A Phase 3 interventional study of Ofatumumab and Observation in Leukaemia, Lymphocytic, Chronic, sponsored by Novartis Pharmaceuticals. Terminated at 203 sites in 25 countries. Per ClinicalTrials.gov, last updated 2019-07-30.
Sponsored by Novartis Pharmaceuticals · Phase 3, Interventional, and Treatment
The purpose of this study was to determine if maintenance therapy with ofatumumab would prolong remission in patients with CLL who have responded to second or third line treatment. This study would also evaluate the safety of ofatumumab maintenance compared to observation (the current standard of care). This study was co-developed with the HOVON and NORDIC CLL group and would be conducted as a collaborative effort with GSK.
The study met its primary objective at the protocol defined interim analysis (data cut-off 19-Jun-2014). The protocol-defined final analysis of the primary endpoint was performed when 280 PFS events were reached (data cut-off 20-Feb-2017).
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Exclusion Criteria:
300 mg IV Week 1 followed by 1000 mg IV Week 2 1000 mg IV (a dose every 8 weeks for up to 2 years following the first 1000 mg dose)
Biological: Ofatumumab
Disease status assessments to determine subject response or progression performed approximately every 8 weeks for up to 2 years for both arms according to IWCLL criteria
Other: Observation
Ofatumumab for maintenance therapy as IV infusions every 8 weeks . The first dose was 300 mg followed 1 week later by 1000 mg and 1000 mg every 8 weeks thereafter for up to 2 years.
Observation/Safety Evaluation
Progression-free Survival, as Assessed by the Investigator
Progression-free survival is defined as the time from randomization to the date of disease progression (PD) or death due to any cause. PD was determined by the investigator according to the definitions of response in the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-Sponsored Working Group (NCI-WG) guidelines. 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 lymphocytes per microliter; transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukemia.
Time frame: From randomization until progression or death (up to 79 months)
Progression-free Survival, as Assessed by the Independent Review Committee (IRC)
Progression-free survival is defined as the time from randomization to the date of disease progression (PD) or death due to any cause. PD was determined by the IRC according to the definitions of response in the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-Sponsored Working Group (NCI-WG) guidelines. 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 lymphocytes per microliter; transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukemia.
Time frame: From randomization until progression or death (up to 79 months)
Overall Survival
Overall survival is defined as time from randomization to date of death.
Time frame: From randomization until death (up to 88 months)
Number of Participants With Improvement in Response From Baseline
Improvement in response was assessed by calculating the percentage of participants who changed from partial response (PR) at Baseline to complete response during the study.
Time frame: From Baseline until the end of the study (up to 88 months)
Time to Next Therapy
Time to next therapy is defined as the time from randomization to the date of receiving the next CLL treatment.
Time frame: From randomization until the end of the study (up to 88 months)
Progression-free Survival After Next-line Therapy
Progression-free survival after next-line therapy is defined as the time from randomization until progression or death following the next-line therapy and counted as events deaths prior to next-line therapy. Participants who received next-line therapy and who did not have progression or death after next-line therapy were censored at their last date of contact. Participant who died prior to next-line therapy, was counted as an event.
Time frame: From randomization until progression or death (up to 88 months)
Time to Progression After Next-line Therapy
Time to progression after next-line therapy is defined as the time from progression following randomization until progression or death following next-line therapy and counted as events deaths prior to next-line therapy. Participants who received next-line therapy with a PD prior to receiving next line therapy and who did not had progression or death after next-line therapy were censored at their last date of contact. If a participant died prior to next-line therapy, this was counted as an event.
Time frame: From randomization until progression or death (up to 88 months)
Change From Baseline (BL) in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Chronic Lymphocytic Leukaemia 16 Item Module (EORTC QLQ-CLL 16)
The EORTC QLQ-CLL16 is comprised of 16 questions that address 5 domains of health-related quality of life (HRQoL) important in CLL. There are 4 multi-item scales - fatigue (2 items), treatment side effects (\[TSE\], 4 items), disease symptoms (disease effects scale \[DES\], 4 items), and infection (4 items) - and single-item scales (social activities \[Social Problems (SP) Scale\] and future health worries \[Future Health (FH) Scale\]). These are measured on a four-point Likert scale, where 1 = not at all and 4 = very much. These scores are transformed to give a rating from 0 - 100, where 0 = no symptoms or problems and 100 = severe symptoms or problems. Changes from Baseline were analyzed by a mixed model-repeated measures analysis of covariance (ANCOVA).
Time frame: From randomization until the end of the study (up to 47 months)
Change From Baseline in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score
The EORTC QLQ-C30 is a self-reported, 30-item cancer-specific instrument that assesses 15 domains: physical functioning (5 items), role functioning (2 items), emotional functioning (4 items), cognitive functioning (2 items), social functioning (2 items), pain (2 items), fatigue (3 items), nausea and vomiting (2 items), five single-item symptom scores (insomnia, loss of appetite, constipation, diarrhea, and dyspnea), a single item asking about financial difficulties, and global health status/quality of life (QOF) consisting of 2 items. Functional and symptoms scales were measured on a four-point Likert scale, where 1 = not at all and 4 = very much, whereas global health status or QOF was assessed using a 7-item Likert scale, ranging from "poor" (worse quality of life) to "excellent" (better quality of life). Changes from Baseline were analyzed by mixed model-repeated measures ANCOVA.
Time frame: From randomization until the end of the study (up to 47 months)
Change From Baseline in the Quality of Life Status as Assessed by the EuroQol-5D (EQ-5D) Scale
EQ-5D is comprised of a 5-item health status measure and a visual analogue scale (VAS) and is used to generate two scores: the utility score and the thermometer score. The utility score measures mobility, self-care, usual activities, pain, discomfort, and anxiety/depression. Responses to each of the 5 health states are measured on a 3-point scale (level 1 = no problem; level 2 = some or moderate problem\[s\] and level 3 = unable, or extreme problems). Responses are typically converted into health utilities or valuations on a scale ranging from 0 (worst health) to 1 (perfect health). The thermometer score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Changes from Baseline were analyzed by mixed model-repeated measures ANCOVA. A negative adjusted mean change from Baseline represents a worsening of quality of life.
Time frame: From screening until the end of the study (up to 47 months)
Number of Participants With an Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status at the Indicated Time Points
Improvement is defined as a decrease from Baseline by at least one step on the ECOG performance status scale (improvement categorized as yes or no). Improvement in ECOG performance status was measured.
Time frame: From randomization until the end of the study (up to 88 months)
Number of Participants With the Indicated Constitutional or B-symptoms at the Indicated Time Points
Participants with the indicated constitutional or B-symptoms (night sweats \[without signs of infection\]; unintentional weight loss \>= 10% within the previous 6 months; recurrent, unexplained fever of \> 38 degrees celcius or 100.5 degrees fahrenheit for 2 weeks; and extreme fatigue) were presented. The proportion of participants with no night sweats, no weight loss, no fever and no extreme fatigue were summarized.
Time frame: From Screening until the end of the study (up to 88 months)
Number of Participants With Grade 3 and Above Adverse Event of Infection
Participants with Grade 3, Grade 4 and Grade 5 adverse event of infection are presented. Adverse events were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) grade, version 4.0 (1=mild; 2=moderate; 3=severe; 4=life-threatening/disabling; 5=death).
