A Phase II, Open Label, Single Arm, Multicenter Study of Chlorambucil in Japanese Previously Untreated Patients With Chronic Lymphocytic Leukemia
Condition: Leukaemia, Lymphoblastic
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma
Intervention: chlorambucil, tablets
Intervention description: 2mg tablets, chlorambucil dose: 10mg/m2 PO at days 1-7 every 28 days; duration: minimum of 3 cycles until best response or maximum of 12 cycles
Intervention MeSH terms: Chlorambucil
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 5.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No

Summary:

      This study is an open-label, single arm, phase II study of chlorambucil in subjects with
      previously untreated CLL.

      The primary objective is to evaluate the response to chlorambucil in Japanese subjects with
      previously untreated CLL.

      Secondary objectives are to evaluate efficacy, safety and pharmacokinetics of chlorambucil in
      Japanese subjects.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis of CLL defined by:Circulating B lymphocytes ≥5,000 /μL AND Flow cytometry
             confirmation of immunophenotype with CD5, CD19, CD20, and CD23 prior to Visit 2.

          -  Considered inappropriate for fludarabine-based therapy.

          -  Active disease and indication for treatment based on the IWCLL updated NCI-WG
             guidelines defined by presenting at least any one of the following conditions:
             Evidence of progressive marrow failure as manifested by development or worsening of
             anemia and/or thrombocytopenia.

        Massive (i.e. at least 6 cm below the left costal margin) or progressive or symptomatic
        splenomegaly.

        Massive nodes (i.e. at least 10 cm in longest diameter) or progressive or symptomatic
        lymphadenopathy.

        Progressive lymphocytosis with an increase of more than 50% over a two month period or an
        lymphocyte doubling time of less than 6 months.

        A minimum of any one of the following disease-related symptoms must be present: a)
        Unintentional weight loss ≥10% within the previous six months; b) Fevers >38.0°C for ≥ 2
        weeks without evidence of infection; or c) Night sweats for more than 1 month without
        evidence of infection

          -  Not been previously treated for CLL (prior autoimmune hemolytic anemia treatment with
             corticosteroids permitted).

          -  ECOG Performance Status of 0-2.

          -  QTc <450 msec or QTc <480 msec for patients with bundle branch block The QTc is the QT
             interval corrected for heart rate according to either Bazett's formula (QTcB) or to
             Fridericia's formula (QTcF), machine or manual overread, for males and females. The
             specific formula that will be used in a protocol should be determined prior to
             initiation of the study, and the formula used to determine inclusion and
             discontinuation should be the same throughout the study.

        The QTc should be based on single or averaged QTc values of triplicate electrocardiograms
        (ECGs) obtained over a brief recording period.

          -  Life expectancy of at least 6 months, in the opinion of the investigator.

          -  Age ≥ 20 years

          -  Signed written informed consent prior to performing any study-specific procedures (the
             results of other procedures predating the informed consent can be used).

        Exclusion Criteria:

          -  Prior immuno- or chemotherapy for CLL or small lymphocytic lymphoma (SLL) with any
             agent except corticosteroids used to treat autoimmune hemolytic anemia.

          -  Previous autologous or allogeneic stem cell transplantation.

          -  Active autoimmune hemolytic anemia (AIHA) requiring corticosteroid therapy >100 mg/day
             equivalent to hydrocortisone, or chemotherapy.

          -  Known transformation of CLL (e.g. Richter).

          -  Known CNS involvement of CLL.

          -  Chronic or current active infectious disease requiring systemic antibiotics,
             antifungal, or antiviral treatment such as, but not limited to, chronic renal
             infection, chronic chest infection with bronchiectasis, tuberculosis and active
             Hepatitis C.

          -  Other past or current 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.

          -  Clinically significant cardiac disease including unstable angina, acute myocardial
             infarction within 6 months prior to screening, congestive heart failure, and
             arrhythmia requiring therapy, with the exception of extra systoles or minor conduction
             abnormalities.

          -  History of significant cerebrovascular disease or event with significant symptoms or
             sequelae.

          -  Glucocorticoid use, unless given in doses ≤ 100 mg/day hydrocortisone (or equivalent
             dose of other glucocorticoid) for <7 days for exacerbations other than CLL (e.g.
             asthma).

          -  Known HIV positive.

          -  Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In
             addition, if negative for HBsAg but HBcAb and/or HBsAb positive, an HBV DNA test will
             be performed, and if positive the subject will be excluded.

          -  Screening laboratory values:

        Creatinine >2.0 times upper normal limit (unless normal creatinine clearance). Total
        bilirubin > 2.0 times upper normal limit (unless due to Gilbert's syndrome).

        Alanine aminotransferase (ALT) > 3.0 times upper normal limit.

          -  Treatment with any known non-marketed drug substance or experimental therapy within 5
             terminal half lives or 4 weeks prior to Visit 1, whichever is longer, treatment with
             any anti-CD20 monoclonal antibody within 3 months of Visit 1, or participation in any
             other interventional clinical study.

          -  Known or suspected inability to comply with study protocol.

          -  Lactating women, women with a positive pregnancy test within 7 days prior to
             administration of the investigational product or women (of childbearing potential) as
             well as men with partners of childbearing potential, who are not willing to use
             adequate contraception from study start through one year following last treatment
             dose. Adequate contraception is defined as oral hormonal birth control, intrauterine
             device, and male partner sterilization (if male partner is sole partner for that
             subject) and the double barrier method (condom or occlusive cap plus spermicidal
             agent).