Leukaemia, Lymphocytic, Chronic
Conditions
Brief summary
This is an open-label study to evaluate tolerability, safety, efficacy and pharmacokinetic profile of ofatumumab in combination with chlorambucil in Japanese patients with previously untreated Chronic Lymphocytic Leukemia (CLL).
Detailed description
This is an open-label study to evaluate tolerability, safety, efficacy and pharmacokinetic profile of ofatumumab in combination with chlorambucil in Japanese patients with previously untreated Chronic Lymphocytic Leukemia (CLL). Ofatumumab will be infused intravenously at Day 1 (300 mg) and Day 8 (1000 mg) in the first 28-day cycle, followed by infusions of 1000 mg at the first day of each 28-day cycle. Chlorambucil will be given 10 mg/m2 at Day 1-7 in each 28-day cycle. The primary objectives are to evaluate tolerability and overall response rate (ORR) of ofatumumab with chlorambucil for previously untreated (frontline) CLL. Secondary objectives include to evaluate complete remission (CR) rate, progression free survival (PFS), overall survival (OS), time to response, duration of response, time to next therapy, incidence and severity of adverse events and serious adverse events, incidences of grade 3 and 4 infections and myelosuppression (anemia, neutropenia, thrombocytopenia), and pharmacokinetics of ofatumumab and chlorambucil.
Interventions
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
iv infusion; dose: cycle 1 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1 every 28 days;
Sponsors
GlaxoSmithKline
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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 modified 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 degree 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 permitted). * ECOG Performance Status of 0-2. * 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. * 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
* 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 (Visit 1), 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 transaminase (ALT) \> 3.0 times upper normal limit. * Previous treatment or known or suspected hypersensitivity to ofatumumab that in the opinion of the investigator or medical monitor is a contraindication to their participation in the present study. * 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. Note: Participation in any other interventional clinical study after disease progression during post PD-follow-up is permitted. * Known or suspected inability to comply with study protocol. * Lactating women, women with a positive pregnancy test at Visit 1 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, male partner sterilization (if male partner is sole partner for that subject) and the double barrier method (condom or occlusive cap plus spermicidal agent).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Developed Toxicity Requiring Discontinuation From Study Treatment During Cycle 1 | From start of treatment through Cycle 1 (Week 4) | Tolerability of ofatumumab in combination with chlorambucil was evaluated based on the number of participants who developed toxicity requiring discontinuation from study treatment during Cycle 1. The treatment was considered tolerable when 0 of 3 participants, or \<=2 of 6 participants developed toxicity which required discontinuation of study treatment during Cycle 1. The toxicity requiring discontinuation was determined based on the pre-defined withdrawal criteria. |
| Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator | From start of treatment until disease progression or death (up to Week 62.3) | Response evaluated as per International Workshop for Chronic Lymphocytic Leukemia (IWCLL) National Cancer Institute-sponsored Working Group (NCI-WG) Guidelines, 2008. Overall response rate (ORR) is defined as percentage of par. achieving complete remission (CR), nodular partial remission (nPR), CR-incomplete (CRi) or PR. CR (\>=2 months after last treatment): lymphocytes (LC) \<4000 per microliter (μL), no lymphadenopathy (Ly)\>1.5 cm/hepatomegaly/splenomegaly/constitutional symptoms; neutrophils (N)\>1500/µL, platelets (PL)\>100,000/µL, hemoglobin (Hb)\>11 grams/deciliter (g/dL), bone marrow (BM) sample must be normocellular for age,\<30% LC, no lymphoid nodule (LN). PR:\>=50% decrease in LC, Ly, size of liver and spleen; and at least one of these: N\>1500/μL, PL\>100,000/µL or 50% improvement over Baseline (BL), Hb\>11 g/dL or 50% improvement over BL. nPR: persistent nodules BM. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From start of treatment until death (up to Week 62.3 | Overall survival is defined as time from start of treatment until death due to any cause. For participants who did not die, time to death was censored at the time of the last date of contact. |
| Time to Response, as Assessed by the IRC | From start of treatment until the first response (CR/CRi/nPR/PR) (up to Week 62.3) | Time to response is defined as the time from start of treatment until the first response (CR/CRi/nPR/PR). Response was determined according to the IWCLL updated NCI-WG guidelines, 2008. This analysis only included participants who had a response while in the study, there was no censoring. |
| Duration of Response, as Assessed by the IRC | From initial response (CR/CRi/nPR/PR) until disease progression or death (up to Week 62.3) | Duration of response is defined as the time from the first documented evidence of CR, CRi, nPR or PR until the first documented sign of PD or death in participants with CR, CRi, nPR or PR. For participants who did not progress or die, duration of response was censored on the date of last assessment. |
| Time to Next Chronic Lymphocytic Leukemia (CLL) Therapy | From start of treatment until the first administration of the next CLL therapy (up to Week 62.3) | Time to next CLL therapy is defined as the time from start of treatment until the first administration of the next CLL treatment other than chlorambucil administrations scheduled in this study. Time to next CLL therapy was restricted to the subgroup of the population who receive a next CLL therapy after experiencing disease progression. |
| Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Baseline, C2-D29, C3-D57, C4-D85, C5-D113, C6-D141, C7-D169, C8-D197, C9 -D225, FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), FU 85-PDFU 85 (84 days after FU-1), and FU 169-PDFU 169 (168 days after FU-1) | The number of participants with no B-symptoms (no night sweat \[without signs of infection\], no unexplained, unintentional weight loss \>= 10% within the previous 6 months, no recurrent, unexplained fever of greater than 38 degrees celcius for 2 weeks and no extreme fatigue) and the number of participants with at least one of the B-symptoms are summarized by assessment time. The presence of the B-symptoms was assessed at Baseline, Day 1 of each treatment cycle and follow-up (FU). Baseline was the last pre-dose assessment performed at Cycle (C) 1-Day (D) 1. |
| Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Baseline, C2-D29, C3-D57, C4-D85, C5-D113, C6-D141, C7-D169, C8-D197, C9 -D225, FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), FU 85-PDFU 85 (84 days after FU-1), and FU 169-PDFU 169 (168 days after FU-1) | ECOG PS is a scale to assess disease progression, extent to which disease affects the daily living abilities and determines appropriate treatment and prognosis. It is scored on a scale of 0 to 5 as, 0 (fully active), 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), 2 (ambulatory and capable of all self cares but unable to carry out any work activities, up and about \> 50% of waking hours), 3 (capable of only limited self cares, confined to bed or chair \> 50% of waking hours), 4 (completely disabled, cannot carry on any self cares, totally confined to bed or chair), 5 (death). Improvement is defined as decrease from Baseline by at least one step on the ECOG performance status scale (yes/no). Baseline was the last pre-dose assessment performed on Cycle 1-Day 1(C1-D1). When C1-D1 was missing, the last assessment performed prior to pre-dose C1-D1 was used. It was performed on Day 1 of each cycle and follow-up (FU). |
| Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | From start of treatment until follow-up for survival (up to Week 62.3) | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed. |
| Number of Participants With AEs of Maximum Severity | From start of treatment until follow-up for survival (up to Week 62.3) | Adverse events were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) grade, version 4.03 (1=mild; 2=moderate; 3=severe; 4=life-threatening/disabling; 5=death). AEs not in the list of CTCAE were graded at discretion of the investigator. |
| Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events | From start of treatment until follow-up for survival (up to Week 62.3) | Adverse events were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) grade, version 4.03 (1=mild; 2=moderate; 3=severe; 4=life-threatening/disabling; 5=death). AEs not in the list of CTCAE were graded at discretion of the investigator. Myelosuppression is defined as the decrease in the ability of the bone marrow to produce blood cells. Participants with Grade (G)3 or G4 adverse event of infection and myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented. Also presented are number of participants with autoimmune hemolytic anemia (AIHA). AIHA is a disease where the body's immune system fails to recognize red blood cells as self and begins destroying these red blood cells. |
| Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points | Screening, Cycle 4-Day 85, FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), and FU 169-PDFU 169 (168 days after FU-1) | HAHA are indicators of immunogenicity induced by ofatumumab. Blood samples were taken from participants at Screening, Cycle 4-Day 85, FU 1-PDFU 1, and FU 169-PDFU 169. The presence of HAHA in human serum was determined using a validated electrochemiluminescent assay in a multi-tier assay format. The results are presented as participants with HAHA results as positive, negative or confirmation required. |
| Mean Change From Baseline in the Immunoglobulins (Ig) Antibodies IgA, IgG, and IgM at the Indicated Time Points | Baseline (Cycle 1-Day 1), FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), and FU 169-PDFU 169 (168 days after FU-1) | 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. Baseline IgA, IgG, and IgM values are the last pre-dose assessment values performed on Cycle 1-Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Immunoglobulins were measured at Cycle 1-Day 1, FU 1-PDFU 1, and FU 169-PDFU 169 for participants in CR, PR, and stable disease (SD). |
