adequate contraception
 (hormonal or barrier method of birth control; abstinence) prior to study entry
 and for the duration of study participation.

 Exclusion Criteria:

 -  Concurrent Conditions:

 -  History of other malignancies, except:

 -  Malignancy treated with curative intent and with no known active disease present
 for ≥ 3 years before the first dose of study drug and felt to be at low risk for
 recurrence by treating physician.

 -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
 of disease.

 -  Adequately treated carcinoma in situ without evidence of disease.

 -  Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc.,
 or chronic administration of >20 mg/day of prednisone) within 28 days of the first
 dose of study drug.

 -  Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

 -  Recent infection requiring systemic treatment that was completed ≤ 14 days before the
 first dose of study drug.

 -  Known bleeding disorders (eg, von Willebrand's disease) or hemophilia.

 -  History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

 -  Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus
 (HCV) or hepatitis B virus (HBV). Patients who are positive for hepatitis B core
 antibody or hepatitis B surface antigen must have a negative polymerase chain reaction
 (PCR) result before enrollment. Those who are PCR positive will be excluded.

 -  Any uncontrolled active systemic infection.

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

 -  Any life-threatening illness, medical condition, or organ system dysfunction that, in
 the investigator's opinion, could compromise the subject's safety or put the study
 outcomes at undue risk.

 -  Currently active, clinically significant cardiovascular disease, such as uncontrolled
 arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart
 Association Functional Classification; or a history of myocardial infarction, unstable
 angina, or acute coronary syndrome within 6 months prior to randomization.

 -  Unable to swallow capsules or malabsorption syndrome, disease significantly affecting
 gastrointestinal function, or resection of the stomach or small bowel, symptomatic
 inflammatory bowel disease or ulcerative colitis, or partial or complete bowel
 obstruction.

 -  Lactating or pregnant.

 -  Patients receiving any other study agents

 -  Patients with known CNS involvement

 -  Baseline QTcF >480 ms. NOTE: This criterion does not apply to patients with a left
 bundle branch block.

 -  Patients who require warfarin or other vitamin K antagonists for anticoagulation
 (other anticoagulants are allowed after consultation with the Principal Investigator).

 -  Concurrent administration of medications or foods that are strong inhibitors or
 inducers of CYP3A

 -  Patients with ongoing use of prophylactic antibiotics are eligible as long as there is
 no evidence of active infection and the antibiotic is not included on the list of
 prohibited medications

 -  Significant co-morbid condition or disease which in the judgment of the Principal
 Investigator would place the patient at undue risk or interfere with the study

 -  Unable to receive prophylactic treatment for pneumocystis

 -  Patients with del(17p) confirmed by FISH in ≥20% of cells or on stimulated
 karyotype3.2.24 Patients with del(17p) confirmed by FISH in ≥20% of cells or on
 stimulated karyotype

 -  Patients with unmutated IGHV who also have a complex karyotype on a stimulated
 karyotype