A Phase II, Open Label, Single Arm, Multicenter Study of Chlorambucil in Japanese Previously Untreated Patients With Chronic Lymphocytic Leukemia

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.

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.

Chlorambucil is an effective and well-tolerated chemotherapeutic agent currently approved for treatment of chronic lymphocytic leukemia (CLL) in the United States of America (US), European Union (EU) and other countries globally but not in Japan. Other more aggressive treatment options such as a combination of fludarabine (F) and cyclophosphamide are available, but are associated with significantly greater toxicities. The addition of ofatumumab to chlorambucil offers potentially a more effective therapy, with limited additional toxicity.

Study OMB110911 has been conducted mainly in the US and EU to evaluate progression-free survival (PFS) and overall response (OR) in subjects with previously untreated CLL with ofatumumab in combination with chlorambucil versus (vs.) chlorambucil monotherapy.

The objective of this study is to evaluate overall response of chlorambucil in Japanese subjects with previously untreated CLL.

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).