Back to resultsA Phase II Trial of Ofatumumab in Subjects With Waldenstrom's Macroglobulinemia
Primary Purpose
Waldenstrom Macroglobulinaemia
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Ofatumumab
Sponsored by
About this trial
This is an interventional treatment trial for Waldenstrom Macroglobulinaemia focused on measuring Waldenstrom's Macroglobulinemia, Ofatumumab
Eligibility Criteria
Inclusion Criteria:
- Confirmed and active Waldenstrom's Macroglobulinemia requiring treatment.
- Ambulatory and capable of all selfcare. Up and about more than 50% of waking hours.
- Adequate organ function.
- Detectable CD20 positive of the tumor cells.
- Measurable disease as defined by a monoclonal IgM paraprotein level greater than 1000 mg/dL.
Exclusion Criteria:
- Treatment of WM within the past 28 days.
- Treatment with rituximab or alemtuzamab within the past 3 months.
- Certain heart problems, chronic or current active infection not controlled with oral antibiotics, other current cancer or within last 5 years.
- Current participation in another interventional clinical study.
- Lactating or pregnant women or female patients of child-bearing potential (or male patients with such partners) not willing to use adequate contraception.
- Active cerebrovascular disease.
Sites / Locations
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Ofatumumab
Arm Description
Ofatumumab is a fully human antibody, targeting a unique epitope on the CD20 molecule expressed on human B cells.
Outcomes
Primary Outcome Measures
Number of Participants With Overall Response (OR) for Cycle 1 (Including the Redosing Cycle), as Assessed by the Investigator
OR (based on the Consensus Panel recommendations from the 2nd and 3rd International Workshop on WM) included Complete Response (CR), Partial Response (PR), or a Minor Response (MR). CR: Complete disappearance of serum monoclonal (SM) Immunoglobulin (Ig) E (IgE), measured centrally; resolution of adenopathy/organomegaly upon physical exam and computerized tomography (CT) scan; lymph nodes =<1.5 centimeters; absence of malignant cell by bone marrow histologic examination. PR: a >=50% reduction from baseline in the SM IgM concentration. MR: >=25%, but a <50% reduction of SM IgM from baseline.
Number of Participants With OR for Cycle 1 (Excluding the Redosing Cycle), as Assessed by the Investigator
OR (based on the Consensus Panel recommendations from the 2nd and 3rd International Workshop on WM) included Complete Response (CR), Partial Response (PR), or a Minor Response (MR). CR: Complete disappearance of serum monoclonal (SM) Immunoglobulin (Ig) E (IgE), measured centrally; resolution of adenopathy/organomegaly upon physical exam and computerized tomography (CT) scan; lymph nodes =<1.5 centimeters; absence of malignant cell by bone marrow histologic examination. PR: a >=50% reduction from baseline in the SM IgM concentration. MR: >=25%, but a <50% reduction of SM IgM from baseline.
Secondary Outcome Measures
Number of Participants With CR, PR, and MR for Cycle 1 (Including the Redosing Cycle), as Assessed by the Investigator
Response criteria were based on the Consensus Panel recommendations from the 2nd and 3rd International Workshop on WM. CR: Complete disappearance of serum monoclonal (SM) Immunoglobulin (Ig) E (IgE), measured centrally; resolution of adenopathy/organomegaly upon physical exam and computerized tomography (CT) scan; lymph nodes =<1.5 centimeters; absence of malignant cell by bone marrow histologic examination. PR: a >=50% reduction from baseline in the SM IgM concentration. MR: >=25%, but a <50% reduction of SM IgM from baseline.
Number of Participants With CR, PR, and MR for Cycle 1 (Excluding the Redosing Cycle), as Assessed by the Investigator
Response criteria were based on the Consensus Panel recommendations from the 2nd and 3rd International Workshop on WM. CR: Complete disappearance of serum monoclonal (SM) Immunoglobulin (Ig) E (IgE), measured centrally; resolution of adenopathy/organomegaly upon physical exam and computerized tomography (CT) scan; lymph nodes =<1.5 centimeters; absence of malignant cell by bone marrow histologic examination. PR: a >=50% reduction from baseline in the SM IgM concentration. MR: >=25%, but a <50% reduction of SM IgM from baseline.
Number of Participants With IgM Flare for Cycle 1 Response (Including the Redosing Cycle)
IgM is a basic antibody that is produced by B cells. It is the first antibody to appear in response to initial exposure to antigen. IgM flare is defined as an IgM level that increases by >25% from baseline (BL) and is associated with a response to treatment. Avoidance of IgM flare indicates the lack of an increase in IgM of >25% from BL.
