A Phase II Study of Ibrutinib Plus FCR in Previously Untreated, Younger Patients With Chronic Lymphocytic Leukemia
Condition: Chronic Lymphocytic Leukemia; Leukemia
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Ibrutinib; Fludarabine; Cyclophosphamide; Rituximab
Intervention description: Oral BTK inhibitor; IV purine analogue chemotherapy agent; IV alkylator chemotherapy agent; IV anti-CD20 monoclonal antibody
Intervention MeSH terms: Cyclophosphamide; Rituximab; Fludarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 85.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Chronic lymphocytic leukemia; Leukemia

Summary:

      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).
    

Eligibility criteria:

        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