A Phase I/II, Open-label Study of Ofatumumab Added to Chlorambucil in Previously Untreated Japanese Patients With Chronic Lymphocytic Leukemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01563055
First received: March 15, 2012
Last updated: July 16, 2015
Last verified: July 2015
  Purpose

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).


Condition Intervention Phase
Leukaemia, Lymphocytic, Chronic
Drug: chlorambucil, tablets
Drug: ofatumumab (GSK1841157) infusion
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II, Open-label Study of Ofatumumab Added to Chlorambucil in Previously Untreated Japanese Patients With Chronic Lymphocytic Leukemia

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Participants Who Developed Toxicity Requiring Discontinuation From Study Treatment During Cycle 1 [ Time Frame: From start of treatment through Cycle 1 (Week 4) ] [ Designated as safety issue: No ]
    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 [ Time Frame: From start of treatment until disease progression or death (up to Week 62.3) ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Number of Participants With CR, as Assessed by the IRC, IRC With CT, and the Investigator [ Time Frame: From start of treatment until disease progression or death (up to Week 62.3) ] [ Designated as safety issue: No ]
    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.

  • Progression-free Survival (PFS), as Assessed by the IRC and the Investigator [ Time Frame: From start of treatment until disease progression or death (up to Week 62.3) ] [ Designated as safety issue: No ]
    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.

  • Overall Survival [ Time Frame: From start of treatment until death (up to Week 62.3 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From start of treatment until the first response (CR/CRi/nPR/PR) (up to Week 62.3) ] [ Designated as safety issue: No ]
    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 [ Time Frame: From initial response (CR/CRi/nPR/PR) until disease progression or death (up to Week 62.3) ] [ Designated as safety issue: No ]
    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 [ Time Frame: From start of treatment until the first administration of the next CLL therapy (up to Week 62.3) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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) [ 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) ] [ Designated as safety issue: No ]
    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) [ Time Frame: From start of treatment until follow-up for survival (up to Week 62.3) ] [ Designated as safety issue: No ]
    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 [ Time Frame: From start of treatment until follow-up for survival (up to Week 62.3) ] [ Designated as safety issue: No ]
    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 [ Time Frame: From start of treatment until follow-up for survival (up to Week 62.3) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ Time Frame: FU 85-PDFU 85 (84 days after FU-1) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1 and Cycle 4-Day 85 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1 and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 4 and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 4 and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1 and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1 and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1 and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1 ] [ Designated as safety issue: No ]
    %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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    %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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    %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 [ Time Frame: Cycle 1-Day 1 and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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.

  • AUC (0-t) of Phenyl Acetic Acid Mustard [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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.

  • Dose Normalized Cmax (Cmax/D) for Chlorambucil [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57 ] [ Designated as safety issue: No ]
    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.


Enrollment: 10
Study Start Date: April 2012
Study Completion Date: November 2014
Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ofatumumab + chlorambucil
ofatumumab dose: cycle 1 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1 every 28 days; chlorambucil dose: 10mg/m2 PO at days 1-7 every 28 days; duration: minimum of 3 cycles until best response or maximum of 12 treatment cycles
Drug: chlorambucil, tablets
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
Drug: ofatumumab (GSK1841157) infusion
iv infusion; dose: cycle 1 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1 every 28 days;

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.

  Eligibility

Ages Eligible for Study:   20 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of CLL defined by : Circulating B lymphocytes ≥5,000 /μL AND Flow cytometry confirmation of immunophenotype with CD5, CD19, CD20, and CD23 prior to Visit 2.
  • Considered inappropriate for fludarabine-based therapy
  • Active disease and indication for treatment based on 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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01563055

Locations
Japan
GSK Investigational Site
Aichi, Japan, 466-8650
GSK Investigational Site
Hokkaido, Japan, 060-8543
GSK Investigational Site
Kanagawa, Japan, 259-1143
GSK Investigational Site
Kyoto, Japan, 602-8566
GSK Investigational Site
Tokyo, Japan, 104-0045
GSK Investigational Site
Tokyo, Japan, 135-8550
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01563055     History of Changes
Other Study ID Numbers: 115601
Study First Received: March 15, 2012
Results First Received: May 28, 2015
Last Updated: July 16, 2015
Health Authority: Japan: Pharmaceuticals and Medical Devices Agency

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Immune System Diseases
Immunoproliferative Disorders
Leukemia, B-Cell
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Chlorambucil
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on August 31, 2015