Duration of Response for All Responders (CR, PR, MR), as Assessed by the Investigator
Duration of response is defined as the time from the initial response to relapse/disease progression (DP) or death. DP for CR is defined as the reappearance of the IgM protein, new signs/symptoms attributable to WM, evidence of active disease or recurrence of bone marrow involvement by lymphoplasmacytic cells, or the appearance of any new lymph node >=1.5 centimeters on any axis. Progression for PR/MR is either a >=25% increase in IgM from the lowest attained response value or progression of lymphadenopathy, organomegaly, cytopenias, or other clinically significant signs/symptoms caused by WM.
Progression-free Survival
Time to disease progression is defined as the time from baseline to disease progression or death.
Time to Response for Responders
Time to response is defined as the time from baseline to the first response date.
Overall Survival
Overall survival is defined as the time from baseline until death due to any cause.
Clearance of Ofatumumab
Clearance (CL) is defined as the volume of plasma that is cleared of drug per unit of time. Blood samples for the quantification of ofatumumab were collected during each cycle and for up to 6 months after the end of each cycle.
Volume of Distribution at Steady State of Ofatumumab
Volume of distribution at steady state (Vss) is defined as the apparent volume of distribution of the drug in the body at steady state. Blood samples for the quantification of ofatumumab were collected during each cycle and for up to 6 months after the end of each cycle.
Half-life of Ofatumumab
Half-life (t½) is defined as the time required for the concentration of the drug in plasma to decrease to one-half of its current value. Blood samples for the quantification of ofatumumab were collected during each cycle and for up to 6 months after the end of each cycle.
Cmax and Ctrough of Ofatumumab
Cmax is defined as the maximum observed drug concentration after administration, and Ctrough is defined as the drug concentration observed prior to the start of the next dose. Blood samples for the quantification of ofatumumab were collected during each cycle and for up to 6 months after the end of each cycle.
AUC(0-tau) and AUC(0-inf) of Ofatumumab
AUC(0-tau) is the area under the drug concentration-time curve over the dosing interval (one week). AUC(0-inf) is the area under the drug concentration-time curve from time zero extrapolated to infinite time. Blood samples for the quantification of ofatumumab were collected during each cycle and for up to 6 months after the end of each cycle.
Number of Participants With at Least One Confirmed Positive Post-ofatumumab HAHA Result
All human-antihuman antibody (HAHA) samples were first tested in a screening assay to identify potential HAHA positives. Next, samples that tested positive in the screening assay were further tested in the confirmation assay to determine the specificity of the signal to ofatumumab. Confirmed positive samples were reported as positive.
Change From Baseline in Blood Counts (CD4+, CD19+, CD50) at Month 3 After Treatment
CD4+ and CD19+ are two key flow cytometry parameters, and total hemolytic complement (CD50) is a complement parameter. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Number of Participants With the Indicated SAEs Related to Study Drug
An SAE is any event occurring at any dose that results in any of the following: death, a life-threatening adverse drug experience (ADE; at immediate risk of death from the experience as it occurred), inpatient hospitalization/prolongation of existing hospitalization, a persistent/significant disability/incapacity, or a congenital anomaly/birth defect. Medical events that may not result in death, be life threatening, or require hospitalization may be considered to be a serious ADEs when based upon appropriate medical judgment. Relatedness was based on the Investigator's medical judgement.
Number of Participants With the Indicated SAEs and Non-serious AEs Related to Study Drug
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The Investigator assessed whether the AE was possibly or probably related to study drug.
Number of Participants With the Indicated AEs Leading to Permanent Discontinuation of Study Drug and Withdrawal From Study
Certain AEs led to permanent discontinuation of study drug and hence resulted in their withdrawal from the study.
Number of Participants With the Indicated >=Grade 3 AEs
AEs were graded using the Common Toxicity Criteria for AEs from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No AE or within normal limits; 1 = Mild AE; 2 = Moderate AE; 3 = Severe and undesirable AE; 4 = Life-threatening or disabling AE; 5 = Death related to AE.