| Number of Participants Who Were Positive or Negative for Minimal Residual Disease (MRD), as Assessed by IRC With CT | FU 85-PDFU 85 (84 days after FU-1) | MRD refers to small number of leukemic cells that remain in the participant's body during treatment or after treatment in participants who achieved a confirmed complete remission. MRD assessment in bone marrow aspiration sample was perfrmed by flow cytometry (cluster of differentiation \[CD\]5, CD19, CD20, CD23). The absence of MRD was defined as less than one CLL cell per 10,000 leukocytes. The number of participants who were positive and negative for MRD are presented. |
| Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | Baseline, C1-D15, C2-D29, C2-D43, C3-D57, C4-D85, C5-D113, C6-D141, C7-D169, C8-D197, C9-D225, FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), FU 85-PDFU 85 (84 days after FU-1), and FU 169-PDFU 169 (168 days after FU-1) | CD5+CD19+ cells were counted in peripheral blood by flow cytometry. Baseline CD5+CD19+ and CD5-CD19+ cell count value is the last pre-dose assessment values performed on Cycle 1-Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. B-cell monitoring (CD5+CD19+ and CD5-CD19+) was performed at Cycle 1 (Day 1, Day 15) and Cycle 2 (Day 29, Day 43), on Day 1 of Cycle 3, 4, 5, 6, 9 and 12 (Day 57, Day 85, Day 113, Day 141, Day 225, Day 309), 28 days after the first day of the last treatment cycle (FU 1-PDFU 1) for all participants depending on the number of cycles administered, and 84 and 168 days after the day of FU 1-PDFU 1 for participants in CR, PR, and SD. |
| Beta-2 Microglobulin at Cycle 1-Day 1 | Cycle 1-Day 1 | Beta-2-microglobulin is a protein present on the surface of most cells. Higher levels indicate a poor prognosis of CLL. Beta-2 microglobulin was measured at Cycle 1-Day 1. |
| Complement (CH50) at Cycle 1-Day 1 and Cycle 4-Day 85 | Cycle 1-Day 1 and Cycle 4-Day 85 | The CH50 is the serum complement to lyse 50% of sensitized red blood cells; it is a marker of complement activation. A high CH50 level suggests evidence for complement activation, whereas a low CH50 level suggests lack of complement activation. Peripheral blood samples were collected for analysis at Cycle 1-Day 1 and Cycle 4-Day 85. |
| Maximum (Peak) Plasma Concentration (Cmax) of Ofatumumab | Cycle 1-Day 1 and Cycle 3-Day 57 | Maximum (peak) plasma drug concentration of ofatumumab was determined at Cycle 1-Day 1 and Cycle 3-Day 57. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr), and Cycle 3-Day 57 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr, 168 hr). |
| Cmax of Serum Chlorambucil | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | Cmax of serum chlorambucil was assesed at Cycle 1-Day 1, Cycle 1-Day 4 and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Cmax of Serum Phenyl Acetic Acid Mustard | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | Cmax of chlorambucil metabolite phenyl acetic acid mustard was assesed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Minimum Plasma Concentration (Cmin) of Ofatumumab | Cycle 1-Day 8, Cycle 2-Day 29, Cycle 3-Day 57, Cycle 4-Day 85, Cycle 5-Day 113, and Cycle 6-Day 141 | Minimum plasma drug concentration of ofatumumab was determined at Cycle 1-Day 8, Cycle 2-Day 29, Cycle 3-Day 57, Cycle 4-Day 85, Cycle 5-Day 113, and Cycle 6-Day 141. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr), Cycle 2-Day 29 (pre-dose), Cycle 3-Day 57 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr, 168 hr), Cycle 4-Day 85 (pre-dose, 30 min post end of infusion), Cycle 5-Day 113 (pre-dose and end of infusion) and Cycle 6-Day 141 (pre-dose and end of infusion). |
| Cmin of Chlorambucil | Cycle 1-Day 4 and Cycle 3-Day 57 | Cmin of chlorambucil was assesed at Cycle 1-Day 4 and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Cmin of Phenyl Acetic Acid Mustard | Cycle 1-Day 4 and Cycle 3-Day 57 | Cmin of chlorambucil metabolite phenyl acetic acid mustard was assesed at Cycle 1-Day 4 and Cycle 3-Day 57. Blood samples were collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Total Plasma Clearance (CL) of Ofatumumab | Cycle 1-Day 1 | Plasma clearance is defined as the plasma volume which is totally cleared of drug per unit of time. Blood samples were collected at Cycle 1-Day1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr). |
| Area Under the Drug Plasma Concentration-time Curve From Dosing to Time Tau (AUC[0-tau]) of Ofatumumab | Cycle 1-Day 1 and Cycle 3-Day 57 | Area under the concentration time curve over the dosing interval (AUC\[0-tau\]) is a measure of drug exposure over time. AUC(0-tau) is defined as the area under the drug plasma/serum concentration-time curve from dosing to time tau, where tau is the length of the dosing interval of the drug. For ofatumumab it was assesed at Cycle 1-Day 1 and Cycle 3-Day 57. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr) and Cycle 3-Day 57 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr, 168 hr). |
| AUC(0-tau) of Chlorambucil | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | Area under the concentration time curve over the dosing interval (AUC\[0-tau\]) is a measure of drug exposure over time. AUC(0-tau) is defined as the area under the drug plasma/serum concentration-time curve from dosing to time tau, where tau is the length of the dosing interval of the drug. It was assesed at 1st (Cycle 1-Day 1), 4th (Cycle 1-Day 4), and 15th (Cycle 3-Day 57) chlorambucil administration. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| AUC(0-tau) of Phenyl Acetic Acid Mustard | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | Area under the concentration time curve over the dosing interval (AUC\[0-tau\]) is a measure of drug exposure over time. AUC(0-tau) is defined as the area under the drug plasma/serum concentration-time curve from dosing to time tau, where tau is the length of the dosing interval of the drug. It was assesed at 1st (Cycle 1-Day 1), 4th (Cycle 1-Day 4), and 15th (Cycle 3-Day 57) chlorambucil administration. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC[0-infinity]) for Ofatumumab | Cycle 1-Day 1 | The total AUC or AUC0-infinity is the area under the curve from time 0 extrapolated to infinite time. It was assesed on Cycle 1-Day 1. The samples were collected at Cycle 1-Day1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr). |
| AUC(0-infinity) for Chlorambucil | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | The total AUC or AUC0-infinity is the area under the curve from time 0 extrapolated to infinite time. It was assesed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| AUC(0-infinity) for Phenyl Acetic Acid Mustard | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | The total AUC or AUC(0-infinity) is the area under the curve from time 0 extrapolated to infinite time. It was assesed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Volume of Distribution at Steady State (Vss) of Ofatumumab | Cycle 1-Day 1 | Volume of distribution at steady state (Vss) is defined as the distribution of a drug between plasma and the rest of the body at steady state. Samples were collected at Cycle 1-Day1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr). |
| Plasma Half-life (t1/2) of Ofatumumab | Cycle 1-Day 1 and Cycle 3-Day 57 | t1/2 is the time required for the plasma concentration of ofatumumab to decrease by half. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr) and Cycle 3-Day 57 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr, 168 hr). |
| Plasma Half-life (t1/2) of Chlorambucil | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | t1/2 is the time required for the serum concentration of chlorambucil to decrease by half. Blood samples for serum concentration of chlorambucil was collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Plasma Half-life (t1/2) of Phenyl Acetic Acid Mustard | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | t1/2 is the time required for the plasma/serum concentration of phenylacetic acid mustard to decrease by half. Blood samples for serum concentration of phenylacetic acid mustard was collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Time to Maximum Concentration (Tmax) of Ofatumumab | Cycle 1-Day 1 and Cycle 3-Day 57 | Tmax is the time required for reaching maximum concentration of drug (Cmax). Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr) and Cycle 3-Day 57 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr, 168 hr). |
| Time to Maximum Concentration (Tmax) of Chlorambucil | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | Tmax is the time required for reaching maximum concentration of drug (Cmax). Blood samples were collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Time to Maximum Concentration (Tmax) of Phenyl Acetic Acid Mustard | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | Tmax is the time required for reaching maximum concentration of drug (Cmax). Blood samples were collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Mean Residence Time to Infinity (MRTinf) of Ofatumumab | Cycle 1-Day 1 | MRTinf is the average amount of time that ofatumumab spends in the body. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr). |
| Mean Residence Time Inf (MRTinf) of Chlorambucil | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | MRTinf is the average amount of time that chlorambucil spends in the body. Blood samples were collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Mean Residence Time Inf (MRTinf) of Phenyl Acetic Acid Mustard | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | MRTinf is the average amount of time that phenyl acetic acid mustard spends in the body. Blood samples were collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Volume of Distribution (Vz) of Ofatumumab | Cycle 1-Day 1 | 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. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr). |
| Apparent Total Clearance of the Drug From Plasma (CL/F) for Chlorambucil | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | CL/F is defined as the apparent total clearance of the drug from plasma after oral administration of chlorambucil. It was assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Apparent Volume of Distribution During Terminal Phase (Vz/F) of Chlorambucil | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | Vz/F of chlorambucil is defined as the apparent volume of distribution during terminal phase after non-intravenous (oral) administration of chlorambucil. It was assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| %AUC_extrap of Ofatumumab | Cycle 1-Day 1 | %AUC\_extrap is defined as the area under the plasma concentration-time curve extrapolated from time t to infinity as a percentage of total AUC. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr). |
