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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
10
ofatumumab , 300mg followed by 7 weekly infusions 2000 mg, followed by 4 monthly infusions 2000mg
GSK Investigational Site
Aichi, Japan
GSK Investigational Site
Kanagawa, Japan
GSK Investigational Site
Nagasaki, Japan
GSK Investigational Site
Tokyo, Japan
GSK Investigational Site
Tokyo, Japan
GSK Investigational Site
Seoul, South Korea
GSK Investigational Site
Seoul, South Korea
Number of Participants With a Dose-limiting Toxicity (DLT)
A DLT was defined as the following toxicological findings, according to the Common Terminology Criteria for Adverse Events (AE) v3.0: any treatment-related Grade (G) \>=3 non-hematotoxic AE, occurrence of G3 infusion reaction (treatment-related AE) at the day of infusion in a participant who received pre-medication or appropriate management during infusion (glucocorticoid) (the severity of the AE must have remained as \>= G3 until the next day); and any of following: \>= G4 hematotoxic treatment-related AEs (neutropenia lasting 7 days or more, febrile neutropenia).
Time frame: Up to Week 8
Percentage of Participants (Par.) With Objective Response (OR), Defined as Complete Remission (CR), CR Incomplete (CRi), Partial Remission (PR), and Nodular PR (nPR) as Assessed by a Safety and Evaluation Review Committee (SERC) and the Investigator
Par. were evaluated in accordance with the National Cancer Institute-sponsored Working Group. CR: no lymphadenopathy (Ly)/hepatomegaly/splenomegaly/constitutional symptoms; neutrophils \>=1.5\*10\^9/liter (L), platelets \>100\*10\^9/L, hemoglobin \>11.0 grams/deciliter, lymphocytes (LC) \<4.0\*10\^9/L, bone marrow (BM) sample must be normocellular for age, \<30% LC, no lymphoid nodule. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to chronic lymphocytic leukemia but related to drug toxicity. PR: \>=50% decrease in LC, Ly, size of liver and spleen, etc. nPR: nodules in BM.
Time frame: Up to Week 48
Progression-free Survival (PFS) as Assessed by a SERC
PFS is defined as the time from the start of treatment to the first documented sign of progressive disease (PD) or death due to any cause (whichever occurs earlier).
Time frame: Up to Week 48
Duration of Response as Assessed by a SERC
Duration of response is defined as the time from the first documented evidence of PR or better until the first documented sign of PD or death due to any reason in participants with PR or better.
Time frame: Up to Week 48
Overall Survival
Overall survival is defined as the time from the first infusion of investigational drug to death due to any cause.
Time frame: Up to Week 48
Time to Response as Assessed by a SERC
Time to response is defined as the time from the first infusion of investigational drug to the first response (PR or better).
Time frame: Up to Week 48
Time to Next Chronic Lymphocytic Leukemia (CLL) Therapy as Assessed by a SERC
Time to next CLL therapy is defined as the time from the first infusion of investigational drug to the first administration of the next CLL treatment. CLL therapy includes anti-cancer chemotherapy, anti-cancer radiotherapy, radio-immunotherapy, and antibody therapy.
Time frame: Up to Week 48
Mean Laboratory Data for Hemoglobin at the Indicated Weeks as Assessed by the Investigator
Blood samples of the participants were collected for the assessment of hemoglobin.
Time frame: Day 1; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
Mean Laboratory Data for Lymphocytes at the Indicated Weeks as Assessed by the Investigator
Blood samples of the participants were collected for the assessment of lymphocytes.
Time frame: Day 1; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
Mean Laboratory Data for Lymphocytes as a Percentage in the Bone Marrow at the Indicated Weeks as Assessed by the Investigator
Bone marrow (BM) aspiration was performed, and the bone marrow smears were prepared for the assessment of lymphocytes in the BM.
Time frame: Weeks 8, 16, 24, 36, and 48
Mean Laboratory Data for Total Neutrophils (Total Absolute Neutrophil Count [ANC]) at the Indicated Weeks as Assessed by the Investigator
Blood samples of the participants were collected for the assessment of total neutrophils.
Time frame: Day 1; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
Mean Laboratory Data for Platelet Count at the Indicated Weeks as Assessed by the Investigator
Blood samples of the participants were collected for the assessment of platelets.
