Lymphocytic Leukemia, Chronic
Conditions
Brief summary
This open-label, multicenter, randomized study compared the efficacy, safety and pharmacokinetics of obinutuzumab (RO5072759; GA101) 1000 mg versus 2000 mg in participants with previously untreated CLL. Participants were randomized to receive a maximum of 8 cycles (28-day cycle) of obinutuzumab (1000 mg intravenous \[IV\] infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of each subsequent cycle up to 8 cycles or maximum of 8 cycles of obinutuzumab (2000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of each subsequent cycle up to 8 cycles.
Interventions
DRUGObinutuzumab
Participants were administered obinutuzumab either at 1000 mg or 2000 mg on Day 1, 8, 15 of Cycle 1 and then on Day 1 of each 21 day cycles for up to 8 cycles.
DRUGCorticosteroids
Participants were administered corticosteroids IV prior to the initial dose.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of CD20-positive B-cell CLL (per International Workshop on Chronic Lymphocytic Leukemia \[IWCLL\] guidelines) * Rai Stage III/IV or Binet Stage C disease, or Rai Stage I/II or Binet Stage B disease that requires treatment according to IWCLL guidelines * No previous treatment for CLL chemotherapy, radiotherapy or immunotherapy; no previous rituximab treatment for autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP); prior use of steroids for AIHA or ITP is allowed * Eastern Cooperative Oncology Group performance status of 0, 1 or 2
Exclusion criteria
* Confirmed diagnosis of Transformation of CLL to aggressive B-cell malignancy * History of severe allergic or anaphylactic reactions to monoclonal antibody therapy * Evidence of severe, uncontrolled concomitant disease * Known active infection or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 4 weeks before the start of Cycle 1 * Seropositive for human immunodeficiency virus (HIV) * Positive for chronic hepatitis B infection (defined as positive hepatitis B surface antigen \[HBsAg\] serology) * Positive for hepatitis C (hepatitis C virus \[HCV\] antibody serology testing) * Pregnant or lactating women * Concurrent (or within 7 days prior to first dose of study treatment) systemic corticosteroid use, except for low-dose corticosteroid therapy used to treat chronic medical conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Week 32 | ORR was defined as the percentage of participants with complete response (CR), CR with incomplete marrow recovery (CRi) or partial response (PR) as assessed by the investigator according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines two months after last treatment. CR required: blood lymphocytes \< 4 x 10\^9/Liter (L), absence of lymphadenopathy (≤ 1.5 centimeter (cm) in long axis by Computed Tomography), no hepatomegaly or splenomegaly, absence of disease, Neutrophils \> 1.5 x 10\^9/L, Platelets \> 100 x 10\^9/L, Hemoglobin \>11 g/dL, bone marrow normal and lymphoid nodules absent. CRi was CR with incomplete marrow recovery. PR required: 50% decrease in peripheral blood lymphocyte count, 50% reduction in lymphadenopathy, 50% reduction of liver and/or spleen enlargement if enlarged at baseline, Neutrophils \> 1.5 x 10\^9/L or \> 50% of pretreatment value, Platelets \> 100 x 10\^9/L or 50% of pretreatment value and Hemoglobin \> 11 g/dL or \> 50% of pretreatment value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | Up to 4 years, 5 months | — |
| Number of Participants Surviving at End-of-Study | Up to 4 years, 5 months | — |
| Percentage of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Up to 4 years, 5 months | An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. A SAE was any AE that was one of the following: fatal, life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product or considered a significant medical event by the investigator. Additional information about AEs can be found in the Adverse Event Section. |
| Percentage of Participants With Adverse Events of Interest | Up to 4 years, 5 months | Adverse Events of interest for this study were: serious infusion related reactions during or within 24 hours of infusion, serious neutropenia, serious infection, tumor lysis syndrome and Hepatitis B reactivation. |
| Percentage of Participants With Adverse Events Leading to Study Discontinuation | Up to 4 years, 5 months | An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. |
| PK Parameter: Maximum Serum Concentration (Cmax) | Day 148 (at end of infusion) | Blood was collected for Pharmacokinetic (PK) Parameter Cmax after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in micrograms per milliliter (μg/mL). |
| Progression-free Survival (PFS) | Up to 4 years, 5 months | PFS was defined as the time from the randomization to the first occurrence of progression or death, whichever occurred first. |