| %AUC_extrap of Chlorambucil | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | %AUC\_extrap is defined as the area under the plasma concentration-time curve extrapolated from time t to infinity as a percentage of total AUC. It was assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| %AUC_extrap of Phenyl Acetic Acid Mustard | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | %AUC\_extrap is defined as the area under the plasma concentration-time curve extrapolated from time t to infinity as a percentage of total AUC. It was assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| AUC (0-t) of Ofatumumab | Cycle 1-Day 1 and Cycle 3-Day 57 | AUC (0-t) represents the area under the concentration curve of ofatumumab in plasma from 0 to time t hours. AUC (0-t) was assessed at 168 hours and 672 hours post-dose. |
| AUC (0-t) of Chlorambucil | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | AUC (0-t) represents the area under the concentration curve of chlorambucil in serum from 0 to time t hours. AUC (0-t) was assessed at 6 hours and 24 hours. |
| Number of Participants With CR, as Assessed by the IRC, IRC With CT, and the Investigator | From start of treatment until disease progression or death (up to Week 62.3) | Response was determined according to the IWCLL updated NCI-WG guidelines, 2008. According to the guidelines, CR (all the criteria at least 2 months after last treatment): peripheral blood lymphocytes below \< 4,000/μL, no Ly \> 1.5 cm/ hepatomegaly/ splenomegaly/ constitutional symptoms; Neu \>1500 /µL, PL \>100,000/µL, Hb \>11 g/dL, BM sample must be normocellular for age, \<30% lymphocytes, no LN. PR: \>=50% decrease in peripheral blood lymphocytes, Ly, size of liver and spleen; and blood count showing at least one of the following results: Neu\>1500/μL, PL \>100,000/µL or 50% improvement over BL, Hb \>11 g/dL or 50% improvement over BL. No increase in LN and no new LN. |
| Dose Normalized Cmax (Cmax/D) for Chlorambucil | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | Cmax/D is defined as the maximum plasma concentration (Cmax) per unit dose. It was assessed at Cycle 1-Day 1, Cycle 1-Day 4 and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| Cmax/D for Phenyl Acetic Acid Mustard | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | Cmax/D is defined as the maximum plasma concentration (Cmax) per unit dose. It was assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | Dose adjusted AUC for the indicated time points were assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | Dose adjusted AUC for the indicated time points were assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr. |
| AUC (0-t) of Phenyl Acetic Acid Mustard | Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 | AUC (0-t) represents the area under the concentration curve of phenyl acetic acid mustard in serum from 0 to time t hours. AUC (0-t) was assessed at 6 hours and 24 hours. |
| Progression-free Survival (PFS), as Assessed by the IRC and the Investigator | From start of treatment until disease progression or death (up to Week 62.3) | Progression free survival is defined as the time from start of treatment until disease progression (PD) or death due to any cause. PD was determined by the IRC or investigator according to the definitions of response in the IWCLL updated NCI-WG guidelines, 2008. According to the guidelines, PD is characterized by at least one of the following: lymphadenopathy (appearance of any new lesion such as enlarged lymph nodes (\>1.5 centimeter \[cm\]), spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site); an increase by 50% or more in the previously noted enlargement of the liver or spleen; an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 per microliter B-lymphocytes; transformation to a more aggressive histology; or occurrence of cytopenia attributable to chronic lymphocytic leukemia. PFS was censored at the last visit with adequate assessment for participants who were alive and had not progressed. |
Countries
Japan
Participant flow
Pre-assignment details
This study consisted of two parts. In part A of the study, the eligible participants (par.) were enrolled to assess the tolerability of ofatumumab with chlorambucil. After confirmation of the tolerability, Part B of the study was initiated. The total number of participants in Part A and Part B was 10.
Participants by arm
| Arm | Count |
|---|---|
| Ofatumumab + Chlorambucil Par. with previously untreated chronic lymphocytic leukemia (CLL) received intravenous (IV) infusions of ofatumumab on Day 1 (300 milligrams \[mg\]) and Day 8 (1000 mg) in the first cycle, followed by 1000 mg on the first day of each subsequent 28-day cycle in combination with oral chlorambucil 10 mg/meter squared (m\^2) on Days 1-7 of each cycle for at least 3 cycles, until best overall response or up to 12 cycles. After the Treatment Phase (for par. in CR, PR or SD), survival and disease status were assessed 28 days after the first day of the last treatment cycle (Follow-up \[FU\] 1), 84 and 168 days after the day of FU1 (FU85 and FU169, respectively). For par. with disease progression (PD) during the Treatment Phase, post PD follow-up were done 28 days after the first day of the last treatment cycle (PDFU1) to assess safety. Survival status, date of next CLL therapy, and type of therapy were subsequently assessed 84 and 168 days after the day of PDFU1 (PDFU85 and PDFU169, respectively). | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Ofatumumab + Chlorambucil |
|---|---|
| Age, Continuous | 71.5 Years STANDARD_DEVIATION 10.38 |
| Age, Customized <65 years | 1 Participants |
| Age, Customized >=65 years | 9 Participants |
| Age, Customized >=75 years | 4 Participants |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 10 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 2 / 10 |
Outcome results
Primary
Number of Participants Who Developed Toxicity Requiring Discontinuation From Study Treatment During Cycle 1
Tolerability of ofatumumab in combination with chlorambucil was evaluated based on the number of participants who developed toxicity requiring discontinuation from study treatment during Cycle 1. The treatment was considered tolerable when 0 of 3 participants, or \<=2 of 6 participants developed toxicity which required discontinuation of study treatment during Cycle 1. The toxicity requiring discontinuation was determined based on the pre-defined withdrawal criteria.
Time frame: From start of treatment through Cycle 1 (Week 4)
Population: All Subjects Population: all participants who received at least one dose of investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ofatumumab + Chlorambucil | Number of Participants Who Developed Toxicity Requiring Discontinuation From Study Treatment During Cycle 1 | 0 Participants |
Primary
Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator
Response evaluated as per International Workshop for Chronic Lymphocytic Leukemia (IWCLL) National Cancer Institute-sponsored Working Group (NCI-WG) Guidelines, 2008. Overall response rate (ORR) is defined as percentage of par. achieving complete remission (CR), nodular partial remission (nPR), CR-incomplete (CRi) or PR. CR (\>=2 months after last treatment): lymphocytes (LC) \<4000 per microliter (μL), no lymphadenopathy (Ly)\>1.5 cm/hepatomegaly/splenomegaly/constitutional symptoms; neutrophils (N)\>1500/µL, platelets (PL)\>100,000/µL, hemoglobin (Hb)\>11 grams/deciliter (g/dL), bone marrow (BM) sample must be normocellular for age,\<30% LC, no lymphoid nodule (LN). PR:\>=50% decrease in LC, Ly, size of liver and spleen; and at least one of these: N\>1500/μL, PL\>100,000/µL or 50% improvement over Baseline (BL), Hb\>11 g/dL or 50% improvement over BL. nPR: persistent nodules BM. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity.
Time frame: From start of treatment until disease progression or death (up to Week 62.3)
Population: All Subjects Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator | IRC with CT Assessed, CR | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator | IRC Assessed, nPR | 1 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator | IRC with CT Assessed, CRi | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator | IRC with CT Assessed, nPR | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator | IRC with CT Assessed, PR | 5 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator | IRC Assessed, CR | 1 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator | IRC Assessed, CRi | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator | IRC Assessed, PR | 5 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator | Investigator Assessed, CR | 1 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator | Investigator Assessed, CRi | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator | Investigator Assessed, nPR | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator | Investigator Assessed, PR | 6 Participants |
Secondary
Apparent Total Clearance of the Drug From Plasma (CL/F) for Chlorambucil
CL/F is defined as the apparent total clearance of the drug from plasma after oral administration of chlorambucil. It was assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Apparent Total Clearance of the Drug From Plasma (CL/F) for Chlorambucil | Cycle 1-Day 1, n=6 | 8.21928 L/hr/m^2 |
| Ofatumumab + Chlorambucil | Apparent Total Clearance of the Drug From Plasma (CL/F) for Chlorambucil | Cycle 1-Day 4, n=6 | 9.06406 L/hr/m^2 |
| Ofatumumab + Chlorambucil | Apparent Total Clearance of the Drug From Plasma (CL/F) for Chlorambucil | Cycle 3-Day 57, n=5 | 7.75166 L/hr/m^2 |
Secondary
Apparent Volume of Distribution During Terminal Phase (Vz/F) of Chlorambucil
Vz/F of chlorambucil is defined as the apparent volume of distribution during terminal phase after non-intravenous (oral) administration of chlorambucil. It was assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Chlorambucil | Cycle 1-Day 1, n=6 | 12.67367 L/m^2 |
| Ofatumumab + Chlorambucil | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Chlorambucil | Cycle 1-Day 4, n=6 | 22.85356 L/m^2 |
| Ofatumumab + Chlorambucil | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Chlorambucil | Cycle 3-Day 57, n=5 | 15.44858 L/m^2 |
Secondary
Area Under the Drug Plasma Concentration-time Curve From Dosing to Time Tau (AUC[0-tau]) of Ofatumumab
Area under the concentration time curve over the dosing interval (AUC\[0-tau\]) is a measure of drug exposure over time. AUC(0-tau) is defined as the area under the drug plasma/serum concentration-time curve from dosing to time tau, where tau is the length of the dosing interval of the drug. For ofatumumab it was assesed at Cycle 1-Day 1 and Cycle 3-Day 57. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr) and Cycle 3-Day 57 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr, 168 hr).