Time frame: From first dose of study medication until 60 days after the last dose of study medication or until the last observation at Visit 14 (up to 26 months)
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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.
Time frame: From first dose of study medication until 60 days after the last dose of study medication or until the last observation at Visit 14 for AEs (up to 26 months) and until end of study for SAEs (88 months)
Number of Participants With a Grade 3 or Grade 4 Myelosuppression (Anemia, Neutropenia, or Thrombocytopenia) at Indicated Time Points
Myelosuppression is defined as the decrease in the ability of the bone marrow to produce blood cells. Number of participants who reported myelosuppression (anemia \[low hemoglobin count\], neutropenia \[low neutrophil count\], and thrombocytopenia \[low platelet count\]) are presented. AEs were graded according to NCI common terminology criteria for adverse events (CTCAE) grade, version 4.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).
Time frame: From first dose of study medication until 60 days after the last dose of study medication or until the last observation at Visit 14 for AEs (up to 26 months) and until the end of the study for SAEs (88 months)
Number of Participants Who Received at Least One Transfusion During the Study
Participants who received at least one transfusion (any blood products or blood supportive care product) during the study are presented.
Time frame: From randomization until the end of the study (up to 88 months)
Number of Participants Diagnosed 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. The number of participants diagnosed with AIHA are presented.
Time frame: From randomization until the end of the study (up to 88 months)
Number of Participants With a Positive Anti-ofatumumab Antibody (Human Anti-human Antibody; HAHA) Result
All serum samples for analysis of HAHA were first tested in a screening step; positive samples from the screening were further evaluated in a confirmation test. The confirmed positive samples were reported as HAHA positive and further evaluated in the titration test to obtain a titer of HAHA. A confirmed positive result at any time point means the participant is positive for HAHA.Results are reported as the number of participants positive for HAHA.
Time frame: Pre-dose (Visit 1), Months 7, 13, 19, and 25 during treatment and at 3 and 6 months after last ofatumumab dose (up to 30 months)
Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM at 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.
Time frame: Baseline, every six months during treatment, and after last treatment visit and/or upon relapse (up to 88 months)
Number of Participants Who Were Positive and Negative for Minimal Residual Disease (MRD) at Any Visit
MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed complete remission. Number of participants who were positive and negative for minimal residual disease (MRD) at any visit is presented.
Time frame: From randomization until the end of the study (up to 88 months)
Change From Baseline in Cluster of Differentiation (CD) CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points
CD5+CD19+ cells were counted by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. 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.
Time frame: Baseline and every two months from Month 3 until Month 25 and at every followup (up to 88 months)
Summary of Covariates to Compute Cox Proportional Hazards Regression Model for Relationship Between Investigator Assessed Progression-free Survival and the Indicated Prognostic Markers
Blood samples were collected for the assessment of the following prognostic markers at Baseline (BL) and upon relapse: immunoglobulin heavy chain variable region (IgVH) mutational status; VH3-21 usage; Cytogenetics (by fluorescent in situ hybridization \[FISH\]) including 6q-, 11q-, +12q, 17p-, 13q- deletions; beta 2 microglobulin. Cox-regression model was used to explore the relationship between progression-free survival and the following explanatory variables: treatment group, cytogenetics (analyzed by FISH) at BL, IgVH mutational status at BL, beta 2 microglobulin at BL, BL CD20 and BL complement level. For each covariate, a hazard ratio \<1 indicates a lower risk on the first effect tested compared with the other effects tested. Cytogenetics Group (based on \>=20%)=CY G.
Time frame: From Baseline until the end of the study (up to 79 months)
Cmax and Ctrough of Ofatumumab
Blood samples were collected to assess the plasma concentration of ofatumumab. Maximum concentration (Cmax) and observed drug concentration prior to the next dose (Ctrough) were determined. Blood samples were collected at pre-dose and 0.5 hours after the end of the infusion at treatment on Month 1 Week 1 (Day 1), Month 1 Week 2 (Day 8), and at every second infusion.
Time frame: Day 1 of Month 1 (Cycle 1 Week 1); Day 8 of Month 1 (Cycle 1 Week 2); and Month 7 (Cycle 4)
Total Plasma Clearance (CL) of Ofatumumab
Plasma clearance is defined as the plasma volume that is cleared of drug per unit of time.
Time frame: Day 1 of Month 1 (Cycle 1 Week 1); Day 8 of Month 1 (Cycle 1 Week 2); and Month 7 (Cycle 4)
AUC(0-tau) of Ofatumumab
Area under the concentration time curve over the dosing interval (AUC\[0-tau\]) is a measure of the drug exposure over time.
Time frame: Day 1 of Month 1 (Cycle 1 Week 1); Day 8 of Month 1 (Cycle 1 Week 2); and Month 7 (Cycle 4)
Vss of Ofatumumab
Volume of distribution at steady state (Vss) is defined as the apparent volume of distribution of a drug between plasma and the rest of the body at steady state. Data from all time points collected were used to calculate one Vss value for each individual.
Time frame: Day 1 Month 1 ( Cycle 1) through Month 7 ( Cycle 4)
Plasma Half-life (t1/2) of Ofatumumab
The terminal half life (t1/2) of ofatumumab is defined as the time required for the plasma concentration of ofatumumab to reach half of its original value.
Time frame: Day 1 of Month 1 (Cycle 1 Week 1); Day 8 of Month 1 (Cycle 1 Week 2); and Month 7 (Cycle 4)
| Milestone | Ofatumumab | Observation |
|---|---|---|
| Started | 240 | 240 |
| Completed | 110 | 114 |
| Not completed | 130 | 126 |
| Withdrew: Lost to follow-up | 5 | 12 |
| Withdrew: Physician decision | 15 | 10 |
| Withdrew: Withdrawal by subject | 20 | 32 |
| Withdrew: Study terminated by sponsor | 90 | 72 |
Progression-free survival is defined as the time from randomization to the date of disease progression (PD) or death due to any cause. PD was determined by the investigator according to the definitions of response in the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-Sponsored Working Group (NCI-WG) guidelines. 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 lymphocytes per microliter; transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukemia.
| Months | Ofatumumab | Observation |
|---|---|---|
| Progression-free Survival, as Assessed by the Investigator | 34.17 (29.70 to 38.01) | 16.89 (12.98 to 20.37) |
Progression-free survival is defined as the time from randomization to the date of disease progression (PD) or death due to any cause. PD was determined by the IRC according to the definitions of response in the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-Sponsored Working Group (NCI-WG) guidelines. 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 lymphocytes per microliter; transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukemia.
| Months | Ofatumumab | Observation |
|---|---|---|
| Progression-free Survival, as Assessed by the Independent Review Committee (IRC) | 33.74 (28.35 to 38.01) | 14.98 (11.63 to 19.12) |
Overall survival is defined as time from randomization to date of death.
| Months | Ofatumumab | Observation |
|---|---|---|
| Overall Survival | NA (68.96 to NA) | 73.63 (66.53 to NA) |
Improvement in response was assessed by calculating the percentage of participants who changed from partial response (PR) at Baseline to complete response during the study.
| Participants | Ofatumumab | Observation |
|---|---|---|
| Number of Participants With Improvement in Response From Baseline | 16 | 8 |
Time to next therapy is defined as the time from randomization to the date of receiving the next CLL treatment.