| PK Parameter: Clearance at Steady State (CLss) | Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion) | Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). CLss is reported in milliliters per day (mL/day). |
| PK Parameter: Volume of Distribution at Steady State (Vss) | Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion) | Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). Vss is reported in liters. |
| PK Parameter: Terminal Half-Life (t1/2) | Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion) | Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). T1/2 was reported in Days. |
| PK: Serum Concentrations of Obinutuzumab (Follow-Up Visits) | Months 3, 6, 9, and 12 | Blood serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in micrograms per milliliter (μg/mL). |
| Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Up to 4 years, 5 months | Blood was sent to a central laboratory for the evaluation of cluster of differentiation 19 (CD19) by flow cytometry. B-cell depletion was defined as a CD19 result \< 0.07 × 10\^9/L after at least one dose of study drug has been administered. |
| Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | Up to 4 years, 5 months | Blood was sent to a central laboratory for the evaluation of cluster of differentiation 19 (CD19) by flow cytometry. B-cell recovery was defined as a CD19 result ≥ 0.07 × 10\^9/L, where CD19 was previously depleted. B-cell recovery was only considered possible following the last dose of study treatment. The number of participants with B-cell recovery from End of Treatment to 6 months of Follow-up is reported in two categories: Recovery with Progressive Disease (PD) \[PD before B-cell recovery or PD within 45 days after recovery\] or Recovery without PD. PD required one of the following: 50% increase in the absolute number of circulating lymphocytes, Appearance of new palpable lymph nodes, 50% increase in the longest diameter of any previous site of lymphadenopathy, 50% increase in the enlargement of the liver and/or spleen or Transformation to a more aggressive histology. |
| PK Parameter: Area Under the Serum Concentration-Time Curve Between Dosing Interval Tau (AUCt ) | Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion) | Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in day times micrograms per milliliter (day\*μg/mL). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Obinutuzumab 1000 mg Participants received a 1000 mg intravenous (IV) infusion, on days 1 (split dose 100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of cycle 1 and day 1 of cycles 2 - 8, 21 day cycles. All participants received corticosteroids IV prior to the initial dose. | 41 |
| Obinutuzumab 2000 mg Participants received a 2000 mg IV infusion, on days 1 (split dose 100 mg Day 1, 900 mg Day 2 and 1000 mg Day 3), 8 and 15 of cycle 1 and day 1 of cycles 2 -8, 21 day cycles. All participants received corticosteroids IV prior to the initial dose. | 39 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 5 | 1 |
| Overall Study | Lost to Follow-up | 1 | 4 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Randomized but not Treated | 1 | 1 |
Baseline characteristics
| Characteristic | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg | Total |
|---|---|---|---|
| Age, Continuous | 67.0 years STANDARD_DEVIATION 10 | 64.3 years STANDARD_DEVIATION 12.4 | 65.7 years STANDARD_DEVIATION 11.2 |
| Sex: Female, Male Female | 16 Participants | 13 Participants | 29 Participants |
| Sex: Female, Male Male | 25 Participants | 26 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 40 / 40 | 38 / 38 |
| serious Total, serious adverse events | 8 / 40 | 8 / 38 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants with complete response (CR), CR with incomplete marrow recovery (CRi) or partial response (PR) as assessed by the investigator according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines two months after last treatment. CR required: blood lymphocytes \< 4 x 10\^9/Liter (L), absence of lymphadenopathy (≤ 1.5 centimeter (cm) in long axis by Computed Tomography), no hepatomegaly or splenomegaly, absence of disease, Neutrophils \> 1.5 x 10\^9/L, Platelets \> 100 x 10\^9/L, Hemoglobin \>11 g/dL, bone marrow normal and lymphoid nodules absent. CRi was CR with incomplete marrow recovery. PR required: 50% decrease in peripheral blood lymphocyte count, 50% reduction in lymphadenopathy, 50% reduction of liver and/or spleen enlargement if enlarged at baseline, Neutrophils \> 1.5 x 10\^9/L or \> 50% of pretreatment value, Platelets \> 100 x 10\^9/L or 50% of pretreatment value and Hemoglobin \> 11 g/dL or \> 50% of pretreatment value.