Time frame: Day 1; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
Percentage of Bone Marrow Infiltration at the Indicated Weeks as Assessed by a SERC
SERC assessed bone marrow infiltration with the bone marrow smears of participants provided by trial sites.
Time frame: Weeks 8, 16, 24, 36, and 48
Mean Laboratory Data for Lymphocytes at the Indicated Weeks as Assessed by a SERC
SERC assessed lymphocytes based on the data provided by trial sites.
Time frame: Weeks 8, 16, 24, 36, and 48
Mean Laboratory Data for Lymphocytes as a Percentage in the Bone Marrow at the Indicated Weeks as Assessed by a SERC
SERC assessed lymphocytes in the bone marrow (BM) based on the data with BM smears provided by trial sites.
Time frame: Weeks 8, 16, 24, 36, and 48
Mean Laboratory Data for Total Neutrophils (Total ANC) at the Indicated Weeks as Assessed by a SERC
SERC assessed total neutrophils based on the data provided by trial sites.
Time frame: Weeks 8, 16, 24, 36, and 48
Number of Peripheral Blood Cluster of Differentiation (CD) CD19+ CD20+ Cells
CD19+ CD20+ cells in the peripheral blood were counted as measures of malignant B-cells and were measured by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus.
Time frame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
Number of Peripheral Blood CD20+ CD23+ Cells
CD20+ CD23+ cells in the peripheral blood were counted as measures of malignant B-cells and were measured by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus.
Time frame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
Number of Peripheral Blood CD19+ CD23+ Cells
CD19+ CD23+ cells in the peripheral blood were counted as measures of malignant B-cells and were measured by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus.
Time frame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
Number of Peripheral Blood CD19+ CD5+ Cells
CD19+ CD5+ cells in the peripheral blood were counted as measures of malignant B-cells and were measured by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus.
Time frame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
Number of Peripheral Blood CD20+ CD5+ Cells
CD20+ CD5+ cells in the peripheral blood were counted as measures of malignant B-cells and were measured by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus.
Time frame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
Number of Peripheral Blood CD23+ CD5+ Cells
CD23+ CD5+ cells in the peripheral blood were counted as measures of malignant B-cells and were measured by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus.
Time frame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
Ratio of Immunoglobulin (Ig) Kappa/Ig Lambda
Peripheral blood Ig kappa and Ig lambda were measured using flow cytometry. Abnormality of a ratio of Ig kappa and Ig lambda indicates clonality of lymphocytes. A normal range of this parameter is between 1.0 and 3.2.
Time frame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
Number of Participants With the Indicated Shift From Baseline (BL) in Night Sweats at the Indicated Weeks
Night sweats are one of the clinical characteristics of CLL. B symptoms are systemic symptoms of fever, night sweats, weight loss, and extreme fatigue, which can be associated with CLL. Participants who had night sweats at BL, and still had night sweats at Week 1, for example, are represented in the BL, yes; Week 1, yes category. Participants who had night sweats at BL, but did not have night sweats at Week 1 are represented in the BL, yes; Week 1, no category.
Time frame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
Number of Participants With the Indicated Shift From Baseline (BL) in Weight Loss at the Indicated Weeks
Weight loss is one of the clinical characteristics of CLL. B symptoms are systemic symptoms of fever, night sweats, weight loss, and extreme fatigue, which can be associated with CLL. Participants who had weight loss at BL, and still had weight loss at Week 1, for example, are represented in the BL, yes; Week 1, yes category. Participants who had weight loss at BL, but did not have weight loss at Week 1 are represented in the BL, yes; Week 1, no category.
Time frame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
Number of Participants With the Indicated Shift From Baseline (BL) in Fever at the Indicated Weeks
Fever is one of the clinical characteristics of CLL. B symptoms are systemic symptoms of fever, night sweats, weight loss, and extreme fatigue, which can be associated with CLL. Participants who had fever at BL, and still had fever at Week 1, for example, are represented in the BL, yes; Week 1, yes category. Participants who had fever at BL, but did not have fever at Week 1 are represented in the BL, yes; Week 1, no category.