Number of Participants With the Indicated Infusion-related >=Grade 3 AE
Infusion-related AEs are the AEs that resulted from administration of study drug through infusion. AEs were graded using the Common Toxicity Criteria for AEs from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No AE or within normal limits; 1 = Mild AE; 2 = Moderate AE; 3 = Severe and undesirable AE; 4 = Life-threatening or disabling AE; 5 = Death related to AE.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00811733
Brief Title
A Phase II Trial of Ofatumumab in Subjects With Waldenstrom's Macroglobulinemia
Official Title
A Phase II Trial of Ofatumumab in Subjects With Waldenstrom's Macroglobulinemia
Study Type
Interventional
2. Study Status
Record Verification Date
March 2015
Overall Recruitment Status
Completed
Study Start Date
March 1, 2009 (undefined)
Primary Completion Date
June 1, 2011 (Actual)
Study Completion Date
February 1, 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Given the tolerability and efficacy of ofatumumab in follicular lymphoma and Chronic Lymphocytic Leukemia, and the need to improve therapy for patients with WM utilizing a non-myelosuppressive agent this phase II trial of ofatumumab is being initiated in patients with Waldenstrom's Macroglobulinemia (WM).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Waldenstrom Macroglobulinaemia
Keywords
Waldenstrom's Macroglobulinemia, Ofatumumab
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
37 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Ofatumumab
Arm Type
Experimental
Arm Description
Ofatumumab is a fully human antibody, targeting a unique epitope on the CD20 molecule expressed on human B cells.
Intervention Type
Biological
Intervention Name(s)
Ofatumumab
Intervention Description
Ofatumumab is a fully human antibody, targeting a unique epitope on the CD20 molecule expressed on human B cells.
Primary Outcome Measure Information:
Title
Number of Participants With Overall Response (OR) for Cycle 1 (Including the Redosing Cycle), as Assessed by the Investigator
Description
OR (based on the Consensus Panel recommendations from the 2nd and 3rd International Workshop on WM) included Complete Response (CR), Partial Response (PR), or a Minor Response (MR). CR: Complete disappearance of serum monoclonal (SM) Immunoglobulin (Ig) E (IgE), measured centrally; resolution of adenopathy/organomegaly upon physical exam and computerized tomography (CT) scan; lymph nodes =<1.5 centimeters; absence of malignant cell by bone marrow histologic examination. PR: a >=50% reduction from baseline in the SM IgM concentration. MR: >=25%, but a <50% reduction of SM IgM from baseline.
Time Frame
Baseline and up to 27 months from the first dose of Cycle 1 (Study Day 1), and before Cycle 2 treatment
Title
Number of Participants With OR for Cycle 1 (Excluding the Redosing Cycle), as Assessed by the Investigator
Description
OR (based on the Consensus Panel recommendations from the 2nd and 3rd International Workshop on WM) included Complete Response (CR), Partial Response (PR), or a Minor Response (MR). CR: Complete disappearance of serum monoclonal (SM) Immunoglobulin (Ig) E (IgE), measured centrally; resolution of adenopathy/organomegaly upon physical exam and computerized tomography (CT) scan; lymph nodes =<1.5 centimeters; absence of malignant cell by bone marrow histologic examination. PR: a >=50% reduction from baseline in the SM IgM concentration. MR: >=25%, but a <50% reduction of SM IgM from baseline.
Time Frame
Baseline and up to Study Week 16
Secondary Outcome Measure Information:
Title
Number of Participants With CR, PR, and MR for Cycle 1 (Including the Redosing Cycle), as Assessed by the Investigator
Description
Response criteria were based on the Consensus Panel recommendations from the 2nd and 3rd International Workshop on WM. CR: Complete disappearance of serum monoclonal (SM) Immunoglobulin (Ig) E (IgE), measured centrally; resolution of adenopathy/organomegaly upon physical exam and computerized tomography (CT) scan; lymph nodes =<1.5 centimeters; absence of malignant cell by bone marrow histologic examination. PR: a >=50% reduction from baseline in the SM IgM concentration. MR: >=25%, but a <50% reduction of SM IgM from baseline.
Time Frame
Baseline and up to 27 months from the first dose of Cycle 1 (Study Day 1), and before Cycle 2 treatment
Title
Number of Participants With CR, PR, and MR for Cycle 1 (Excluding the Redosing Cycle), as Assessed by the Investigator
Description
Response criteria were based on the Consensus Panel recommendations from the 2nd and 3rd International Workshop on WM. CR: Complete disappearance of serum monoclonal (SM) Immunoglobulin (Ig) E (IgE), measured centrally; resolution of adenopathy/organomegaly upon physical exam and computerized tomography (CT) scan; lymph nodes =<1.5 centimeters; absence of malignant cell by bone marrow histologic examination. PR: a >=50% reduction from baseline in the SM IgM concentration. MR: >=25%, but a <50% reduction of SM IgM from baseline.