Time frame: Week 32
Population: Intent-to-treat population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Obinutuzumab 1000 mg | Objective Response Rate (ORR) | 48.8 Percentage of participants |
| Obinutuzumab 2000 mg | Objective Response Rate (ORR) | 66.7 Percentage of participants |
p-value: 0.077995% CI: [-4.95, 40.72]Cochran-Mantel-Haenszel
Secondary
Duration of Response
Time frame: Up to 4 years, 5 months
Population: Duration of response was not analyzed as investigators did not perform response assessments at regular intervals during the follow-up period.
Secondary
Number of Participants Surviving at End-of-Study
Time frame: Up to 4 years, 5 months
Population: Intent-to-treat population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Obinutuzumab 1000 mg | Number of Participants Surviving at End-of-Study | 35 Participants |
| Obinutuzumab 2000 mg | Number of Participants Surviving at End-of-Study | 37 Participants |
Secondary
Percentage of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. A SAE was any AE that was one of the following: fatal, life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product or considered a significant medical event by the investigator. Additional information about AEs can be found in the Adverse Event Section.
Time frame: Up to 4 years, 5 months
Population: Safety population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Obinutuzumab 1000 mg | Percentage of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Adverse Events | 100.0 Percentage of participants |
| Obinutuzumab 1000 mg | Percentage of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Serious Adverse Events | 20.0 Percentage of participants |
| Obinutuzumab 2000 mg | Percentage of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Adverse Events | 100.0 Percentage of participants |
| Obinutuzumab 2000 mg | Percentage of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Serious Adverse Events | 21.1 Percentage of participants |
Secondary
Percentage of Participants With Adverse Events Leading to Study Discontinuation
An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution.
Time frame: Up to 4 years, 5 months
Population: Safety population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Obinutuzumab 1000 mg | Percentage of Participants With Adverse Events Leading to Study Discontinuation | 0 Percentage of participants |
| Obinutuzumab 2000 mg | Percentage of Participants With Adverse Events Leading to Study Discontinuation | 0 Percentage of participants |
Secondary
Percentage of Participants With Adverse Events of Interest
Adverse Events of interest for this study were: serious infusion related reactions during or within 24 hours of infusion, serious neutropenia, serious infection, tumor lysis syndrome and Hepatitis B reactivation.