| Months | Ofatumumab | Observation |
|---|---|---|
| Time to Next Therapy | 36.21 (30.49 to 41.40) | 27.56 (23.49 to 32.49) |
Progression-free survival after next-line therapy is defined as the time from randomization until progression or death following the next-line therapy and counted as events deaths prior to next-line therapy. Participants who received next-line therapy and who did not have progression or death after next-line therapy were censored at their last date of contact. Participant who died prior to next-line therapy, was counted as an event.
| Months | Ofatumumab | Observation |
|---|---|---|
| Progression-free Survival After Next-line Therapy | NA (NA to NA) | NA (NA to NA) |
Time to progression after next-line therapy is defined as the time from progression following randomization until progression or death following next-line therapy and counted as events deaths prior to next-line therapy. Participants who received next-line therapy with a PD prior to receiving next line therapy and who did not had progression or death after next-line therapy were censored at their last date of contact. If a participant died prior to next-line therapy, this was counted as an event.
| Months | Ofatumumab | Observation |
|---|---|---|
| Time to Progression After Next-line Therapy | NA (NA to NA) | NA (NA to NA) |
The EORTC QLQ-CLL16 is comprised of 16 questions that address 5 domains of health-related quality of life (HRQoL) important in CLL. There are 4 multi-item scales - fatigue (2 items), treatment side effects (\[TSE\], 4 items), disease symptoms (disease effects scale \[DES\], 4 items), and infection (4 items) - and single-item scales (social activities \[Social Problems (SP) Scale\] and future health worries \[Future Health (FH) Scale\]). These are measured on a four-point Likert scale, where 1 = not at all and 4 = very much. These scores are transformed to give a rating from 0 - 100, where 0 = no symptoms or problems and 100 = severe symptoms or problems. Changes from Baseline were analyzed by a mixed model-repeated measures analysis of covariance (ANCOVA).
| Scores on a scale | Ofatumumab | Observation |
|---|---|---|
| Disease Effects Scale | 0.36 ± 1.81 | 2.56 ± 1.78 |
| Fatigue Scale | -0.16 ± 2.96 | 3.63 ± 2.93 |
| Future Health Scale | -8.66 ± 3.69 | -5.08 ± 3.65 |
| Infection Scale | 0.77 ± 2.20 | 0.25 ± 2.17 |
| Social Problems Scale | 5.69 ± 3.20 | 10.02 ± 3.16 |
| Treatment Side Effects Scale | -0.54 ± 1.77 | 1.95 ± 1.74 |
The EORTC QLQ-C30 is a self-reported, 30-item cancer-specific instrument that assesses 15 domains: physical functioning (5 items), role functioning (2 items), emotional functioning (4 items), cognitive functioning (2 items), social functioning (2 items), pain (2 items), fatigue (3 items), nausea and vomiting (2 items), five single-item symptom scores (insomnia, loss of appetite, constipation, diarrhea, and dyspnea), a single item asking about financial difficulties, and global health status/quality of life (QOF) consisting of 2 items. Functional and symptoms scales were measured on a four-point Likert scale, where 1 = not at all and 4 = very much, whereas global health status or QOF was assessed using a 7-item Likert scale, ranging from "poor" (worse quality of life) to "excellent" (better quality of life). Changes from Baseline were analyzed by mixed model-repeated measures ANCOVA.
| Scores on a scale | Ofatumumab | Observation |
|---|---|---|
| Appetite Loss | -0.63 ± 2.33 | 0.85 ± 2.30 |
| Cognitive Functioning | -1.63 ± 2.30 | -3.03 ± 2.29 |
| Constipation | -1.71 ± 2.30 | 0.27 ± 2.27 |
| Diarrhoea | -1.99 ± 2.23 | -2.49 ± 2.20 |
| Dyspnoea | 0.44 ± 2.71 | 2.76 ± 2.67 |
| Emotional Functioning | -0.83 ± 2.47 | -4.72 ± 2.44 |
| Fatigue | -0.02 ± 2.89 | 4.61 ± 2.85 |
| Financial Difficulties | 4.09 ± 3.31 | 5.85 ± 3.26 |
| Nausea and Vomiting | 0.28 ± 1.12 | 1.50 ± 1.11 |
| Pain | 1.82 ± 2.89 | 4.87 ± 2.87 |
| Physical Functioning | -2.25 ± 2.01 | -4.07 ± 2.01 |
| Global Health Status/QOL | -0.17 ± 2.52 | -1.94 ± 2.49 |
| Role Functioning | -6.94 ± 3.04 | -10.51 ± 3.00 |
| Social Functioning | -4.15 ± 2.71 | -7.80 ± 2.69 |
| Insomnia | -4.49 ± 3.51 | -2.70 ± 3.48 |
EQ-5D is comprised of a 5-item health status measure and a visual analogue scale (VAS) and is used to generate two scores: the utility score and the thermometer score. The utility score measures mobility, self-care, usual activities, pain, discomfort, and anxiety/depression. Responses to each of the 5 health states are measured on a 3-point scale (level 1 = no problem; level 2 = some or moderate problem\[s\] and level 3 = unable, or extreme problems). Responses are typically converted into health utilities or valuations on a scale ranging from 0 (worst health) to 1 (perfect health). The thermometer score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Changes from Baseline were analyzed by mixed model-repeated measures ANCOVA. A negative adjusted mean change from Baseline represents a worsening of quality of life.
| Scores on a scale | Ofatumumab | Observation |
|---|---|---|
| Utility Score | -0.02 ± 0.03 | -0.05 ± 0.03 |
| Thermometer Score | -0.37 ± 2.05 | -1.75 ± 2.04 |
Improvement is defined as a decrease from Baseline by at least one step on the ECOG performance status scale (improvement categorized as yes or no). Improvement in ECOG performance status was measured.
| Participants | Ofatumumab | Observation |
|---|---|---|
| C1 W2/M1 | 10 | 12 |
| C2 W9/M3 | 20 | 17 |
| C3 W17/M5 | 16 | 17 |
| C4 W25/M7 | 18 | 16 |
| C5 W33/M9 | 16 | 18 |
| C6 W41/M11 | 14 | 12 |
| C7 W49/M13 | 18 | 14 |
| C8 W57/M15 | 14 | 15 |
| C9 W65/M17 | 11 | 12 |
| C10 W73/M19 | 14 | 10 |
| C11 W81/M21 | 10 | 9 |
| C12 W89/M23 | 11 | 7 |
| C13 W97/M25 | 9 | 7 |
| 3M FU | 11 | 6 |
| 6M FU | 9 | 4 |
| 9M FU | 5 | 5 |
| 12M FU | 6 | 5 |
| 15M FU | 4 | 4 |
| 18M FU | 4 | 3 |
| 21M FU | 3 | 3 |
| 24M FU | 3 | 2 |
| 27M FU | 3 | 1 |
| 30M FU | 3 | 1 |
| 33M FU | 3 | 1 |
| 36M FU | 3 | 1 |
| 39M FU | 1 | 2 |
| 42M FU | 0 | 0 |
| 45M FU | 0 | 1 |
| 48M FU | 0 | 1 |
| 51M FU | 0 | 1 |
| 54M FU | 1 | 1 |
| 57M FU | 0 | 1 |
| 60M FU | 0 | 1 |
| Withdrawal | 5 | 10 |
| Worst-Case Post Baseline | 3 | 5 |
Participants with the indicated constitutional or B-symptoms (night sweats \[without signs of infection\]; unintentional weight loss \>= 10% within the previous 6 months; recurrent, unexplained fever of \> 38 degrees celcius or 100.5 degrees fahrenheit for 2 weeks; and extreme fatigue) were presented. The proportion of participants with no night sweats, no weight loss, no fever and no extreme fatigue were summarized.