Time frame: Cycle 1-Day 1 and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Area Under the Drug Plasma Concentration-time Curve From Dosing to Time Tau (AUC[0-tau]) of Ofatumumab | Cycle 1-Day 1, n=6 | 1438.65082 Hours*nanogram/milliliter (hr*ng/mL |
| Ofatumumab + Chlorambucil | Area Under the Drug Plasma Concentration-time Curve From Dosing to Time Tau (AUC[0-tau]) of Ofatumumab | Cycle 3-Day 57, n=5 | 62463.2072 Hours*nanogram/milliliter (hr*ng/mL |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC[0-infinity]) for Ofatumumab
The total AUC or AUC0-infinity is the area under the curve from time 0 extrapolated to infinite time. It was assesed on Cycle 1-Day 1. The samples were collected at Cycle 1-Day1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr).
Time frame: Cycle 1-Day 1
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ofatumumab + Chlorambucil | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC[0-infinity]) for Ofatumumab | 1737.67475 Hr*ug/mL |
Secondary
AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil
Dose adjusted AUC for the indicated time points were assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil | AUC(0-24)/D, Cycle 1-Day 4, n=6 | 70.89263 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil | AUC(0-24)/D, Cycle 3-Day 57, n=5 | 88.34439 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil | AUC(0-tau)/D, Cycle 1-Day 1, n=6 | 76.58665 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil | AUC(0-6)/D, Cycle 1-Day 1, n=6 | 68.74861 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil | AUC(0-6)/D, Cycle 1-Day 4, n=6 | 61.52734 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil | AUC(0-6)/D, Cycle 3-Day 57, n=5 | 78.04287 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil | AUC(0-24)/D, Cycle 1-Day 1, n=6 | 78.20923 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil | AUC(0-tau)/D, Cycle 1-Day 4, n=6 | 68.17087 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil | AUC(0-tau)/D, Cycle 3-Day 57, n=5 | 86.24639 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil | AUC(0-inf)/D, Cycle 1-Day 1, n=6 | 78.22474 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil | AUC(0-inf)/D, Cycle 1-Day 4, n=6 | 70.93409 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil | AUC(0-inf)/D, Cycle 3-Day 57, n=5 | 88.35489 hr*ng/mL/mg |
Secondary
AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard
Dose adjusted AUC for the indicated time points were assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard | AUC(0-inf)/D, Cycle 3-Day 57, n=5 | 80.91593 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard | AUC(0-6)/D, Cycle 1-Day 1, n=6 | 48.57834 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard | AUC(0-6)/D, Cycle 1-Day 4, n=6 | 46.25349 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard | AUC(0-6)/D, Cycle 3-Day 57, n=5 | 50.92019 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard | AUC(0-24)/D, Cycle 1-Day 1, n=6 | 77.89921 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard | AUC(0-24)/D, Cycle 1-Day 4, n=6 | 72.96523 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard | AUC(0-24)/D, Cycle 3-Day 57, n=5 | 80.47565 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard | AUC(0-tau)/D, Cycle 1-Day 1, n=6 | 69.18564 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard | AUC(0-tau)/D, Cycle 1-Day 4, n=6 | 63.26787 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard | AUC(0-tau)/D, Cycle 3-Day 57, n=5 | 71.15233 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard | AUC(0-inf)/D, Cycle 1-Day 1, n=6 | 77.98872 hr*ng/mL/mg |
| Ofatumumab + Chlorambucil | AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard | AUC(0-inf)/D, Cycle 1-Day 4, n=6 | 73.26780 hr*ng/mL/mg |
Secondary
AUC(0-infinity) for Chlorambucil
The total AUC or AUC0-infinity is the area under the curve from time 0 extrapolated to infinite time. It was assesed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | AUC(0-infinity) for Chlorambucil | Cycle 3-Day 57, n=5 | 1290.04709 Hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC(0-infinity) for Chlorambucil | Cycle 1-Day 1, n=6 | 1216.65216 Hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC(0-infinity) for Chlorambucil | Cycle 1-Day 4, n=6 | 1103.25854 Hr*ng/mL |
Secondary
AUC(0-infinity) for Phenyl Acetic Acid Mustard
The total AUC or AUC(0-infinity) is the area under the curve from time 0 extrapolated to infinite time. It was assesed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | AUC(0-infinity) for Phenyl Acetic Acid Mustard | Cycle 1-Day 1, n=6 | 1212.98123 Hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC(0-infinity) for Phenyl Acetic Acid Mustard | Cycle 1-Day 4, n=6 | 1139.55544 Hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC(0-infinity) for Phenyl Acetic Acid Mustard | Cycle 3-Day 57, n=5 | 1181.43279 Hr*ng/mL |
Secondary
AUC(0-tau) of Chlorambucil
Area under the concentration time curve over the dosing interval (AUC\[0-tau\]) is a measure of drug exposure over time. AUC(0-tau) is defined as the area under the drug plasma/serum concentration-time curve from dosing to time tau, where tau is the length of the dosing interval of the drug. It was assesed at 1st (Cycle 1-Day 1), 4th (Cycle 1-Day 4), and 15th (Cycle 3-Day 57) chlorambucil administration. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | AUC(0-tau) of Chlorambucil | Cycle 1-Day 4, n=6 | 1060.28140 Hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC(0-tau) of Chlorambucil | Cycle 1-Day 1, n=6 | 1191.17448 Hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC(0-tau) of Chlorambucil | Cycle 3-Day 57, n=5 | 1259.26147 Hr*ng/mL |
Secondary
AUC(0-tau) of Phenyl Acetic Acid Mustard
Area under the concentration time curve over the dosing interval (AUC\[0-tau\]) is a measure of drug exposure over time. AUC(0-tau) is defined as the area under the drug plasma/serum concentration-time curve from dosing to time tau, where tau is the length of the dosing interval of the drug. It was assesed at 1st (Cycle 1-Day 1), 4th (Cycle 1-Day 4), and 15th (Cycle 3-Day 57) chlorambucil administration. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | AUC(0-tau) of Phenyl Acetic Acid Mustard | Cycle 3-Day 57, n=5 | 1038.87699 Hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC(0-tau) of Phenyl Acetic Acid Mustard | Cycle 1-Day 1, n=6 | 1076.06435 Hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC(0-tau) of Phenyl Acetic Acid Mustard | Cycle 1-Day 4, n=6 | 984.02359 Hr*ng/mL |
Secondary
AUC (0-t) of Chlorambucil
AUC (0-t) represents the area under the concentration curve of chlorambucil in serum from 0 to time t hours. AUC (0-t) was assessed at 6 hours and 24 hours.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | AUC (0-t) of Chlorambucil | AUC(0-6), Cycle 1-Day 1, n=6 | 1069.26703 hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC (0-t) of Chlorambucil | AUC(0-6), Cycle 1-Day 4, n=6 | 956.95261 hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC (0-t) of Chlorambucil | AUC(0-6), Cycle 3-Day 57, n=5 | 1139.48401 hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC (0-t) of Chlorambucil | AUC(0-24), Cycle 1-Day 1, n=6 | 1216.41085 hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC (0-t) of Chlorambucil | AUC(0-24), Cycle 1-Day 4, n=6 | 1102.61367 hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC (0-t) of Chlorambucil | AUC(0-24), Cycle 3-Day 57, n=5 | 1289.89389 hr*ng/mL |
Secondary
AUC (0-t) of Ofatumumab
AUC (0-t) represents the area under the concentration curve of ofatumumab in plasma from 0 to time t hours. AUC (0-t) was assessed at 168 hours and 672 hours post-dose.
Time frame: Cycle 1-Day 1 and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | AUC (0-t) of Ofatumumab | AUC(0-168), Cycle 1-Day 1, n=6 | 1526.32835 hr*µg/mL |
| Ofatumumab + Chlorambucil | AUC (0-t) of Ofatumumab | AUC (0-672), Cycle 3-Day 57, n=5 | 58769.6326 hr*µg/mL |
Secondary
AUC (0-t) of Phenyl Acetic Acid Mustard
AUC (0-t) represents the area under the concentration curve of phenyl acetic acid mustard in serum from 0 to time t hours. AUC (0-t) was assessed at 6 hours and 24 hours.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | AUC (0-t) of Phenyl Acetic Acid Mustard | AUC(0-24), Cycle 1-Day 1, n=6 | 1211.58911 hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC (0-t) of Phenyl Acetic Acid Mustard | AUC(0-24), Cycle 1-Day 4, n=6 | 1134.84945 hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC (0-t) of Phenyl Acetic Acid Mustard | AUC(0-24), Cycle 3-Day 57, n=5 | 1175.00443 hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC (0-t) of Phenyl Acetic Acid Mustard | AUC(0-6), Cycle 1-Day 1, n=6 | 755.55297 hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC (0-t) of Phenyl Acetic Acid Mustard | AUC(0-6), Cycle 1-Day 4, n=6 | 719.39401 hr*ng/mL |
| Ofatumumab + Chlorambucil | AUC (0-t) of Phenyl Acetic Acid Mustard | AUC(0-6), Cycle 3-Day 57, n=5 | 743.47268 hr*ng/mL |
Secondary
%AUC_extrap of Chlorambucil
%AUC\_extrap is defined as the area under the plasma concentration-time curve extrapolated from time t to infinity as a percentage of total AUC. It was assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | %AUC_extrap of Chlorambucil | Cycle 1-Day 4, n=6 | 3.20042 percentage of AUC after extrapolation |
| Ofatumumab + Chlorambucil | %AUC_extrap of Chlorambucil | Cycle 3-Day 57, n=5 | 2.01046 percentage of AUC after extrapolation |
| Ofatumumab + Chlorambucil | %AUC_extrap of Chlorambucil | Cycle 1-Day 1, n=6 | 1.51853 percentage of AUC after extrapolation |
Secondary
%AUC_extrap of Ofatumumab
%AUC\_extrap is defined as the area under the plasma concentration-time curve extrapolated from time t to infinity as a percentage of total AUC. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr).