Time frame: Up to 4 years, 5 months
Population: Safety population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Obinutuzumab 1000 mg | Percentage of Participants With Adverse Events of Interest | Serious Neutropenia | 5.0 Percentage of participants |
| Obinutuzumab 1000 mg | Percentage of Participants With Adverse Events of Interest | Tumor Lysis Syndrome | 0.0 Percentage of participants |
| Obinutuzumab 1000 mg | Percentage of Participants With Adverse Events of Interest | Serious Infection | 5.0 Percentage of participants |
| Obinutuzumab 1000 mg | Percentage of Participants With Adverse Events of Interest | Hepatitis B Reactivation | 0.0 Percentage of participants |
| Obinutuzumab 1000 mg | Percentage of Participants With Adverse Events of Interest | Serious Infusion-Related Reactions (IRR) | 7.5 Percentage of participants |
| Obinutuzumab 2000 mg | Percentage of Participants With Adverse Events of Interest | Hepatitis B Reactivation | 0.0 Percentage of participants |
| Obinutuzumab 2000 mg | Percentage of Participants With Adverse Events of Interest | Serious Infusion-Related Reactions (IRR) | 5.3 Percentage of participants |
| Obinutuzumab 2000 mg | Percentage of Participants With Adverse Events of Interest | Serious Neutropenia | 5.3 Percentage of participants |
| Obinutuzumab 2000 mg | Percentage of Participants With Adverse Events of Interest | Serious Infection | 5.3 Percentage of participants |
| Obinutuzumab 2000 mg | Percentage of Participants With Adverse Events of Interest | Tumor Lysis Syndrome | 2.6 Percentage of participants |
Secondary
Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion
Blood was sent to a central laboratory for the evaluation of cluster of differentiation 19 (CD19) by flow cytometry. B-cell depletion was defined as a CD19 result \< 0.07 × 10\^9/L after at least one dose of study drug has been administered.
Time frame: Up to 4 years, 5 months
Population: Participants from the Safety Evaluable Population, all randomized participants who received at least one dose of study drug, who had data available for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | At Last Antibody Administration (n=40, 38) | 31 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Within 24-30 Months of Follow-up (n=4, 6) | 2 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Within 12-18 Months of Follow-up (n=17, 17) | 11 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Within 30-36 Months of Follow-up (n=1, 3) | 1 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Within 6-12 Months of Follow-up (n=24, 24) | 16 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Within 36-42 Months of Follow-up (n=0, 0) | 0 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Within 18-24 Months of Follow-up (n=10, 9) | 5 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | After 42 Months of Follow-up (n=0, 0) | 0 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Up to 6 Months of Follow-Up (FU) (n=30, 31) | 28 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | After 42 Months of Follow-up (n=0, 0) | 0 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | At Last Antibody Administration (n=40, 38) | 31 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Up to 6 Months of Follow-Up (FU) (n=30, 31) | 28 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Within 6-12 Months of Follow-up (n=24, 24) | 17 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Within 12-18 Months of Follow-up (n=17, 17) | 9 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Within 18-24 Months of Follow-up (n=10, 9) | 8 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Within 24-30 Months of Follow-up (n=4, 6) | 5 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Within 30-36 Months of Follow-up (n=1, 3) | 3 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion | Within 36-42 Months of Follow-up (n=0, 0) | 0 Participants |
Secondary
Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery
Blood was sent to a central laboratory for the evaluation of cluster of differentiation 19 (CD19) by flow cytometry. B-cell recovery was defined as a CD19 result ≥ 0.07 × 10\^9/L, where CD19 was previously depleted. B-cell recovery was only considered possible following the last dose of study treatment. The number of participants with B-cell recovery from End of Treatment to 6 months of Follow-up is reported in two categories: Recovery with Progressive Disease (PD) \[PD before B-cell recovery or PD within 45 days after recovery\] or Recovery without PD. PD required one of the following: 50% increase in the absolute number of circulating lymphocytes, Appearance of new palpable lymph nodes, 50% increase in the longest diameter of any previous site of lymphadenopathy, 50% increase in the enlargement of the liver and/or spleen or Transformation to a more aggressive histology.