| Participants | Ofatumumab | Observation |
|---|---|---|
| SCR, extreme fatigue | 0 | 7 |
| SCR, fever | 0 | 1 |
| SCR, night sweats | 13 | 8 |
| SCR, weight loss | 2 | 1 |
| C1 W2/M1, extreme fatigue | 0 | 2 |
| C1 W2/M1, fever | 0 | 0 |
| C1 W2/M1, night sweats | 9 | 6 |
| C1 W2/M1, weight loss | 4 | 1 |
| C2 W9/M3, extreme fatigue | 3 | 3 |
| C2 W9/M3, fever | 1 | 2 |
| C2 W9/M3, night sweats | 6 | 10 |
| C2 W9/M3, weight loss | 3 | 1 |
| C3 W17/M5, extreme fatigue | 4 | 5 |
| C3 W17/M5, fever | 1 | 2 |
| C3 W17/M5, night sweats | 6 | 10 |
| C3 W17/M5, weight loss | 3 | 3 |
| C4 W25/M7, extreme fatigue (n=203, 187) | 1 | 3 |
| C4 W25/M7, fever | 1 | 2 |
| C4 W25/M7, night sweats | 5 | 7 |
| C4 W25/M7, weight loss | 1 | 1 |
| C5 W33/M9, extreme fatigue | 1 | 5 |
| C5 W33/M9, fever | 1 | 0 |
| C5 W33/M9, night sweats fatigue | 7 | 8 |
| C5 W33/M9, weight loss | 0 | 4 |
| C6 W41/M11, extreme fatigue | 1 | 2 |
| C6 W41/M11, fever | 2 | 0 |
| C6 W41/M11, night sweats | 7 | 7 |
| C6 W41/M11, weight loss | 0 | 0 |
| C7 W49/M13, extreme fatigue | 1 | 1 |
| C7 W49/M13, fever | 0 | 0 |
| C7 W49/M13, night sweats | 3 | 5 |
| C7 W49/M13, weight loss | 2 | 1 |
| C8 W57/M15, extreme fatigue | 1 | 1 |
| C8 W57/M15, fever | 2 | 0 |
| C8 W57/M15, night sweats | 4 | 4 |
| C8 W57/M15, weight loss | 2 | 3 |
| C9 W65/M17, extreme fatigue | 2 | 2 |
| C9 W65/M17, fever | 2 | 0 |
| C9 W65/M17, night sweats | 7 | 4 |
| C9 W65/M17, weight loss | 1 | 2 |
| C10 W73/M19, extreme fatigue | 2 | 2 |
| C10 W73/M19, fever | 1 | 0 |
| C10 W73/M19, night sweats | 7 | 4 |
| C10 W73/M19, weight loss | 2 | 1 |
| C11 W81/M21, extreme fatigue | 0 | 3 |
| C11 W81/M21, fever | 1 | 0 |
| C11 W81/M21, night sweats | 2 | 4 |
| C11 W81/M21, weight loss | 0 | 0 |
| C12 W89/M23, extreme fatigue | 1 | 0 |
| C12 W89/M23, fever | 0 | 0 |
| C12 W89/M23, night sweats | 3 | 3 |
| C12 W89/M23, weight loss | 0 | 1 |
| C13 W97/M25, extreme fatigue | 1 | 0 |
| C13 W97/M25, fever | 0 | 0 |
| C13 W97/M25, night sweats | 2 | 1 |
| C13 W97/M25, weight loss | 1 | 3 |
| 3M follow up, extreme fatigue | 3 | 2 |
| 3M follow up, fever | 1 | 1 |
| 3M follow up, night sweats | 4 | 4 |
| 3M follow up, weight loss | 2 | 0 |
| 6M follow up, extreme fatigue | 3 | 2 |
| 6M follow up, fever | 1 | 0 |
| 6M follow up, night sweats | 2 | 2 |
| 6M follow up, weight loss | 1 | 1 |
| 9M follow up, extreme fatigue | 2 | 2 |
| 9M follow up, fever | 0 | 0 |
| 9M follow up, night sweats | 4 | 2 |
| 9M follow up, weight loss | 0 | 2 |
| 12M follow up, extreme fatigue | 0 | 3 |
| 12M follow up, fever | 1 | 1 |
| 12M follow up, night sweats | 2 | 4 |
| 12M follow up, weight loss | 0 | 1 |
| 15M follow up, extreme fatigue | 0 | 0 |
| 15M follow up, fever | 0 | 1 |
| 15M follow up, night sweats | 2 | 1 |
| 15M follow up, weight loss | 1 | 0 |
| 18M follow up, extreme fatigue | 1 | 1 |
| 18M follow up, fever | 0 | 0 |
| 18M follow up, night sweats | 2 | 1 |
| 18M follow up, weight loss | 0 | 0 |
| 21M follow up, extreme fatigue | 0 | 1 |
| 21M follow up, fever | 0 | 0 |
| 21M follow up, night sweats | 1 | 2 |
| 21M follow up, weight loss | 0 | 0 |
| 27M follow up, extreme fatigue | 0 | 0 |
| 27M follow up, fever | 0 | 0 |
| 27M follow up, night sweats | 2 | 1 |
| 27M follow up, weight loss | 1 | 1 |
| 30M follow up, extreme fatigue | 0 | 0 |
| 30M follow up, fever | 0 | 0 |
| 30M follow up, night sweats | 1 | 1 |
| 30M follow up, weight loss | 0 | 0 |
| 33M follow up, extreme fatigue | 0 | 0 |
| 33M follow up, fever | 1 | 0 |
| 33M follow up, night sweats | 2 | 2 |
| 33M follow up, weight loss | 0 | 0 |
| 36M follow up, extreme fatigue | 1 | 0 |
| 36M follow up, fever | 0 | 0 |
| 36M follow up, night sweats | 1 | 0 |
| 36M follow up, weight loss | 0 | 0 |
| 39M follow up, extreme fatigue | 1 | 0 |
| 39M follow up, fever | 0 | 0 |
| 39M follow up, night sweats | 1 | 0 |
| 39M follow up, weight loss | 0 | 0 |
| 42M follow up, extreme fatigue | 0 | 0 |
| 42M follow up, fever | 0 | 1 |
| 42M follow up, night sweats | 0 | 1 |
| 42M follow up,, weight loss | 0 | 0 |
| 51M follow up, extreme fatigue | 0 | 0 |
| 51M follow up, fever | 1 | 0 |
| 51M follow up, night sweats | 0 | 1 |
| 51M follow up, weight loss | 0 | 0 |
| 54M follow up, extreme fatigue | 0 | 0 |
| 54M follow up, fever | 1 | 0 |
| 54M follow up, night sweats | 0 | 0 |
| 54M follow up, weight loss | 0 | 0 |
| Withdrawal, extreme fatigue | 9 | 12 |
| Withdrawal, fever | 7 | 3 |
| Withdrawal, night sweats | 14 | 15 |
| Withdrawal, weight loss | 4 | 10 |
Participants with Grade 3, Grade 4 and Grade 5 adverse event of infection are presented. Adverse events were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) grade, version 4.0 (1=mild; 2=moderate; 3=severe; 4=life-threatening/disabling; 5=death).
