A Phase I/II, a Single Arm, Open-label Study of Ofatumumab (GSK1841157) in Patients With Previously Treated Chronic Lymphocytic Leukemia

Ofatumumab is an IgG1κ fully human monoclonal antibody (mAb) that specifically recognizes an epitope on the human differentiation antigen CD20 molecule. In vitro and in vivo studies demonstrated that ofatumumab depletes CD20 positive (CD20+) B cells through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), which results in the antitumour effect.

This is an open-label study to evaluate safety, tolerability, efficacy and PK profile of ofatumumab monotherapy in chronic lymphocytic leukemia (CLL) patients. Ofatumumab will be administered intravenously at the first dose of 300mg followed by 7 weekly infusions of 2000mg, followed by 4 infusions of 2000mg at every 4 weeks.

Primary objective of the study (Part A) is to evaluate tolerability, and the study (Part B) is to assess overall response rate in CLL population.

10 subjects will be enrolled into this study. Subjects will be followed for 48 weeks.

Ofatumumab is an IgG1κ fully human monoclonal antibody (mAb) that specifically recognizes an epitope on the human differentiation antigen CD20 molecule. In vitro and in vivo studies demonstrated that ofatumumab depletes CD20 positive (CD20+) B cells through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), which results in the antitumour effect.

This is an open-label study to evaluate safety, tolerability, efficacy and PK profile of ofatumumab monotherapy in chronic lymphocytic leukemia (CLL) patients. Ofatumumab will be administered intravenously at the first dose of 300mg followed by 7 weekly infusions of 2000mg, followed by 4 infusions of 2000mg at every 4 weeks.

Primary objective of the study (Part A) is to evaluate tolerability, and the study (Part B) is to assess overall response rate in CLL population.

10 subjects will be enrolled into this study. Subjects will be followed for 48 weeks.

Eligibility Criteria:
Inclusion Criteria:

Subjects eligible for enrolment in the study must meet all of the following criteria at the time of screening:

* Patients who gave consent to this study participation and signed into informed consent form.
* Previously treated(Patients who received at least one prior CLL therapy and have either relapsed or have refractory disease, both requiring therapy.) CLL with at least 5 x 109 B lymphocytes/ L (5000/μL). The diagnosis of CLL requires CD5, CD19, CD20 and CD23 positivity, according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines \[Hallek, 2008\].
* Laboratory test values meet the following criteria which indicate that patients have sufficient physiological functions;

Neutrophils:1≥ 500 /mm3 ALT ≤ 2.5 times upper local normal limit Creatinine ≤ 1.5 times upper local normal limit Total bilirubin≤ 1.5 times upper local normal limit

1:Patients should not receive any hematopoietic cytokine such as G-CSF preparations within 1 week before screening laboratory test for neutrophil counting.

- Patients who passed the following periods from the last anti-cancer treatments at the time of screening: At least 4 weeks after anti-cancer chemotherapy. At least 4 weeks after anti-cancer radiotherapy. At least 4 weeks after glucocorticoids treatment for CLL unless ≤ 10 mg of prednisolone /day.

At least 12 weeks after radio-immunotherapy and/or antibody therapy.

* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1, or 2.
* Life expectancy more than 24 weeks after screening test.
* Aged ≥ 20 (at the time of signing informed consent).
* Patients possible to stay at the trial site for at least two days (the day of the first infusion and a subsequent day).

Exclusion Criteria:

A subject will not be eligible for inclusion in this study if any of the following criteria is met:

* Active malignancy which needs therapy with anti-cancer drug, except for CLL.
* Known Richter's transformation.
* Previous autologous stem cell transplantation, within 24 weeks prior to screening.
* Previous allogenic stem cell transplantation.
* Known CNS involvement.
* History of significant cerebrovascular disease.
* Current cardiac disease requiring medical treatment (e.g. atrial flutter treated with acetylsalicylic acid and beta blocking agents).
* Chronic or active infectious disease requiring systemic (intravenous or oral) treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis and tuberculosis.
* Suspected/known immediate or delayed hypersensitivity to components of ofatumumab.
* Patients previously treated with ofatumumab.
* Positive serology test for any of HBsAg, anti-HBcAb or anti-HCVAb. If only anti-HBcAb results is positive, HBV-DNA test will be performed. If HBV-DNA results in negative, the patient is eligible.
* HIV positivity.
* Pregnant or lactating women.
* Women of childbearing potential not willing to use adequate contraception during the study and one year after the last dose of ofatumumab, and male patients not willing to use adequate contraception during the study. Adequate contraception is defined as follows but not limited to; Abstinence. Oral Contraceptive (exclude oral progesterone alone). Intrauterine device (IUD) or intrauterine system (IUS). Male partner sterilization. Double barrier method: condom or occlusive cap (diaphragm or cervical / vault caps) plus spermicidal agent (gel / film) etc.
* Use of an investigational drug within 4 weeks prior to screening.
* Current participation in any other clinical study.
* Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease.
* Patients who an investigator (or sub investigator) judges ineligible to this study.

Note; Child-bearing potential: a woman with functioning ovaries and uterine, or no documented sterility (i.e., a woman with functioning ovaries who have a current documented tubal ligation, women who have had a hysterectomy, women who are post-menopausal, or women who have had both ovaries surgically removed).