Time Frame
Baseline and up to Study Week 16
Title
Number of Participants With IgM Flare for Cycle 1 Response (Including the Redosing Cycle)
Description
IgM is a basic antibody that is produced by B cells. It is the first antibody to appear in response to initial exposure to antigen. IgM flare is defined as an IgM level that increases by >25% from baseline (BL) and is associated with a response to treatment. Avoidance of IgM flare indicates the lack of an increase in IgM of >25% from BL.
Time Frame
Baseline and up to 27 months from the first dose of Cycle 1 (Study Day 1), and before Cycle 2 treatment
Title
Duration of Response for All Responders (CR, PR, MR), as Assessed by the Investigator
Description
Duration of response is defined as the time from the initial response to relapse/disease progression (DP) or death. DP for CR is defined as the reappearance of the IgM protein, new signs/symptoms attributable to WM, evidence of active disease or recurrence of bone marrow involvement by lymphoplasmacytic cells, or the appearance of any new lymph node >=1.5 centimeters on any axis. Progression for PR/MR is either a >=25% increase in IgM from the lowest attained response value or progression of lymphadenopathy, organomegaly, cytopenias, or other clinically significant signs/symptoms caused by WM.
Time Frame
From baseline up to approximately 5 years
Title
Progression-free Survival
Description
Time to disease progression is defined as the time from baseline to disease progression or death.
Time Frame
From baseline up to approximately 5 years
Title
Time to Response for Responders
Description
Time to response is defined as the time from baseline to the first response date.
Time Frame
From baseline up to approximately 5 years
Title
Overall Survival
Description
Overall survival is defined as the time from baseline until death due to any cause.
Time Frame
From baseline up to approximately 5 years
Title
Clearance of Ofatumumab
Description
Clearance (CL) is defined as the volume of plasma that is cleared of drug per unit of time. Blood samples for the quantification of ofatumumab were collected during each cycle and for up to 6 months after the end of each cycle.
Time Frame
From the first dose (Cycle 1 Day 1) up to 6 months after the end of the last cycle of treatment; blood collected on each dosing day, weekly up to Week 8, and every 4 weeks up to Week 24/Month 7
Title
Volume of Distribution at Steady State of Ofatumumab
Description
Volume of distribution at steady state (Vss) is defined as the apparent volume of distribution of the drug in the body at steady state. Blood samples for the quantification of ofatumumab were collected during each cycle and for up to 6 months after the end of each cycle.
Time Frame
From the first dose (Cycle 1 Day 1) up to 6 months after the end of the last cycle of treatment; blood collected on each dosing day, weekly up to Week 8, and every 4 weeks up to Week 24/Month 7
Title
Half-life of Ofatumumab
Description
Half-life (t½) is defined as the time required for the concentration of the drug in plasma to decrease to one-half of its current value. Blood samples for the quantification of ofatumumab were collected during each cycle and for up to 6 months after the end of each cycle.
Time Frame
From the first dose (Cycle 1 Day 1) up to 6 months after the end of the last cycle of treatment; blood collected on each dosing day, weekly up to Week 8, and every 4 weeks up to Week 24/Month 7
Title
Cmax and Ctrough of Ofatumumab
Description
Cmax is defined as the maximum observed drug concentration after administration, and Ctrough is defined as the drug concentration observed prior to the start of the next dose. Blood samples for the quantification of ofatumumab were collected during each cycle and for up to 6 months after the end of each cycle.
Time Frame
From the first dose (Cycle 1 Day 1) up to 6 months after the end of the last cycle of treatment; blood collected on each dosing day, weekly up to Week 8, and every 4 weeks up to Week 24/Month 7
Title
AUC(0-tau) and AUC(0-inf) of Ofatumumab
Description
AUC(0-tau) is the area under the drug concentration-time curve over the dosing interval (one week). AUC(0-inf) is the area under the drug concentration-time curve from time zero extrapolated to infinite time. Blood samples for the quantification of ofatumumab were collected during each cycle and for up to 6 months after the end of each cycle.