Time frame: Cycle 1-Day 1
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ofatumumab + Chlorambucil | %AUC_extrap of Ofatumumab | 3.99041 percentage of AUC after extrapolation |
Secondary
%AUC_extrap of Phenyl Acetic Acid Mustard
%AUC\_extrap is defined as the area under the plasma concentration-time curve extrapolated from time t to infinity as a percentage of total AUC. It was assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | %AUC_extrap of Phenyl Acetic Acid Mustard | Cycle 1-Day 1, n=6 | 10.12009 percentage of AUC after extrapolation |
| Ofatumumab + Chlorambucil | %AUC_extrap of Phenyl Acetic Acid Mustard | Cycle 1-Day 4, n=6 | 11.57955 percentage of AUC after extrapolation |
| Ofatumumab + Chlorambucil | %AUC_extrap of Phenyl Acetic Acid Mustard | Cycle 3-Day 57, n=5 | 8.34549 percentage of AUC after extrapolation |
Secondary
Beta-2 Microglobulin at Cycle 1-Day 1
Beta-2-microglobulin is a protein present on the surface of most cells. Higher levels indicate a poor prognosis of CLL. Beta-2 microglobulin was measured at Cycle 1-Day 1.
Time frame: Cycle 1-Day 1
Population: All Subjects Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Beta-2 Microglobulin at Cycle 1-Day 1 | 301.442 Nanomoles per liter (NMOL/L) | Standard Deviation 157.5521 |
Secondary
Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points
CD5+CD19+ cells were counted in peripheral blood by flow cytometry. Baseline CD5+CD19+ and CD5-CD19+ cell count value is the last pre-dose assessment values performed on Cycle 1-Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. B-cell monitoring (CD5+CD19+ and CD5-CD19+) was performed at Cycle 1 (Day 1, Day 15) and Cycle 2 (Day 29, Day 43), on Day 1 of Cycle 3, 4, 5, 6, 9 and 12 (Day 57, Day 85, Day 113, Day 141, Day 225, Day 309), 28 days after the first day of the last treatment cycle (FU 1-PDFU 1) for all participants depending on the number of cycles administered, and 84 and 168 days after the day of FU 1-PDFU 1 for participants in CR, PR, and SD.
Time frame: Baseline, C1-D15, C2-D29, C2-D43, C3-D57, C4-D85, C5-D113, C6-D141, C7-D169, C8-D197, C9-D225, FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), FU 85-PDFU 85 (84 days after FU-1), and FU 169-PDFU 169 (168 days after FU-1)
Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD19+CD5-, Cycle 5-Day 113, n=7 | -1792.43 Cells per microliter | Standard Deviation 3668.705 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD19+CD5-, Cycle 6-Day 141, n=7 | -1794.14 Cells per microliter | Standard Deviation 3668.713 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD19+CD5-, FU 1-PDFU 1, n=10 | -7534.40 Cells per microliter | Standard Deviation 13238.65 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD5+CD19+, Cycle 1-Day 15, n=8 | -71066.50 Cells per microliter | Standard Deviation 114877.018 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD5+CD19+, Cycle 2-Day 29, n=8 | -50441.25 Cells per microliter | Standard Deviation 56969.08 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD5+CD19+, Cycle 2-Day 43, n=8 | -36755.88 Cells per microliter | Standard Deviation 36719.313 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD5+CD19+, Cycle 3-Day 57, n=8 | -31823.50 Cells per microliter | Standard Deviation 37479.968 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD5+CD19+, Cycle 4-Day 85, n=7 | -35679.00 Cells per microliter | Standard Deviation 39379.825 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD5+CD19+, Cycle 5-Day 113, n=7 | -35754.71 Cells per microliter | Standard Deviation 39502.575 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD5+CD19+, Cycle 6-Day 141, n=7 | -35791.43 Cells per microliter | Standard Deviation 39535.868 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD5+CD19+, Cycle 7-Day 169, n=2 | -61591.00 Cells per microliter | Standard Deviation 19469.478 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD5+CD19+, Cycle 8-Day 197, n=2 | -61589.00 Cells per microliter | Standard Deviation 19473.721 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD5+CD19+, Cycle 9-Day 225, n=2 | -61591.00 Cells per microliter | Standard Deviation 19470.892 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD5+CD19+, FU 1-PDFU 1, n=10 | -59868.20 Cells per microliter | Standard Deviation 96360.514 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD5+CD19+, FU 85-PDFU 85, n=9 | -31370.78 Cells per microliter | Standard Deviation 36239.779 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD5+CD19+, FU 169- PDFU 169, n=8 | -31270.25 Cells per microliter | Standard Deviation 38733.484 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD19+CD5-, Cycle 1-Day 15, n=8 | -6752.50 Cells per microliter | Standard Deviation 14473.357 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD19+CD5-, Cycle 2-Day 29, n=8 | -6616.13 Cells per microliter | Standard Deviation 14070.593 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD19+CD5-, Cycle 2-Day 43, n=8 | -6044.00 Cells per microliter | Standard Deviation 12496.749 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD19+CD5-, Cycle 3-Day 57, n=8 | -2867.13 Cells per microliter | Standard Deviation 4561.234 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD19+CD5-, Cycle 4-Day 85, n=7 | -1792.57 Cells per microliter | Standard Deviation 3669.425 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD19+CD5-, Cycle 7-Day 169, n=2 | -362.50 Cells per microliter | Standard Deviation 64.347 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD19+CD5-, Cycle 8-Day 197, n=2 | -362.00 Cells per microliter | Standard Deviation 63.64 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD19+CD5-, Cycle 9-Day 225, n=2 | -362.00 Cells per microliter | Standard Deviation 63.64 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD19+CD5-, FU 85-PDFU 85, n=9 | -3911.67 Cells per microliter | Standard Deviation 6060.974 |
| Ofatumumab + Chlorambucil | Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points | CD19+CD5-, FU 169-PDFU 169, n=8 | -2170.38 Cells per microliter | Standard Deviation 3568.904 |
Secondary
Cmax/D for Phenyl Acetic Acid Mustard
Cmax/D is defined as the maximum plasma concentration (Cmax) per unit dose. It was assessed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Cmax/D for Phenyl Acetic Acid Mustard | Cycle 1-Day 1, n=6 | 15.26100 ng/mL/mg |
| Ofatumumab + Chlorambucil | Cmax/D for Phenyl Acetic Acid Mustard | Cycle 1-Day 4, n=6 | 13.85946 ng/mL/mg |
| Ofatumumab + Chlorambucil | Cmax/D for Phenyl Acetic Acid Mustard | Cycle 3-Day 57, n=5 | 15.49565 ng/mL/mg |
Secondary
Cmax of Serum Chlorambucil
Cmax of serum chlorambucil was assesed at Cycle 1-Day 1, Cycle 1-Day 4 and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Cmax of Serum Chlorambucil | Cycle 1-Day 1, n=6 | 412.1241 ng/mL |
| Ofatumumab + Chlorambucil | Cmax of Serum Chlorambucil | Cycle 1-Day 4, n=6 | 388.1516 ng/mL |
| Ofatumumab + Chlorambucil | Cmax of Serum Chlorambucil | Cycle 3-Day 57, n=5 | 420.9367 ng/mL |
Secondary
Cmax of Serum Phenyl Acetic Acid Mustard
Cmax of chlorambucil metabolite phenyl acetic acid mustard was assesed at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Cmax of Serum Phenyl Acetic Acid Mustard | Cycle 1-Day 1, n=6 | 237.3587 ng/mL |
| Ofatumumab + Chlorambucil | Cmax of Serum Phenyl Acetic Acid Mustard | Cycle 1-Day 4, n=6 | 215.5603 ng/mL |
| Ofatumumab + Chlorambucil | Cmax of Serum Phenyl Acetic Acid Mustard | Cycle 3-Day 57, n=5 | 226.2480 ng/mL |
Secondary
Cmin of Chlorambucil
Cmin of chlorambucil was assesed at Cycle 1-Day 4 and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 4 and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Cmin of Chlorambucil | Cycle 1-Day 4, n=6 | NA ng/mL |
| Ofatumumab + Chlorambucil | Cmin of Chlorambucil | Cycle 3-Day 57, n=5 | NA ng/mL |
Secondary
Cmin of Phenyl Acetic Acid Mustard
Cmin of chlorambucil metabolite phenyl acetic acid mustard was assesed at Cycle 1-Day 4 and Cycle 3-Day 57. Blood samples were collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 4 and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Cmin of Phenyl Acetic Acid Mustard | Cycle 1-Day 4, n=6 | NA ng/mL |
| Ofatumumab + Chlorambucil | Cmin of Phenyl Acetic Acid Mustard | Cycle 3-Day 57, n=5 | NA ng/mL |
Secondary
Complement (CH50) at Cycle 1-Day 1 and Cycle 4-Day 85
The CH50 is the serum complement to lyse 50% of sensitized red blood cells; it is a marker of complement activation. A high CH50 level suggests evidence for complement activation, whereas a low CH50 level suggests lack of complement activation. Peripheral blood samples were collected for analysis at Cycle 1-Day 1 and Cycle 4-Day 85.