| Participants | Ofatumumab | Observation |
|---|---|---|
| Number of Participants With Grade 3 and Above Adverse Event of Infection | 38 | 23 |
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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.
| Participants | Ofatumumab | Observation |
|---|---|---|
| Any AE | 221 | 198 |
| Any SAE | 120 | 120 |
Myelosuppression is defined as the decrease in the ability of the bone marrow to produce blood cells. Number of participants who reported myelosuppression (anemia \[low hemoglobin count\], neutropenia \[low neutrophil count\], and thrombocytopenia \[low platelet count\]) are presented. AEs were graded according to NCI common terminology criteria for adverse events (CTCAE) grade, version 4.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).
| Participants | Ofatumumab | Observation |
|---|---|---|
| SCR | 7 | 5 |
| C1 W1/M1 | 1 | 1 |
| C1 W2/M1 | 13 | 8 |
| C2 W9/M3 | 12 | 15 |
| C2, unscheduled | 1 | 0 |
| C3 W17/M5 | 18 | 7 |
| C3, unscheduled | 1 | 0 |
| C4 W25/M7 | 12 | 8 |
| C4 Unscheduled | 1 | — |
| C5 W33/M9 | 15 | 5 |
| C5, unscheduled | 1 | — |
| C6 W41/M11 | 13 | 5 |
| C6 unscheduled_1 | 4 | — |
| C6 unscheduled_2 | 1 | — |
| C7 W49/M13 | 9 | 2 |
| C8 W57/M15 | 10 | 3 |
| C9 W65/M17 | 5 | 1 |
| C9, unscheduled | 0 | 1 |
| C10 W73/M19 | 2 | 2 |
| C11 W81/M21 | 5 | 1 |
| C11 unscheduled_1 | 1 | 0 |
| C11 unscheduled_2 | 1 | — |
| C12 W89/M23 | 3 | 2 |
| C13 W97/M25 | 3 | 2 |
| C13, unscheduled | 1 | — |
| 3M follow-up | 2 | 1 |
| 6M follow-up | 2 | 1 |
| 9M follow-up | 2 | 1 |
| 12M follow-up | 1 | 2 |
| 15M follow-up | 1 | 0 |
| 18M follow-up | 0 | 1 |
| 27M follow-up | 0 | 1 |
| 30M follow-up | 0 | 1 |
| 33M follow-up | 1 | 0 |
| 60M follow-up | 1 | 0 |
| Withdrawal | 11 | 8 |
| Unscheduled_1 | 0 | 1 |
| Unscheduled_2 | 0 | 2 |
| Unscheduled_3 | 1 | 0 |
Participants who received at least one transfusion (any blood products or blood supportive care product) during the study are presented.
| Participants | Ofatumumab | Observation |
|---|---|---|
| Number of Participants Who Received at Least One Transfusion During the Study | 96 | 64 |
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. The number of participants diagnosed with AIHA are presented.
| Participants | Ofatumumab | Observation |
|---|---|---|
| Haemolytic anaemia | 2 | 2 |
| Autoimmune haemolytic anaemia | 1 | 4 |
| Thrombocytopenic purpura | 0 | 1 |
All serum samples for analysis of HAHA were first tested in a screening step; positive samples from the screening were further evaluated in a confirmation test. The confirmed positive samples were reported as HAHA positive and further evaluated in the titration test to obtain a titer of HAHA. A confirmed positive result at any time point means the participant is positive for HAHA.Results are reported as the number of participants positive for HAHA.
| Participants | Ofatumumab | Observation |
|---|---|---|
| Number of Participants With a Positive Anti-ofatumumab Antibody (Human Anti-human Antibody; HAHA) Result | 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.
| grams per liter | Ofatumumab | Observation |
|---|---|---|
| IgA, C2 W9, M3 | — | 0.2 ± 0.23 |
| IgA, C3 W17, M5 | 0.0 ± 0.12 | -0.1 ± 0.24 |
| IgA, C4 W25, M7 | -0.1 ± 0.17 | -0.0 ± 0.41 |
| IgA, C5 W33, M9 | -0.0 ± NA | -0.0 ± 0.01 |
| IgA, C6 W41, M11 | 0.0 ± NA | -0.1 ± NA |
| IgA, C7 W49, M13 | -0.1 ± 0.24 | -0.0 ± 0.63 |
| IgA, C8 W57, M15 | -0.1 ± 0.15 | 0.0 ± 0.02 |
| IgA, C9 W65, M17 | -0.2 ± 0.17 | 0.1 ± 0.04 |
| IgA, C10 W73, M19 | -0.1 ± 0.20 | 0.1 ± 0.37 |
| IgA, C11 W81, M21 | -0.0 ± NA | 0.2 ± 0.21 |
| IgA, C12 W89, M23 | -0.3 ± NA | 0.2 ± 0.39 |
| IgA, C13 W97, M25 | -0.1 ± 0.23 | 0.1 ± 0.38 |
| IgA, 3M FU | -0.1 ± 0.22 | 0.2 ± 0.37 |
| IgA, 6M FU | -0.1 ± 0.18 | 0.1 ± 0.39 |
| IgA, 9M FU | -0.1 ± 0.22 | 0.1 ± 0.38 |
| IgA, 12M FU | -0.1 ± 0.30 | 0.2 ± 0.36 |
| IgA, 15M FU | -0.0 ± 0.27 | 0.2 ± 0.44 |
| IgA, 18M FU | 0.1 ± 0.57 | 0.1 ± 0.25 |