Time frame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
Number of Participants With the Indicated Shift From Baseline (BL) in Extreme Fatigue at the Indicated Weeks
Extreme fatigue is one of the clinical characteristics of CLL. B symptoms are systemic symptoms of fever, night sweats, weight loss, and extreme fatigue, which can be associated with CLL. Participants who had extreme fatigue at BL, and still had extreme fatigue at Week 1, for example, are represented in the BL, yes; Week 1, yes category. Participants who had extreme fatigue at BL, but did not have extreme fatigue at Week 1 are represented in the BL, yes; Week 1, no category.
Time frame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM at Weeks 8, 24, and 48
Immunoglobulins, or antibodies, are large proteins used by the immune system to identify and neutralize foreign particles such as bacteria and viruses. Their normal blood levels indicate proper immune status. Low levels indicate immuno-suppression. IgA, IgG, and IgM were measured in the blood samples of the participants.
Time frame: Baseline and Weeks 8, 24, and 48
Number of Participants Who Tested Positive/Negative for Human Anti-human Antibodies (HAHA) at Screening and at Weeks 24 and 48
HAHA are indicators of immunogenicity to ofatumumab.
Time frame: Screening; Weeks 24 and 48
Number of Participants With a Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
ECOG PS is used to assess how a participant's disease is progressing, to assess how the disease affects the daily living abilities of the participant, and to determine appropriate treatment and prognosis. The grades for the scale range from 0 (fully active) to 4 (completely disabled), with increasing severity.
Time frame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
Maximum (Peak) Plasma Concentration (Cmax) of Ofatumumab
Blood sampling on Day 1 and at Weeks 7 and 24 for pharmacokinetic (PK) evaluation was performed at the following time points: 0.5 hour (hr) before infusion; end of infusion; and 10 minutes (min), 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Time frame: Day 1; Weeks 7 and 24
Minimum Plasma Concentration (Cmin) of Ofatumumab
Blood sampling at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), 120 hr (5 days), 168 hr (7 days), and 336 hr (14 days) after infusion of ofatumumab.
Time frame: Weeks 7 and 24
Time to Reach Cmax (Tmax) Following Ofatumumab Administration
Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Time frame: Day 1; Weeks 7 and 24
Half-life (t1/2) of Ofatumumab
t1/2 of ofatumumab is the time required for the plasma concentration of ofatumumab to decrease by half. Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Time frame: Day 1; Weeks 7 and 24
Area Under the Plasma Concentration-time Curve From Time Zero to Time t (AUC[0-t]) for Ofatumumab
AUC(0-t) was evaluated from the plasma concentration versus time curve from time zero to the last measurable time point (time t). Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Time frame: Day 1; Weeks 7 and 24
Area Under the Plasma Concentration-time Curve From Time Zero to 168 hr (AUC[0-168]) for Ofatumumab at Week 7
Blood sampling at Week 7 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), 120 hr (5 days), 168 hr (7 days), and 336 hr (14 days) after infusion of ofatumumab.
Time frame: Week 7
Area Under the Plasma Concentration-time Curve From Time Zero to 672 hr (AUC[0-672]) for Ofatumumab at Week 24
Blood sampling at Week 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), 120 hr (5 days), 168 hr (7 days), and 336 hr (14 days) after infusion of ofatumumab.
Time frame: Week 24
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC[0-infinity]) for Ofatumumab
Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Time frame: Day 1; Weeks 7 and 24
Clearance (CL) of Ofatumumab From Plasma
CL of ofatumumab from plasma of participants was evaluated. Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Time frame: Day 1; Weeks 7 and 24
Volume of Distribution (Vz) During the Terminal Phase for Ofatumumab
Vz for ofatumumab was calculated as a ratio of the amount of ofatumumab in the body during the terminal phase to the plasma concentration during the terminal phase. Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Time frame: Day 1; Weeks 7 and 24
Volume of Distribution at Steady State (Vss) for Ofatumumab
Vss for ofatumumab was calculated as a ratio of the amount of ofatumumab in the body in equilibrium conditions to steady-state plasma concentrations. Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Time frame: Day 1; Weeks 7 and 24
Mean Residence Time (MRTinf) of Ofatumumab
MRTinf is the average amount of time that ofatumumab spends in the body. Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Time frame: Day 1; Weeks 7 and 24
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