Time frame: Cycle 1-Day 1 and Cycle 4-Day 85
Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects pPopulation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ofatumumab + Chlorambucil | Complement (CH50) at Cycle 1-Day 1 and Cycle 4-Day 85 | Cycle 1-Day 1, n=10 | 42.63 Kilo units per liter (KU/L) | Standard Deviation 4.549 |
| Ofatumumab + Chlorambucil | Complement (CH50) at Cycle 1-Day 1 and Cycle 4-Day 85 | Cycle 4-Day 85, n=7 | 39.80 Kilo units per liter (KU/L) | Standard Deviation 5.791 |
Secondary
Dose Normalized Cmax (Cmax/D) for Chlorambucil
Cmax/D is defined as the maximum plasma concentration (Cmax) per unit dose. It was assessed at Cycle 1-Day 1, Cycle 1-Day 4 and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Dose Normalized Cmax (Cmax/D) for Chlorambucil | Cycle 1-Day 1, n=6 | 26.49755 ng/mL/mg |
| Ofatumumab + Chlorambucil | Dose Normalized Cmax (Cmax/D) for Chlorambucil | Cycle 1-Day 4, n=6 | 24.95624 ng/mL/mg |
| Ofatumumab + Chlorambucil | Dose Normalized Cmax (Cmax/D) for Chlorambucil | Cycle 3-Day 57, n=5 | 28.82981 ng/mL/mg |
Secondary
Duration of Response, as Assessed by the IRC
Duration of response is defined as the time from the first documented evidence of CR, CRi, nPR or PR until the first documented sign of PD or death in participants with CR, CRi, nPR or PR. For participants who did not progress or die, duration of response was censored on the date of last assessment.
Time frame: From initial response (CR/CRi/nPR/PR) until disease progression or death (up to Week 62.3)
Population: All Subjects Population. Only those participants classified as responders (CR, CRi, PR, nPR) were evaluated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ofatumumab + Chlorambucil | Duration of Response, as Assessed by the IRC | NA Weeks |
Secondary
Maximum (Peak) Plasma Concentration (Cmax) of Ofatumumab
Maximum (peak) plasma drug concentration of ofatumumab was determined at Cycle 1-Day 1 and Cycle 3-Day 57. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr), and Cycle 3-Day 57 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr, 168 hr).
Time frame: Cycle 1-Day 1 and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Maximum (Peak) Plasma Concentration (Cmax) of Ofatumumab | Cycle 1-Day 1, n=6 | 59.4051 Micrograms/milliliter (µg/mL) |
| Ofatumumab + Chlorambucil | Maximum (Peak) Plasma Concentration (Cmax) of Ofatumumab | Cycle 3-Day 57, n=5 | 296.1851 Micrograms/milliliter (µg/mL) |
Secondary
Mean Change From Baseline in the Immunoglobulins (Ig) Antibodies IgA, IgG, and IgM at the Indicated Time Points
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. Baseline IgA, IgG, and IgM values are the last pre-dose assessment values performed on Cycle 1-Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Immunoglobulins were measured at Cycle 1-Day 1, FU 1-PDFU 1, and FU 169-PDFU 169 for participants in CR, PR, and stable disease (SD).
Time frame: Baseline (Cycle 1-Day 1), FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), and FU 169-PDFU 169 (168 days after FU-1)
Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ofatumumab + Chlorambucil | Mean Change From Baseline in the Immunoglobulins (Ig) Antibodies IgA, IgG, and IgM at the Indicated Time Points | IgG, FU 1-PDFU 1, n=10 | -0.025 Grams per liter | Standard Deviation 1.4555 |
| Ofatumumab + Chlorambucil | Mean Change From Baseline in the Immunoglobulins (Ig) Antibodies IgA, IgG, and IgM at the Indicated Time Points | IgG, FU 169-PDFU 169, n=8 | 0.611 Grams per liter | Standard Deviation 1.0636 |
| Ofatumumab + Chlorambucil | Mean Change From Baseline in the Immunoglobulins (Ig) Antibodies IgA, IgG, and IgM at the Indicated Time Points | IgM, FU 169-PDFU 169, n=8 | -0.045 Grams per liter | Standard Deviation 0.1466 |
| Ofatumumab + Chlorambucil | Mean Change From Baseline in the Immunoglobulins (Ig) Antibodies IgA, IgG, and IgM at the Indicated Time Points | IgA, FU 1-PDFU 1, n=10 | 0.111 Grams per liter | Standard Deviation 0.2816 |
| Ofatumumab + Chlorambucil | Mean Change From Baseline in the Immunoglobulins (Ig) Antibodies IgA, IgG, and IgM at the Indicated Time Points | IgA, FU 169-PDFU 169, n=8 | 0.326 Grams per liter | Standard Deviation 0.4172 |
| Ofatumumab + Chlorambucil | Mean Change From Baseline in the Immunoglobulins (Ig) Antibodies IgA, IgG, and IgM at the Indicated Time Points | IgM, FU 1-PDFU 1, n=10 | -0.053 Grams per liter | Standard Deviation 0.1466 |
Secondary
Mean Residence Time Inf (MRTinf) of Chlorambucil
MRTinf is the average amount of time that chlorambucil spends in the body. Blood samples were collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Mean Residence Time Inf (MRTinf) of Chlorambucil | Cycle 1-Day 1, n=6 | 3.63147 hours |
| Ofatumumab + Chlorambucil | Mean Residence Time Inf (MRTinf) of Chlorambucil | Cycle 1-Day 4, n=6 | 3.36698 hours |
| Ofatumumab + Chlorambucil | Mean Residence Time Inf (MRTinf) of Chlorambucil | Cycle 3-Day 57, n=5 | 3.46924 hours |
Secondary
Mean Residence Time Inf (MRTinf) of Phenyl Acetic Acid Mustard
MRTinf is the average amount of time that phenyl acetic acid mustard spends in the body. Blood samples were collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Mean Residence Time Inf (MRTinf) of Phenyl Acetic Acid Mustard | Cycle 1-Day 1, n=6 | 5.71852 hours |
| Ofatumumab + Chlorambucil | Mean Residence Time Inf (MRTinf) of Phenyl Acetic Acid Mustard | Cycle 1-Day 4, n=6 | 5.62096 hours |
| Ofatumumab + Chlorambucil | Mean Residence Time Inf (MRTinf) of Phenyl Acetic Acid Mustard | Cycle 3-Day 57, n=5 | 5.58632 hours |
Secondary
Mean Residence Time to Infinity (MRTinf) of Ofatumumab
MRTinf is the average amount of time that ofatumumab spends in the body. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr).
Time frame: Cycle 1-Day 1
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ofatumumab + Chlorambucil | Mean Residence Time to Infinity (MRTinf) of Ofatumumab | 33.19679 hours |
Secondary
Minimum Plasma Concentration (Cmin) of Ofatumumab
Minimum plasma drug concentration of ofatumumab was determined at Cycle 1-Day 8, Cycle 2-Day 29, Cycle 3-Day 57, Cycle 4-Day 85, Cycle 5-Day 113, and Cycle 6-Day 141. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr), Cycle 2-Day 29 (pre-dose), Cycle 3-Day 57 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr, 168 hr), Cycle 4-Day 85 (pre-dose, 30 min post end of infusion), Cycle 5-Day 113 (pre-dose and end of infusion) and Cycle 6-Day 141 (pre-dose and end of infusion).
Time frame: Cycle 1-Day 8, Cycle 2-Day 29, Cycle 3-Day 57, Cycle 4-Day 85, Cycle 5-Day 113, and Cycle 6-Day 141
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Minimum Plasma Concentration (Cmin) of Ofatumumab | Cycle 1-Day 8, n=6 | 1.8693 Micrograms/milliliter (µg/mL) |
| Ofatumumab + Chlorambucil | Minimum Plasma Concentration (Cmin) of Ofatumumab | Cycle 2-Day 29, n=4 | 73.0911 Micrograms/milliliter (µg/mL) |
| Ofatumumab + Chlorambucil | Minimum Plasma Concentration (Cmin) of Ofatumumab | Cycle 3-Day 57, n=5 | 57.8542 Micrograms/milliliter (µg/mL) |
| Ofatumumab + Chlorambucil | Minimum Plasma Concentration (Cmin) of Ofatumumab | Cycle 4-Day 85, n=4 | 82.1944 Micrograms/milliliter (µg/mL) |
| Ofatumumab + Chlorambucil | Minimum Plasma Concentration (Cmin) of Ofatumumab | Cycle 5-Day 113, n=4 | 98.3353 Micrograms/milliliter (µg/mL) |
| Ofatumumab + Chlorambucil | Minimum Plasma Concentration (Cmin) of Ofatumumab | Cycle 6-Day 141, n=4 | 82.9519 Micrograms/milliliter (µg/mL) |
Secondary
Number of Participants Who Were Positive or Negative for Minimal Residual Disease (MRD), as Assessed by IRC With CT
MRD refers to small number of leukemic cells that remain in the participant's body during treatment or after treatment in participants who achieved a confirmed complete remission. MRD assessment in bone marrow aspiration sample was perfrmed by flow cytometry (cluster of differentiation \[CD\]5, CD19, CD20, CD23). The absence of MRD was defined as less than one CLL cell per 10,000 leukocytes. The number of participants who were positive and negative for MRD are presented.