Time Frame
From the first dose (Cycle 1 Day 1) up to 6 months after the end of the last cycle of treatment; blood collected on each dosing day, weekly up to Week 8, and every 4 weeks up to Week 24/Month 7
Title
Number of Participants With at Least One Confirmed Positive Post-ofatumumab HAHA Result
Description
All human-antihuman antibody (HAHA) samples were first tested in a screening assay to identify potential HAHA positives. Next, samples that tested positive in the screening assay were further tested in the confirmation assay to determine the specificity of the signal to ofatumumab. Confirmed positive samples were reported as positive.
Time Frame
From baseline up to approximately 5 years
Title
Change From Baseline in Blood Counts (CD4+, CD19+, CD50) at Month 3 After Treatment
Description
CD4+ and CD19+ are two key flow cytometry parameters, and total hemolytic complement (CD50) is a complement parameter. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time Frame
Baseline and Month 3
Title
Number of Participants With the Indicated SAEs Related to Study Drug
Description
An SAE is any event occurring at any dose that results in any of the following: death, a life-threatening adverse drug experience (ADE; at immediate risk of death from the experience as it occurred), inpatient hospitalization/prolongation of existing hospitalization, a persistent/significant disability/incapacity, or a congenital anomaly/birth defect. Medical events that may not result in death, be life threatening, or require hospitalization may be considered to be a serious ADEs when based upon appropriate medical judgment. Relatedness was based on the Investigator's medical judgement.
Time Frame
From baseline up to approximately 5 years
Title
Number of Participants With the Indicated SAEs and Non-serious AEs Related to Study Drug
Description
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The Investigator assessed whether the AE was possibly or probably related to study drug.
Time Frame
From baseline up to approximately 5 years
Title
Number of Participants With the Indicated AEs Leading to Permanent Discontinuation of Study Drug and Withdrawal From Study
Description
Certain AEs led to permanent discontinuation of study drug and hence resulted in their withdrawal from the study.
Time Frame
From baseline up to approximately 5 years
Title
Number of Participants With the Indicated >=Grade 3 AEs
Description
AEs were graded using the Common Toxicity Criteria for AEs from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No AE or within normal limits; 1 = Mild AE; 2 = Moderate AE; 3 = Severe and undesirable AE; 4 = Life-threatening or disabling AE; 5 = Death related to AE.
Time Frame
From baseline up to approximately 5 years
Title
Number of Participants With the Indicated Infusion-related >=Grade 3 AE
Description
Infusion-related AEs are the AEs that resulted from administration of study drug through infusion. AEs were graded using the Common Toxicity Criteria for AEs from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No AE or within normal limits; 1 = Mild AE; 2 = Moderate AE; 3 = Severe and undesirable AE; 4 = Life-threatening or disabling AE; 5 = Death related to AE.
Time Frame
From baseline up to approximately 5 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Confirmed and active Waldenstrom's Macroglobulinemia requiring treatment.
Ambulatory and capable of all selfcare. Up and about more than 50% of waking hours.
Adequate organ function.
Detectable CD20 positive of the tumor cells.
Measurable disease as defined by a monoclonal IgM paraprotein level greater than 1000 mg/dL.
Exclusion Criteria:
Treatment of WM within the past 28 days.
Treatment with rituximab or alemtuzamab within the past 3 months.
Certain heart problems, chronic or current active infection not controlled with oral antibiotics, other current cancer or within last 5 years.
Current participation in another interventional clinical study.
Lactating or pregnant women or female patients of child-bearing potential (or male patients with such partners) not willing to use adequate contraception.
Active cerebrovascular disease.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline
Official's Role
Study Director
Facility Information:
Facility Name
GSK Investigational Site
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095-6984
Country
United States
Facility Name
GSK Investigational Site
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
GSK Investigational Site
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
GSK Investigational Site
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
GSK Investigational Site
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
GSK Investigational Site
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210-1228
Country
United States
Facility Name
GSK Investigational Site
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
27914971
Citation
Furman RR, Eradat HA, DiRienzo CG, Hofmeister CC, Hayman SR, Leonard JP, Coleman M, Advani R, Chanan-Khan A, Switzky J, Liao QM, Shah D, Jewell RC, Lisby S, Lin TS. Once-weekly ofatumumab in untreated or relapsed Waldenstrom's macroglobulinaemia: an open-label, single-arm, phase 2 study. Lancet Haematol. 2017 Jan;4(1):e24-e34. doi: 10.1016/S2352-3026(16)30166-1. Epub 2016 Dec 1.
Results Reference
derived
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A Phase II Trial of Ofatumumab in Subjects With Waldenstrom's Macroglobulinemia
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