| IgA, 21M FU | -0.1 ± 0.40 | 0.1 ± 0.34 |
| IgA, 24M FU | 0.2 ± 1.06 | 0.1 ± 0.37 |
| IgA, 27M FU | 0.1 ± 0.70 | 0.1 ± 0.46 |
| IgA, 30M FU | 0.2 ± 0.85 | 0.1 ± 0.58 |
| IgA, 33M FU | 0.4 ± 1.48 | 0.2 ± 0.60 |
| IgA, 36M FU | 0.2 ± 1.06 | 0.2 ± 0.63 |
| IgA, 39M FU | 0.2 ± 0.86 | 0.3 ± 0.71 |
| IgA, 42M FU | 0.4 ± 1.67 | 0.2 ± 0.72 |
| IgA, 45M FU | -0.2 ± 0.20 | 0.4 ± 0.94 |
| IgA, 48M FU | -0.1 ± 0.83 | -0.0 ± 0.25 |
| IgA, 51M FU | 0.3 ± 1.15 | 0.2 ± 0.70 |
| IgA, 54M FU | 0.0 ± 0.89 | 0.7 ± 1.34 |
| IgA, 57M FU | -0.4 ± 0.36 | 0.4 ± 1.04 |
| IgA, 60M FU | -0.5 ± 0.42 | 0.4 ± 1.05 |
| IgA, Withdrawal | 0.0 ± 0.53 | -0.1 ± 0.08 |
| IgG, C2 W9, M3 | — | -0.4 ± 0.21 |
| IgG, C3 W17, M5 | 0.0 ± 1.17 | 0.2 ± 0.39 |
| IgG, C4 W25, M7 | -0.7 ± 2.03 | -0.1 ± 1.83 |
| IgG, C5 W33, M9 | -1.0 ± NA | 0.5 ± 2.20 |
| IgG, C6 W41, M11 | -1.9 ± NA | 1.0 ± NA |
| IgG, C7 W49, M13 | -1.1 ± 1.9 | 0.2 ± 2.88 |
| IgG, C8 W57, M15 | -1.3 ± 1.03 | -0.9 ± 0.08 |
| IgG, C9 W65, M17 | -3.7 ± 4.96 | 0.9 ± 0.71 |
| IgG, C10 W73, M19 | -1.0 ± 2.15 | 0.6 ± 4.61 |
| IgG, C11 W81, M21 | 0.2 ± NA | -0.3 ± 1.39 |
| IgG, C12 W89, M23 | -0.5 ± NA | 0.2 ± 0.89 |
| IgG, C13 W97, M25 | -1.1 ± 2.45 | 0.3 ± 3.02 |
| IgG, 3M FU | -0.7 ± 2.46 | 0.2 ± 2.83 |
| IgG, 6M FU | -0.9 ± 2.24 | 0.2 ± 2.89 |
| IgG, 9M FU | -0.7 ± 2.29 | 0.1 ± 2.87 |
| IgG, 12M FU | -0.5 ± 2.17 | -0.3 ± 3.26 |
| IgG, 15M FU | -0.4 ± 2.49 | -0.1 ± 3.29 |
| IgG, 18M FU | -0.5 ± 2.71 | -0.3 ± 3.45 |
| IgG, 21M FU | -0.9 ± 2.39 | 0.1 ± 3.81 |
| IgG, 24M FU ( | -0.1 ± 2.17 | 0.0 ± 3.43 |
| IgG, 27M FU | -0.3 ± 2.32 | -0.5 ± 3.97 |
| IgG, 30M FU | 0.3 ± 2.67 | -0.9 ± 4.83 |
| IgG, 33M FU | 0.7 ± 2.91 | -1.1 ± 5.63 |
| IgG, 36M FU | -0.1 ± 2.71 | -1.2 ± 3.87 |
| IgG, 39M FU | 0.3 ± 2.53 | -0.9 ± 5.60 |
| IgG, 42M FU | 0.6 ± 3.03 | 0.9 ± 4.82 |
| IgG, 45M FU | -0.6 ± 2.11 | 2.3 ± 4.00 |
| IgG, 48M FU | -0.6 ± 2.30 | 3.5 ± 3.14 |
| IgG, 51M FU | 0.1 ± 3.25 | 2.4 ± 4.02 |
| IgG, 54M FU | -1.0 ± 2.35 | 5.6 ± 4.14 |
| IgG, 57M FU | 1.3 ± 4.01 | 5.3 ± 5.68 |
| IgG, 60M FU | 0.8 ± 4.43 | 4.6 ± 4.28 |
| IgG, Withdrawal | -0.7 ± 0.91 | -1.5 ± 1.86 |
| IgM, C2 W9, M3 | — | 0.1 ± 0.12 |
| IgM, C3 W17, M5 | -0.0 ± 0.09 | -0.0 ± 0.06 |
| IgM, C4 W25, M7 | -0.1 ± 0.43 | 0.1 ± 0.42 |
| IgM, C5 W33, M9 | -0.1 ± NA | -0.1 ± 0.07 |
| IgM, C6 W41, M11 | -0.5 ± NA | 0.0 ± NA |
| IgM, C7 W49, M13 | -0.1 ± 0.29 | 0.2 ± 0.90 |
| IgM, C8 W57, M15 | -0.0 ± 0.05 | -0.0 ± 0.01 |
| IgM, C9 W65, M17 | -0.3 ± 0.54 | 0.3 ± 0.49 |
| IgM, C10 W73, M19 | -0.1 ± 0.36 | 0.2 ± 0.86 |
| IgM, C11 W81, M21 | 0.0 ± NA | 0.2 ± 0.04 |
| IgM, C12 W89, M23 | 0.0 ± NA | -0.0 ± 0.11 |
| IgM, C13 W97, M25 | -0.1 ± 0.45 | 0.2 ± 0.79 |
| IgM, 3M FU | -0.0 ± 0.35 | 0.3 ± 1.30 |
| IgM, 6M FU ( | -0.1 ± 0.36 | 0.4 ± 1.60 |
| IgM, 9M FU | -0.1 ± 0.17 | 0.6 ± 2.93 |
| IgM, 12M FU | -0.0 ± 0.18 | 0.6 ± 2.49 |
| IgM, 15M FU | -0.0 ± 0.15 | 0.3 ± 1.08 |
| IgM, 18M FU | 0.1 ± 0.25 | 1.2 ± 4.95 |
| IgM, 21M FU | 0.1 ± 0.41 | 1.4 ± 5.48 |
| IgM, 24M FU | 0.0 ± 0.14 | 2.0 ± 8.19 |
| IgM, 27M FU | 0.2 ± 0.41 | -0.2 ± 1.14 |
| IgM, 30M FU (n=18, 12) | 0.1 ± 0.17 | -0.0 ± 1.51 |
| IgM, 33M FU | 0.1 ± 0.22 | 0.1 ± 0.36 |
| IgM, 36M FU | 0.2 ± 0.28 | -0.3 ± 1.31 |
| IgM, 39M FU | 0.1 ± 0.21 | -0.4 ± 1.54 |
| IgM, 42M FU | 0.1 ± 0.23 | -0.6 ± 1.79 |
| IgM, 45M FU | 0.2 ± 0.32 | 0.2 ± 0.27 |
| IgM, 48M FU | 0.1 ± 0.28 | 0.4 ± 0.38 |
| IgM, 51M FU | -0.0 ± 0.06 | 0.3 ± 0.39 |
| IgM, 54M FU | 0.1 ± 0.24 | 0.5 ± 0.26 |
| IgM, 57M FU | 0.2 ± 0.49 | 0.4 ± 0.41 |
| IgM, 60M FU | 0.6 ± 0.84 | 0.4 ± 0.42 |
| IgM, Withdrawal | 0.3 ± 0.73 | -0.0 ± 0.03 |
MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed complete remission. Number of participants who were positive and negative for minimal residual disease (MRD) at any visit is presented.
| Participants | Ofatumumab | Observation |
|---|---|---|
| Positive | 150 | 122 |
| Negative | 27 | 37 |
CD5+CD19+ cells were counted by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. 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.