Time frame: FU 85-PDFU 85 (84 days after FU-1)
Population: All Subjects Population. Only those participants who were positive and negative for MRD were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Number of Participants Who Were Positive or Negative for Minimal Residual Disease (MRD), as Assessed by IRC With CT | Positive | 4 Participants |
| Ofatumumab + Chlorambucil | Number of Participants Who Were Positive or Negative for Minimal Residual Disease (MRD), as Assessed by IRC With CT | Negative | 4 Participants |
Secondary
Number of Participants With AEs of Maximum Severity
Adverse events were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) grade, version 4.03 (1=mild; 2=moderate; 3=severe; 4=life-threatening/disabling; 5=death). AEs not in the list of CTCAE were graded at discretion of the investigator.
Time frame: From start of treatment until follow-up for survival (up to Week 62.3)
Population: All Subjects Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Number of Participants With AEs of Maximum Severity | Any AE Grade 4 | 1 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With AEs of Maximum Severity | Any AE Grade 1 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With AEs of Maximum Severity | Any AE Grade 2 | 4 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With AEs of Maximum Severity | Any AE Grade 3 | 5 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With AEs of Maximum Severity | Any AE Grade 5 | 0 Participants |
Secondary
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed.
Time frame: From start of treatment until follow-up for survival (up to Week 62.3)
Population: All Subjects Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | Any AE | 10 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | Any SAE | 2 Participants |
Secondary
Number of Participants With CR, as Assessed by the IRC, IRC With CT, and the Investigator
Response was determined according to the IWCLL updated NCI-WG guidelines, 2008. According to the guidelines, CR (all the criteria at least 2 months after last treatment): peripheral blood lymphocytes below \< 4,000/μL, no Ly \> 1.5 cm/ hepatomegaly/ splenomegaly/ constitutional symptoms; Neu \>1500 /µL, PL \>100,000/µL, Hb \>11 g/dL, BM sample must be normocellular for age, \<30% lymphocytes, no LN. PR: \>=50% decrease in peripheral blood lymphocytes, Ly, size of liver and spleen; and blood count showing at least one of the following results: Neu\>1500/μL, PL \>100,000/µL or 50% improvement over BL, Hb \>11 g/dL or 50% improvement over BL. No increase in LN and no new LN.
Time frame: From start of treatment until disease progression or death (up to Week 62.3)
Population: All Subjects Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Number of Participants With CR, as Assessed by the IRC, IRC With CT, and the Investigator | IRC with CT Assessed, CR | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With CR, as Assessed by the IRC, IRC With CT, and the Investigator | IRC Assessed, CR | 1 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With CR, as Assessed by the IRC, IRC With CT, and the Investigator | Investigator Assessed, CR | 1 Participants |
Secondary
Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
ECOG PS is a scale to assess disease progression, extent to which disease affects the daily living abilities and determines appropriate treatment and prognosis. It is scored on a scale of 0 to 5 as, 0 (fully active), 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), 2 (ambulatory and capable of all self cares but unable to carry out any work activities, up and about \> 50% of waking hours), 3 (capable of only limited self cares, confined to bed or chair \> 50% of waking hours), 4 (completely disabled, cannot carry on any self cares, totally confined to bed or chair), 5 (death). Improvement is defined as decrease from Baseline by at least one step on the ECOG performance status scale (yes/no). Baseline was the last pre-dose assessment performed on Cycle 1-Day 1(C1-D1). When C1-D1 was missing, the last assessment performed prior to pre-dose C1-D1 was used. It was performed on Day 1 of each cycle and follow-up (FU).
Time frame: Baseline, C2-D29, C3-D57, C4-D85, C5-D113, C6-D141, C7-D169, C8-D197, C9 -D225, FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), FU 85-PDFU 85 (84 days after FU-1), and FU 169-PDFU 169 (168 days after FU-1)
Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 6-Day 141, No change, n=7 | 6 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 3-Day 57, Improved, n=8 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 4-Day 85, No change, n=7 | 7 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 5-Day 113, Deteriorated, n=7 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 8-Day 197, Deteriorated, n=2 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 9-Day 225, Deteriorated, n=2 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 2-Day 29, Improved, n=8 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 2-Day 29, No change, n=8 | 8 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 2-Day 29, Deteriorated, n=8 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 3-Day 57, No change, n=8 | 8 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 3-Day 57, Deteriorated, n=8 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 4-Day 85, Improved, n=7 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 4-Day 85, Deteriorated, n=7 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 5-Day 113, Improved, n=7 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 5-Day 113, No change, n=7 | 7 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 6-Day 141, Improved, n=7 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 6-Day 141, Deteriorated, n=7 | 1 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 7-Day 169, Improved, n=2 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 7-Day 169, No change, n=2 | 2 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 7-Day 169, Deteriorated, n=2 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 8-Day 197, Improved, n=2 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 8-Day 197, No change, n=2 | 2 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 9-Day 225, Improved, n=2 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Cycle 9-Day 225, No change, n=2 | 2 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | FU 1-PDFU 1, Improved, n=9 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | FU 1-PDFU 1, No change, n=9 | 9 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | FU 1-PDFU 1, Deteriorated, n=9 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | FU 85-PDFU 85, Improved, n=9 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | FU 85-PDFU 85, No change, n=9 | 8 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | FU 85-PDFU 85, Deteriorated, n=9 | 1 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | FU 169-PDFU 169, Improved, n=8 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | FU 169-PDFU 169, No change, n=8 | 8 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | FU 169-PDFU 169, Deteriorated, n=8 | 0 Participants |
Secondary
Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points
The number of participants with no B-symptoms (no night sweat \[without signs of infection\], no unexplained, unintentional weight loss \>= 10% within the previous 6 months, no recurrent, unexplained fever of greater than 38 degrees celcius for 2 weeks and no extreme fatigue) and the number of participants with at least one of the B-symptoms are summarized by assessment time. The presence of the B-symptoms was assessed at Baseline, Day 1 of each treatment cycle and follow-up (FU). Baseline was the last pre-dose assessment performed at Cycle (C) 1-Day (D) 1.
Time frame: Baseline, C2-D29, C3-D57, C4-D85, C5-D113, C6-D141, C7-D169, C8-D197, C9 -D225, FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), FU 85-PDFU 85 (84 days after FU-1), and FU 169-PDFU 169 (168 days after FU-1)
Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 9-Day 225, With no B-symptom, n=2 | 2 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 9-Day 225, With at least one B-symptom, n=2 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | FU 1-PDFU 1, With no B-symptom, n=9 | 9 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Baseline, With no B-symptom, n=10 | 9 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Baseline, With at least one B-symptom, n=10 | 1 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 2-Day 29, With no B-symptom, n=8 | 8 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 2-Day 29, With at least one B-symptom, n=8 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 3-Day 57, With no B-symptom, n=8 | 8 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 3-Day 57, With at least one B-symptom, n=8 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 4-Day 85, With no B-symptom, n=7 | 7 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 4-Day 85, With at least one B-symptom, n=7 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 5-Day 113, With no B-symptom, n=7 | 7 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 5-Day 113, With at least one B-symptom, n=7 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 6-Day 141, With no B-symptom, n=7 | 7 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 6-Day 141, With at least one B-symptom, n=7 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 7-Day 169, With no B-symptom, n=2 | 2 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 7-Day 169, With at least one B-symptom, n=2 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 8-Day 197, With no B-symptom, n=2 | 2 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | Cycle 8-Day 197, With at least one B-symptom, n=2 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | FU 1-PDFU 1, With at least one B-symptom, n=9 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | FU 85-PDFU 85, With no B-symptom, n=9 | 9 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | FU 85-PDFU 85, With at least one B-symptom, n=9 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | FU 169-PDFU 169, With no B-symptom, n=8 | 8 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points | FU 169-PDFU 169, With at least one B-symptom, n=8 | 0 Participants |
Secondary
Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events
Adverse events were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) grade, version 4.03 (1=mild; 2=moderate; 3=severe; 4=life-threatening/disabling; 5=death). AEs not in the list of CTCAE were graded at discretion of the investigator. Myelosuppression is defined as the decrease in the ability of the bone marrow to produce blood cells. Participants with Grade (G)3 or G4 adverse event of infection and myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented. Also presented are number of participants with autoimmune hemolytic anemia (AIHA). AIHA is a disease where the body's immune system fails to recognize red blood cells as self and begins destroying these red blood cells.
Time frame: From start of treatment until follow-up for survival (up to Week 62.3)
Population: All Subjects Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events | Neutropenia, G4 | 1 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events | Infections, G3 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events | Infections, G4 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events | Thrombocytopenia, G3 | 2 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events | Thrombocytopenia, G4 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events | Neutropenia, G3 | 2 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events | Anemia, G3 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events | Anemia, G4 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events | Autoimmune Hematologic Complication | 0 Participants |
Secondary
Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points
HAHA are indicators of immunogenicity induced by ofatumumab. Blood samples were taken from participants at Screening, Cycle 4-Day 85, FU 1-PDFU 1, and FU 169-PDFU 169. The presence of HAHA in human serum was determined using a validated electrochemiluminescent assay in a multi-tier assay format. The results are presented as participants with HAHA results as positive, negative or confirmation required.
