Phase 2 Study to Assess Activity & Safety of Front-line Ibrutinib + Rituximab in Unfit Chronic Lymphocytic Leukemia
Phase 2 Study to Assess Activity & Safety of Front-line Ibrutinib + Rituximab in Unfit Chronic Lymphocytic Leukemia
The present study aims at evaluating whether treatment with two different drugs, Ibrutinib
 and Rituximab is both efficient and safe for newly diagnosed patients with chronic
 lymphocytic leukemia.
Given that:

 -  Ibrutinib as single agent has been associated with a high response rate and PFS in
 previously treated patients, and in patients with poor prognosis clinical and biologic
 features.

 -  Ibrutinib as single agent has proven activity and is associated with a good safety
 profile in elderly patients with CLL.

 -  The Ibrutinib plus Rituximab combination has been associated with a high response rate
 and PFS in previously treated patients, and in patients with poor prognosis clinical and
 biologic features.

 -  The combined administration of Ibrutinib and Rituximab could be an effective and safe
 front-line treatment schedule for unfit patients with CLL.

 -  The current study is designed to evaluate whether first line treatment with Ibrutinib
 and Rituximab results in a significant improvement in PFS at 12 months as compared with
 chlorambucil plus rituximab in patients unfit for fludarabine- or bendamustine-based
 treatments.
Inclusion Criteria:

 1. 18 years of age or older.

 2. Diagnosis of CLL meeting IWCLL criteria.

 3. The diagnosis of CLL requires a history of lymphocytosis with a B-lymphocyte count
 ≥5,000/μL. Prolymphocytes may comprise no more than 55% of blood lymphocytes.

 4. Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring
 treatment:

 1. Evidence of progressive marrow failure as manifested by the development of, or
 worsening of, anemia or thrombocytopenia.

 2. Massive (ie, at least 6 cm below the left costal margin), progressive, or
 symptomatic splenomegaly.

 3. Massive nodes (ie, at least 10 cm in longest diameter), progressive, or
 symptomatic lymphadenopathy.

 4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period
 or a lymphocyte doubling time (LDT) of less than 6 months (which may be
 extrapolated). Lymphocyte doubling time can be obtained by linear regression
 extrapolation of ALCs obtained at intervals of 2 weeks over an observation period
 of 2 to 3 months. For patients with initial blood lymphocyte counts of less than
 30 x 109/L (30,000/μL), 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.

 5. Constitutional symptoms, defined as 1 or more of the following disease-related
 symptoms or signs:

 -  Unintentional weight loss >10% within the previous 6 months prior to
 screening

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

 -  Fevers higher than 38.0°C for 2 or more weeks without evidence of infection;
 or

 -  Night sweats for more than 1 month without evidence of infection

 -  Measurable nodal disease by computed tomography (CT). Measurable nodal
 disease is defined as at least one lymph node >1.5 cm in longest diameter in
 a site that has not been previously irradiated. An irradiated lesion may be
 assessed for measurable disease only if there has been documented
 progression in that lesion since radiotherapy has ended.

 5. No prior treatment.

 6. Total CIRS >6 and/or creatinine clearance <70 ml/min [Cockcroft-Gault]).

 7. Hematology values within the following limits: Absolute neutrophil count (ANC) ≥1 x
 109/L (ie, ≥1000/μL) independent of growth factor support. Platelets ≥50,000/mm3 if
 bone marrow involvement independent of transfusion support

 8. Biochemical values within the following limits:

 1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x upper
 limit of normal (ULN)

 2. Total bilirubin ≤1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or
 of non-hepatic origin

 3. Serum creatinine ≤2 x ULN or estimated Glomerular Filtration Rate (Cockroft
 Gault) ≥40 mL/min

 9. Women of childbearing potential and men who are sexually active must be practicing a
 highly effective method of birth control during and after the study consistent with
 local regulations regarding the use of birth control methods for subjects
 participating in clinical trials. Men must agree not to donate sperm during and after
 the study. For females, these restrictions apply for 1 month after the last dose of
 study drug. For males, these restrictions apply for 3 months after the last dose of
 study drug.

 10. Women of childbearing potential must have a negative serum (beta-human chorionic
 gonadotropin [β-hCG]) or urine pregnancy test at Screening. Women who are pregnant or
 breastfeeding are ineligible for this study.

 11. A signed (or signed by their legally-acceptable representatives) informed consent
 document indicating that they understand the purpose of and procedures required for
 the study, including biomarkers, and are willing to participate in the study.

 Exclusion Criteria:

 1. Any significant concurrent, uncontrolled medical condition or organ system dysfunction
 and/or laboratory abnormality or psychiatric disease which, in the investigator's
 opinion, could compromise the subject's safety, interfere with the absorption or
 metabolism of ibrutinib capsules, or put the study outcomes at undue risk or prevent
 the subject from signing the informed consent form.

 2. Pregnant or lactating females

 3. Known presence of alcohol and/or drug abuse.

 4. Any potential subject who meets any of the following criteria will be excluded from
 participating in the study.

 5. Major surgery within 4weeks of randomization.

 6. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.

 7. Known central nervous system lymphoma.

 8. History of stroke or intracranial hemorrhage within 6 months prior to randomization,
 or of a significant cerebrovascular disease in the past 6 months or ongoing event with
 active symptoms or sequelae.

 9. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg,
 phenprocoumon) in any moment of the study.

 10. Requires treatment with strong CYP3A inhibitors.

 11. Clinically significant cardiovascular disease such as uncontrolled or symptomatic
 arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
 Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by
 the New York Heart Association

 12. Vaccinated with live, attenuated vaccines within 4 weeks of randomization.

 13. Known history of human immunodeficiency virus (HIV) positive serology for HIV; active
 Hepatitis B Virus infection or positive serology for Hepatitis B (HBV) defined as a
 positive test for HBsAg and HBV-DNA; active Hepatitis C or HCV-RNA positive; any
 uncontrolled active systemic infection requiring intravenous (IV) antibiotics,
 antifungal, or antiviral treatment such as, but not limited to, chronic renal
 infection, chronic chest infection; history of tuberculosis within the last five years
 or recent exposure to tuberculosis equal to or less than 6 months.

 14. Richter's syndrome (RS), concomitant or past malignancy. Subjects who have been free
 of malignancy for at least 5 years, or have a history of completely resected
 non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.