| Cells per microliter | Ofatumumab | Observation |
|---|---|---|
| CD5+CD19+, C2 W9, M3 | -284.1 ± 2101.26 | 598.6 ± 3155.69 |
| CD5+CD19+, C3 W17, M5 | 52.0 ± 3554.94 | 750.5 ± 1995.47 |
| CD5+CD19+, C4 W25, M7 | -177.6 ± 4105.41 | 2102.2 ± 9866.31 |
| CD5+CD19+, C5 W33, M9 | -113.6 ± 3336.44 | 1905.2 ± 6104.84 |
| CD5+CD19+, C6 W41, M11 | -450.3 ± 2851.41 | 1550.9 ± 5483.76 |
| CD5+CD19+, C7 W49, M13 | -505.3 ± 2716.66 | 1429.2 ± 4408.69 |
| CD5+CD19+, C8 W57, M15 | -625.9 ± 3003.35 | 1107.6 ± 3371.04 |
| CD5+CD19+, C9 W65, M17 | -649.5 ± 3057.32 | 967.0 ± 1826.90 |
| CD5+CD19+, C10 W73, M19 | -238.6 ± 4061.13 | 1146.0 ± 1914.02 |
| CD5+CD19+, C11 W81, M21 | -579.0 ± 3446.95 | 1656.7 ± 2662.28 |
| CD5+CD19+, C12 W89, M23 | -569.5 ± 3510.43 | 1608.3 ± 3220.20 |
| CD5+CD19+, C13 W97, M25 | -361.3 ± 2702.79 | 2059.0 ± 4987.97 |
| CD5+CD19+, 3M FU | 121.1 ± 5479.03 | 2143.9 ± 4280.66 |
| CD5+CD19+, 6M FU | 1968.3 ± 15975.52 | 2363.5 ± 4937.00 |
| CD5+CD19+, 9M FU | 1411.3 ± 6965.41 | 4008.5 ± 13550.03 |
| CD5+CD19+, 12M FU | 2198.5 ± 10743.58 | 2316.0 ± 8763.12 |
| CD5+CD19+, 15M FU | -84.4 ± 4140.77 | 1246.2 ± 2894.20 |
| CD5+CD19+, 18M FU | 1844.1 ± 10091.28 | 1250.9 ± 3182.14 |
| CD5+CD19+, 21M FU | -395.1 ± 4521.30 | 1147.5 ± 2191.69 |
| CD5+CD19+, 24M FU | 279.4 ± 6250.23 | 2354.0 ± 6726.31 |
| CD5+CD19+, 27M FU | -368.6 ± 4829.16 | 2250.8 ± 5833.72 |
| CD5+CD19+, 30M FU | -354.4 ± 5686.14 | 2189.3 ± 6246.05 |
| CD5+CD19+, 33M FU | -397.0 ± 2767.27 | 3024.8 ± 7543.26 |
| CD5+CD19+, 36M FU | -354.8 ± 2767.77 | 3668.4 ± 8581.98 |
| CD5+CD19+, 39M FU | -163.7 ± 3116.92 | 1217.1 ± 2441.59 |
| CD5+CD19+, 42M FU | -81.7 ± 3426.53 | 2005.9 ± 4327.53 |
| CD5+CD19+, 45M FU | 466.9 ± 919.60 | 450.4 ± 1031.86 |
| CD5+CD19+, 48M FU | 1255.3 ± 2289.34 | 643.4 ± 1270.16 |
| CD5+CD19+, 51M FU | 4341.4 ± 8803.05 | 1104.8 ± 2004.49 |
| CD5+CD19+, 54M FU | 1689.8 ± 2357.27 | 237.5 ± 251.02 |
| CD5+CD19+, 57M FU | 703.3 ± 898.82 | 186.0 ± 145.66 |
| CD5+CD19+, 60M FU | 237.0 ± 326.68 | 278.5 ± 392.44 |
| CD5+CD19+, withdrawal | 8916.4 ± 25922.35 | 13991.9 ± 23553.42 |
| CD5-CD19+, C2 W9, M3 | -17.9 ± 588.42 | 81.1 ± 781.76 |
| CD5-CD19+, C3 W17, M5 | 5.2 ± 358.12 | 50.7 ± 168.87 |
| CD5-CD19+, C4 W25, M7 | 73.9 ± 687.62 | 228.2 ± 2037.16 |
| CD5-CD19+, C5 W33, M9 | 87.5 ± 971.22 | 98.9 ± 401.27 |
| CD5-CD19+, C6 W41, M11 | -13.1 ± 257.81 | 92.7 ± 296.23 |
| CD5-CD19+, C7 W49, M13 | 5.3 ± 368.66 | 77.5 ± 125.81 |
| CD5-CD19+, C8 W57, M15 | -13.3 ± 279.89 | 95.9 ± 143.95 |
| CD5-CD19+, C9 W65, M17 | -4.4 ± 349.91 | 128.3 ± 294.11 |
| CD5-CD19+, C10 W73, M19 | 3.3 ± 421.97 | 172.5 ± 555.27 |
| CD5-CD19+, C11 W81, M21 | -20.7 ± 303.21 | 127.2 ± 150.18 |
| CD5-CD19+, C12 W89, M23 | -13.5 ± 306.57 | 143.7 ± 251.88 |
| CD5-CD19+, C13 W97, M25 | 7.9 ± 103.85 | 184.0 ± 403.97 |
| CD5-CD19+, 3M FU | 27.4 ± 522.67 | 145.7 ± 229.93 |
| CD5-CD19+, 6M FU | 22.6 ± 428.70 | 153.8 ± 330.63 |
| CD5-CD19+, 9M FU | 13.2 ± 368.63 | 140.9 ± 107.92 |
| CD5-CD19+, 12M FU | 86.4 ± 769.73 | 147.2 ± 136.93 |
| CD5-CD19+, 15M FU | 10.8 ± 393.47 | 154.8 ± 120.86 |
| CD5-CD19+, 18M FU | 84.7 ± 146.38 | 173.5 ± 142.95 |
| CD5-CD19+, 21M FU | 16.2 ± 450.95 | 175.9 ± 158.31 |
| CD5-CD19+, 24M FU | 574.7 ± 2993.58 | 223.2 ± 200.06 |
| CD5-CD19+, 27M FU | 102.0 ± 643.44 | 153.3 ± 110.37 |
| CD5-CD19+, 30M FU | 38.7 ± 271.84 | 142.9 ± 106.57 |
| CD5-CD19+, 33M FU | 98.3 ± 117.18 | 157.5 ± 96.69 |
| CD5-CD19+, 36M FU | 141.1 ± 179.33 | 215.2 ± 298.90 |
| CD5-CD19+, 39M FU | 134.3 ± 167.33 | 183.9 ± 249.78 |
| CD5-CD19+, 42M FU | 113.3 ± 131.48 | 361.1 ± 601.36 |
| CD5-CD19+, 45M FU | 108.6 ± 140.97 | 157.7 ± 116.04 |
| CD5-CD19+, 48M FU | 147.7 ± 185.10 | 180.6 ± 175.93 |
| CD5-CD19+, 51M FU | 162.6 ± 229.87 | 139.3 ± 82.75 |
| CD5-CD19+, 54M FU | 221.2 ± 217.75 | 315.0 ± 43.84 |
| CD5-CD19+, 57M FU | 138.3 ± 196.32 | 195.5 ± 17.68 |
| CD5-CD19+, 60M FU | 180.5 ± 222.74 | 127.0 ± 173.95 |
| CD5-CD19+, withdrawal | 593.5 ± 2028.89 | 552.7 ± 1799.49 |
Blood samples were collected for the assessment of the following prognostic markers at Baseline (BL) and upon relapse: immunoglobulin heavy chain variable region (IgVH) mutational status; VH3-21 usage; Cytogenetics (by fluorescent in situ hybridization \[FISH\]) including 6q-, 11q-, +12q, 17p-, 13q- deletions; beta 2 microglobulin. Cox-regression model was used to explore the relationship between progression-free survival and the following explanatory variables: treatment group, cytogenetics (analyzed by FISH) at BL, IgVH mutational status at BL, beta 2 microglobulin at BL, BL CD20 and BL complement level. For each covariate, a hazard ratio \<1 indicates a lower risk on the first effect tested compared with the other effects tested. Cytogenetics Group (based on \>=20%)=CY G.