Time frame: Screening, Cycle 4-Day 85, FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), and FU 169-PDFU 169 (168 days after FU-1)
Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points | Screening, Positive, n=10 | 1 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points | Screening, Negative, n=10 | 9 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points | Screening, Confirmation required, n=10 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points | Cycle 4-Day 85, Positive, n=7 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points | Cycle 4-Day 85, Negative, n=7 | 7 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points | Cycle 4-Day 85, Confirmation required, n=7 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points | FU 1-PDFU 1, Positive, n=10 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points | FU 1-PDFU 1, Negative, n=10 | 10 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points | FU 1-PDFU 1, Confirmation required, n=10 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points | FU 169-PDFU 169, Positive, n=8 | 0 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points | FU 169-PDFU 169, Negative, n=8 | 8 Participants |
| Ofatumumab + Chlorambucil | Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points | FU 169-PDFU 169, Confirmation required, n=8 | 0 Participants |
Secondary
Overall Survival
Overall survival is defined as time from start of treatment until death due to any cause. For participants who did not die, time to death was censored at the time of the last date of contact.
Time frame: From start of treatment until death (up to Week 62.3
Population: All Subjects Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ofatumumab + Chlorambucil | Overall Survival | NA Weeks |
Secondary
Plasma Half-life (t1/2) of Chlorambucil
t1/2 is the time required for the serum concentration of chlorambucil to decrease by half. Blood samples for serum concentration of chlorambucil was collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Plasma Half-life (t1/2) of Chlorambucil | Cycle 1-Day 1, n=6 | 1.06879 hours |
| Ofatumumab + Chlorambucil | Plasma Half-life (t1/2) of Chlorambucil | Cycle 1-Day 4, n=6 | 1.74766 hours |
| Ofatumumab + Chlorambucil | Plasma Half-life (t1/2) of Chlorambucil | Cycle 3-Day 57, n=5 | 1.38140 hours |
Secondary
Plasma Half-life (t1/2) of Ofatumumab
t1/2 is the time required for the plasma concentration of ofatumumab to decrease by half. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr) and Cycle 3-Day 57 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr, 168 hr).
Time frame: Cycle 1-Day 1 and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Plasma Half-life (t1/2) of Ofatumumab | Cycle 1-Day 1, n=6 | 33.69818 hours |
| Ofatumumab + Chlorambucil | Plasma Half-life (t1/2) of Ofatumumab | Cycle 3-Day 57, n=5 | 259.94722 hours |
Secondary
Plasma Half-life (t1/2) of Phenyl Acetic Acid Mustard
t1/2 is the time required for the plasma/serum concentration of phenylacetic acid mustard to decrease by half. Blood samples for serum concentration of phenylacetic acid mustard was collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Plasma Half-life (t1/2) of Phenyl Acetic Acid Mustard | Cycle 1-Day 1, n=6 | 2.11378 hours |
| Ofatumumab + Chlorambucil | Plasma Half-life (t1/2) of Phenyl Acetic Acid Mustard | Cycle 1-Day 4, n=6 | 2.52918 hours |
| Ofatumumab + Chlorambucil | Plasma Half-life (t1/2) of Phenyl Acetic Acid Mustard | Cycle 3-Day 57, n=5 | 2.11552 hours |
Secondary
Progression-free Survival (PFS), as Assessed by the IRC and the Investigator
Progression free survival is defined as the time from start of treatment until disease progression (PD) or death due to any cause. PD was determined by the IRC or investigator according to the definitions of response in the IWCLL updated NCI-WG guidelines, 2008. According to the guidelines, PD is characterized by at least one of the following: lymphadenopathy (appearance of any new lesion such as enlarged lymph nodes (\>1.5 centimeter \[cm\]), spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site); an increase by 50% or more in the previously noted enlargement of the liver or spleen; an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 per microliter B-lymphocytes; transformation to a more aggressive histology; or occurrence of cytopenia attributable to chronic lymphocytic leukemia. PFS was censored at the last visit with adequate assessment for participants who were alive and had not progressed.
Time frame: From start of treatment until disease progression or death (up to Week 62.3)
Population: All Subjects Population. Only participants who progressed or died were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Progression-free Survival (PFS), as Assessed by the IRC and the Investigator | IRC Assessed, Response, n=1 | NA Weeks |
| Ofatumumab + Chlorambucil | Progression-free Survival (PFS), as Assessed by the IRC and the Investigator | Investigator Assessed, Response, n=1 | NA Weeks |
Secondary
Time to Maximum Concentration (Tmax) of Chlorambucil
Tmax is the time required for reaching maximum concentration of drug (Cmax). Blood samples were collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Time to Maximum Concentration (Tmax) of Chlorambucil | Cycle 1-Day 4, n=6 | 1.9850 hours |
| Ofatumumab + Chlorambucil | Time to Maximum Concentration (Tmax) of Chlorambucil | Cycle 3-Day 57, n=5 | 3.0000 hours |
| Ofatumumab + Chlorambucil | Time to Maximum Concentration (Tmax) of Chlorambucil | Cycle 1-Day 1, n=6 | 2.9850 hours |
Secondary
Time to Maximum Concentration (Tmax) of Ofatumumab
Tmax is the time required for reaching maximum concentration of drug (Cmax). Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr) and Cycle 3-Day 57 (pre-dose, end of infusion, 10 min, 1 hr, 2 hr, 24 hr, 72 hr, 120 hr, 168 hr).
Time frame: Cycle 1-Day 1 and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Time to Maximum Concentration (Tmax) of Ofatumumab | Cycle 1-Day 1, n=6 | 7.5400 hours |
| Ofatumumab + Chlorambucil | Time to Maximum Concentration (Tmax) of Ofatumumab | Cycle 3-Day 57, n=5 | 5.3200 hours |
Secondary
Time to Maximum Concentration (Tmax) of Phenyl Acetic Acid Mustard
Tmax is the time required for reaching maximum concentration of drug (Cmax). Blood samples were collected at Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57. In each sampling, blood samples were collected at pre-dose, and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, and 10 hr.
Time frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ofatumumab + Chlorambucil | Time to Maximum Concentration (Tmax) of Phenyl Acetic Acid Mustard | Cycle 1-Day 1, n=6 | 3.9600 hours |
| Ofatumumab + Chlorambucil | Time to Maximum Concentration (Tmax) of Phenyl Acetic Acid Mustard | Cycle 1-Day 4, n=6 | 3.4150 hours |
| Ofatumumab + Chlorambucil | Time to Maximum Concentration (Tmax) of Phenyl Acetic Acid Mustard | Cycle 3-Day 57, n=5 | 3.9200 hours |
Secondary
Time to Next Chronic Lymphocytic Leukemia (CLL) Therapy
Time to next CLL therapy is defined as the time from start of treatment until the first administration of the next CLL treatment other than chlorambucil administrations scheduled in this study. Time to next CLL therapy was restricted to the subgroup of the population who receive a next CLL therapy after experiencing disease progression.
Time frame: From start of treatment until the first administration of the next CLL therapy (up to Week 62.3)
Population: All Subjects Population. Only those participants who received next CLL therapy were evaluated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ofatumumab + Chlorambucil | Time to Next Chronic Lymphocytic Leukemia (CLL) Therapy | 11.4 Weeks |
Secondary
Time to Response, as Assessed by the IRC
Time to response is defined as the time from start of treatment until the first response (CR/CRi/nPR/PR). Response was determined according to the IWCLL updated NCI-WG guidelines, 2008. This analysis only included participants who had a response while in the study, there was no censoring.
Time frame: From start of treatment until the first response (CR/CRi/nPR/PR) (up to Week 62.3)
Population: All Subjects Population. Only those participants classified as responders (CR, CRi, PR, nPR) were evaluated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ofatumumab + Chlorambucil | Time to Response, as Assessed by the IRC | 4.1 Weeks |
Secondary
Total Plasma Clearance (CL) of Ofatumumab
Plasma clearance is defined as the plasma volume which is totally cleared of drug per unit of time. Blood samples were collected at Cycle 1-Day1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr).
Time frame: Cycle 1-Day 1
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ofatumumab + Chlorambucil | Total Plasma Clearance (CL) of Ofatumumab | 172.64451 Milliliters/hour (mL/hr) |
Secondary
Volume of Distribution at Steady State (Vss) of Ofatumumab
Volume of distribution at steady state (Vss) is defined as the distribution of a drug between plasma and the rest of the body at steady state. Samples were collected at Cycle 1-Day1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr).
Time frame: Cycle 1-Day 1
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ofatumumab + Chlorambucil | Volume of Distribution at Steady State (Vss) of Ofatumumab | 5731.24330 mL |
Secondary
Volume of Distribution (Vz) of 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. Samples were collected at Cycle 1-Day 1 (pre-dose, end of infusion, 10 min, 1hr, 2 hr, 24 hr, 72 hr, 120 hr).
Time frame: Cycle 1-Day 1
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ofatumumab + Chlorambucil | Volume of Distribution (Vz) of Ofatumumab | 8393.31979 mL |