Time frame: Up to 4 years, 5 months
Population: Participants from the Safety Evaluable Population, all randomized participants who received at least one dose of study drug, with B-Cell depletion.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | Up to 6 Months FU: Recovery with PD (n=30, 31) | 0 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | Up to 6 Months FU: Recovery without PD (n=30, 31) | 2 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 6-12 Months FU: Recovery with PD (n=24, 24) | 1 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 6-12 Months FU: Recovery without PD (n=24, 24) | 7 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 12-18 Months FU: Recovery with PD (n=17, 17) | 0 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 12-18 Months FU: Recovery without PD (n=17, 17) | 6 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 18-24 Months FU: Recovery with PD (n=10, 9) | 0 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 18-24 Months FU: Recovery without PD (n=10, 9) | 5 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 24-30 Months FU: Recovery with PD (n=4, 6) | 0 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 24-30 Months FU: Recovery without PD (n=4, 6) | 2 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 30-36 Months FU: Recovery with PD (n=1, 3) | 0 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 30-36 Months FU: Recovery without PD (n=1, 3) | 0 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 36-42 Months FU: Recovery with PD (n=0, 0) | 0 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 36-42 Months FU: Recovery without PD (n=0, 0) | 0 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | After 42 Months FU: Recovery with PD (n=0, 0) | 0 Participants |
| Obinutuzumab 1000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | After 42 Months FU: Recovery without PD (n=0, 0) | 0 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | After 42 Months FU: Recovery without PD (n=0, 0) | 0 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | Up to 6 Months FU: Recovery with PD (n=30, 31) | 0 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 24-30 Months FU: Recovery with PD (n=4, 6) | 0 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | Up to 6 Months FU: Recovery without PD (n=30, 31) | 3 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 36-42 Months FU: Recovery with PD (n=0, 0) | 0 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 6-12 Months FU: Recovery with PD (n=24, 24) | 0 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 24-30 Months FU: Recovery without PD (n=4, 6) | 1 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 6-12 Months FU: Recovery without PD (n=24, 24) | 7 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | After 42 Months FU: Recovery with PD (n=0, 0) | 0 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 12-18 Months FU: Recovery with PD (n=17, 17) | 0 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 30-36 Months FU: Recovery with PD (n=1, 3) | 0 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 12-18 Months FU: Recovery without PD (n=17, 17) | 8 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 36-42 Months FU: Recovery without PD (n=0, 0) | 0 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 18-24 Months FU: Recovery with PD (n=10, 9) | 0 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 30-36 Months FU: Recovery without PD (n=1, 3) | 0 Participants |
| Obinutuzumab 2000 mg | Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery | 18-24 Months FU: Recovery without PD (n=10, 9) | 1 Participants |
Secondary
PK Parameter: Area Under the Serum Concentration-Time Curve Between Dosing Interval Tau (AUCt )
Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in day times micrograms per milliliter (day\*μg/mL).
Time frame: Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion)
Population: All randomized participants who received study drug with PK data available for analysis. Participants with insufficient data points for PK estimation were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Obinutuzumab 1000 mg | PK Parameter: Area Under the Serum Concentration-Time Curve Between Dosing Interval Tau (AUCt ) | 8230 day*μg/mL | Geometric Coefficient of Variation 58.3 |
| Obinutuzumab 2000 mg | PK Parameter: Area Under the Serum Concentration-Time Curve Between Dosing Interval Tau (AUCt ) | 16500 day*μg/mL | Geometric Coefficient of Variation 50.3 |
Secondary
PK Parameter: Clearance at Steady State (CLss)
Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). CLss is reported in milliliters per day (mL/day).
Time frame: Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion)
Population: All randomized participants who received study drug with PK data available for analysis. Participants with insufficient data points for PK estimation were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Obinutuzumab 1000 mg | PK Parameter: Clearance at Steady State (CLss) | 121 mL/day | Geometric Coefficient of Variation 58.3 |
| Obinutuzumab 2000 mg | PK Parameter: Clearance at Steady State (CLss) | 122 mL/day | Geometric Coefficient of Variation 50.3 |
Secondary
PK Parameter: Maximum Serum Concentration (Cmax)
Blood was collected for Pharmacokinetic (PK) Parameter Cmax after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in micrograms per milliliter (μg/mL).