| Participants | Ofatumumab | Observation |
|---|---|---|
| CY G: 6q- or +12q or 13q | 36 | 12 |
| CY G: 17p- | 7 | 4 |
| CY G: 11q- | 11 | 10 |
| CY G: no aberration | 166 | 181 |
| CY G: missing | 20 | 33 |
| B2 Microglobulin G 2: > 3500 μg/L | 80 | 68 |
| B2 Microglobulin G 2: <=3500 μg/L | 157 | 171 |
| B2 Microglobulin G 2: missing | 3 | 1 |
| IgVH Mutational Status 1: mutated | 54 | 74 |
| IgVH Mutational Status 1: unmutated | 139 | 116 |
| IgVH Mutational Status 1: not available | 3 | 1 |
| IgVH Mutational Status 1: missing | 44 | 49 |
| VH3-21 Usage Flag: Yes | 7 | 7 |
| VH3-21 Usage Flag: No | 233 | 233 |
Blood samples were collected to assess the plasma concentration of ofatumumab. Maximum concentration (Cmax) and observed drug concentration prior to the next dose (Ctrough) were determined. Blood samples were collected at pre-dose and 0.5 hours after the end of the infusion at treatment on Month 1 Week 1 (Day 1), Month 1 Week 2 (Day 8), and at every second infusion.
| micrograms per milliliter (µg/mL) | Ofatumumab | Observation |
|---|---|---|
| Cmax, Cycle 1 Week 1 | 73.8 ± 65 | — |
| Cmax, Cycle 1 Week 2 | 264 ± 50 | — |
| Cmax, Cycle 4 | 275 ± 31 | — |
| Ctrough, Cycle 1 Week 2 | 16.3 ± 254 | — |
| Ctrough, Cycle 4 | 9.9 ± 1323 | — |
Plasma clearance is defined as the plasma volume that is cleared of drug per unit of time.
| millileters per hour (mL/hour) | Ofatumumab | Observation |
|---|---|---|
| Cycle 1 Week 1 | 49.1 ± 38 | — |
| Cycle 1 Week 2 | 9.6 ± 43 | — |
| Cycle 4 | 8.1 ± 50 | — |
Area under the concentration time curve over the dosing interval (AUC\[0-tau\]) is a measure of the drug exposure over time.
| micrograms*hour per mL (µg*hour/mL) | Ofatumumab | Observation |
|---|---|---|
| Cycle 1 Week 1 | 6113 ± 38 | — |
| Cycle 1 Week 2 | 104013 ± 43 | — |
| Cycle 4 | 122782 ± 50 | — |
Volume of distribution at steady state (Vss) is defined as the apparent volume of distribution of a drug between plasma and the rest of the body at steady state. Data from all time points collected were used to calculate one Vss value for each individual.
| Liters (L) | Ofatumumab | Observation |
|---|---|---|
| Vss of Ofatumumab | 6.0 ± 27 | — |
The terminal half life (t1/2) of ofatumumab is defined as the time required for the plasma concentration of ofatumumab to reach half of its original value.
| hours | Ofatumumab | Observation |
|---|---|---|
| Cycle 1 Week 1 | 126 ± 35 | — |
| Cycle 1 Week 2 | 458 ± 36 | — |
| Cycle 4 | 542 ± 48 | — |
Collected over From first dose of study medication until 60 days after the last dose of study medication or until the last observation at Visit 14 for AEs (up to 26 months) and until end of study for SAEs (88 months).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Ofatumumab | 88/239 (36.8%) | 120/239 (50.2%) | 202/239 (84.5%) |
| Observation | 87/241 (36.1%) | 120/241 (49.8%) | 139/241 (57.7%) |
| Total | 175/480 (36.5%) | 240/480 (50%) | 341/480 (71%) |
| Event | Ofatumumab | Observation | Total |
|---|---|---|---|
| PneumoniaInfections and infestations | 37/239 | 35/241 | 72/480 |
| PyrexiaGeneral disorders | 19/239 | 18/241 | 37/480 |
| Febrile neutropeniaBlood and lymphatic system disorders | 18/239 | 10/241 | 28/480 |
| SepsisInfections and infestations | 8/239 | 5/241 | 13/480 |
| AnaemiaBlood and lymphatic system disorders | 5/239 | 7/241 | 12/480 |
| NeutropeniaBlood and lymphatic system disorders | 5/239 | 5/241 | 10/480 |
| Lung infectionInfections and infestations | 5/239 | 3/241 | 8/480 |
| Septic shockInfections and infestations | 5/239 | 3/241 | 8/480 |
| Bronchopulmonary aspergillosisInfections and infestations | 1/239 | 5/241 | 6/480 |
| CellulitisInfections and infestations | 2/239 | 5/241 | 7/480 |
| Event | Ofatumumab | Observation | Total |
|---|---|---|---|
| NeutropeniaBlood and lymphatic system disorders | 61/239 | 22/241 | 83/480 |
| CoughRespiratory, thoracic and mediastinal disorders | 58/239 | 28/241 | 86/480 |
| Upper respiratory tract infectionInfections and infestations | 52/239 | 26/241 | 78/480 |
| Infusion related reactionInjury, poisoning and procedural complications | 42/239 | 0/241 | 42/480 |
| DiarrhoeaGastrointestinal disorders | 41/239 | 13/241 | 54/480 |
| PyrexiaGeneral disorders | 41/239 | 23/241 | 64/480 |
| FatigueGeneral disorders | 33/239 | 22/241 | 55/480 |
| RashSkin and subcutaneous tissue disorders | 26/239 | 10/241 | 36/480 |
| HeadacheNervous system disorders | 23/239 | 7/241 | 30/480 |
| PruritusSkin and subcutaneous tissue disorders | 23/239 | 9/241 | 32/480 |
Intent-to-treat (ITT) population included subjects who were randomized in the study. Subjects were grouped based on how they were randomized regardless of which treatment they received. This population was used for evaluation of all efficacy assessments.
| Age, Categorical(Participants) | Ofatumumab | Observation | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 121 | 120 | 241 |
| >=65 years | 119 | 120 | 239 |
| Age, Continuous(Years) | Ofatumumab | Observation | Total |
|---|---|---|---|
| Mean | 63.9 ± 10.31 | 64.1 ± 9.61 | 64.0 ± 9.96 |
| Sex: Female, Male(Participants) | Ofatumumab | Observation | Total |
|---|---|---|---|
| Female | 79 | 80 | 159 |
| Male | 161 | 160 | 321 |
| Race/Ethnicity, Customized(Participants) | Ofatumumab | Observation | Total |
|---|---|---|---|
| Hispanic/Latino | 15 | 18 | 33 |
| Not Hispanic/Latino | 225 | 221 | 446 |
| Missing | 0 | 1 | 1 |
Showing the first 100 of 203 sites across 25 countries.
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Plan to share: Yes — Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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