Time frame: Day 148 (at end of infusion)
Population: All randomized participants who received study drug with PK data available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Obinutuzumab 1000 mg | PK Parameter: Maximum Serum Concentration (Cmax) | 600 μg/mL | Geometric Coefficient of Variation 45.6 |
| Obinutuzumab 2000 mg | PK Parameter: Maximum Serum Concentration (Cmax) | 1190 μg/mL | Geometric Coefficient of Variation 34.9 |
Secondary
PK Parameter: Terminal Half-Life (t1/2)
Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). T1/2 was reported in Days.
Time frame: Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion)
Population: All randomized participants who received study drug with PK data available for analysis. Participants with insufficient data points for PK estimation were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Obinutuzumab 1000 mg | PK Parameter: Terminal Half-Life (t1/2) | 30.6 Days | Geometric Coefficient of Variation 87.1 |
| Obinutuzumab 2000 mg | PK Parameter: Terminal Half-Life (t1/2) | 26.3 Days | Geometric Coefficient of Variation 80.1 |
Secondary
PK Parameter: Volume of Distribution at Steady State (Vss)
Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). Vss is reported in liters.
Time frame: Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion)
Population: All randomized participants who received study drug with PK data available for analysis. Participants with insufficient data points for PK estimation were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Obinutuzumab 1000 mg | PK Parameter: Volume of Distribution at Steady State (Vss) | 7.08 Liters | Geometric Coefficient of Variation 73.2 |
| Obinutuzumab 2000 mg | PK Parameter: Volume of Distribution at Steady State (Vss) | 6.68 Liters | Geometric Coefficient of Variation 74.7 |
Secondary
PK: Serum Concentrations of Obinutuzumab (Follow-Up Visits)
Blood serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in micrograms per milliliter (μg/mL).
Time frame: Months 3, 6, 9, and 12
Population: All randomized participants who received study drug with PK data available for analysis. Participants with insufficient data points for PK estimation were excluded.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Obinutuzumab 1000 mg | PK: Serum Concentrations of Obinutuzumab (Follow-Up Visits) | Month 3 (n=14, 10) | 41.2 μg/mL | Standard Deviation 63.3 |
| Obinutuzumab 1000 mg | PK: Serum Concentrations of Obinutuzumab (Follow-Up Visits) | Month 6 (n=19, 15) | 15 μg/mL | Standard Deviation 21.4 |
| Obinutuzumab 1000 mg | PK: Serum Concentrations of Obinutuzumab (Follow-Up Visits) | Month 9 (n=24, 23) | 2.63 μg/mL | Standard Deviation 4.4 |
| Obinutuzumab 1000 mg | PK: Serum Concentrations of Obinutuzumab (Follow-Up Visits) | Month 12 (n=16, 18) | 0.633 μg/mL | Standard Deviation 1.11 |
| Obinutuzumab 2000 mg | PK: Serum Concentrations of Obinutuzumab (Follow-Up Visits) | Month 12 (n=16, 18) | 0.857 μg/mL | Standard Deviation 1.74 |
| Obinutuzumab 2000 mg | PK: Serum Concentrations of Obinutuzumab (Follow-Up Visits) | Month 3 (n=14, 10) | 98.9 μg/mL | Standard Deviation 88.9 |
| Obinutuzumab 2000 mg | PK: Serum Concentrations of Obinutuzumab (Follow-Up Visits) | Month 9 (n=24, 23) | 4.09 μg/mL | Standard Deviation 9.42 |
| Obinutuzumab 2000 mg | PK: Serum Concentrations of Obinutuzumab (Follow-Up Visits) | Month 6 (n=19, 15) | 12.6 μg/mL | Standard Deviation 17.7 |
Secondary
Progression-free Survival (PFS)
PFS was defined as the time from the randomization to the first occurrence of progression or death, whichever occurred first.
Time frame: Up to 4 years, 5 months
Population: Intent-to-treat population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Obinutuzumab 1000 mg | Progression-free Survival (PFS) | 25.2 Months |
| Obinutuzumab 2000 mg | Progression-free Survival (PFS) | 26.0 Months |