Lymphocytic Leukemia, Chronic, Diffuse Large B-cell Lymphoma, Follicular Lymphoma
Conditions
Brief summary
This multi-center, open-label, single-arm study will evaluate the pharmacokinetics and safety of obinutuzumab in participants with cluster of differentiation (CD) 20 positive (+) malignant disease. Participants will receive multiple doses of obinutuzumab. The anticipated time on study treatment is 24 weeks.
Interventions
DRUGObinutuzumab
Multiple doses of obinutuzumab.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of CD20+ B-cell lymphoma or B-CLL * Refractory/relapsed CLL, FL, and DLBCL * At least 1 measurable lesion (greater than \[\>\] 1.5 centimeters \[cm\] in its largest dimension) with the exception of CLL * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Life expectancy \>6 months
Exclusion criteria
* Prior use of any investigational antibody therapy within 6 months of study start * Prior use of any anti-cancer vaccine * Prior administration of rituximab within 3 months of study start * Prior administration of radioimmunotherapy 3 months prior to study entry * Central nervous system lymphoma * History of other malignancy * Evidence of significant, uncontrolled concomitant disease * Abnormal laboratory values * Patients with progressive multifocalleukoencephalopathy (PML) * Infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Serum Concentration Time Curve From Zero to Day 7 (AUC0-7) of Obinutuzumab on Day 1, Cycle 1 | Cycle 1-NHL: within 2 hours (h) pre-dose (Pr-D), end of infusion (EoI), 4, 24, 72 and 120 h post-infusion (Po-I) on Day 1; CLL: within 2 h Pr-D, EoI on Days 1,2; 4, 24, 72 and 120 h Po-I on Day 2. NHL and CLL: within 2 h Pr-D on Day 8 | DLBCL and FL are sub-types of Non-Hodgkin's Lymphoma (NHL) and time frame for these 2 groups was presented under NHL. For CLL, pharmacokinetic (PK) parameters were from Cycle 1 Day 1 and Day 2 dosing, due to split dosing. |
| Maximum Observed Serum Concentration (Cmax) of Obinutuzumab on Day 1, Cycle 1 | Cycle 1-NHL: within 2 h Pr-D, EoI, 4, 24, 72 and 120 h Po-I on Day 1; CLL: within 2 h Pr-D, EoI on Days 1,2; 4, 24, 72 and 120 h Po-I on Day 2. NHL and CLL: within 2 h Pr-D on Day 8 | DLBCL and FL are sub-types of NHL and time frame for these 2 groups was presented under NHL. For CLL, PK parameters were from Cycle 1 Day 1 and Day 2 dosing, due to split dosing. |
| Area Under the Serum Concentration Versus Time Curve From 0 to Day 21 (AUC0-21) of Obinutuzumab at Cycle 8 | Cycle 8: within 2 h Pr-D, EoI, 4, 24, 72, 120, 168, 336 (Day 15), and 504 (Day 22) h Po-I on Day 1 | — |
| Cmax of Obinutuzumab at Cycle 8 | Cycle 8: within 2 h Pr-D, EoI, 4, 24, 72, 120, 168, 336 (Day 15), and 504 (Day 22) h Po-I on Day 1 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Minimum Observed Serum Concentration of Obinutuzumab | Within 2 hours Pr-D on Day 1 of Cycles 2-8 and on Days 8,15 of Cycle 1 | — |
| Percentage of Participants With Complete Response (CR), CR Unconfirmed (CRu) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | 1 month after the last dose (received on Day 148) of study drug | CR: 1) Disappearance of clinical and radiographic evidence of disease, related symptoms and normalization of biochemical abnormalities definitely assignable to NHL, 2) Lymph nodes (LN) and nodal masses regressed to normal size after therapy (AT) (≤1.5 centimeters \[cm\] in their greatest transverse diameter \[GTD\] for LN greater than (\>) 1.5 cm before therapy \[BT\]). LN that were 1.1 to 1.5 cm in their GTD BT decreased to ≤1 cm in GTD AT, or \>75% in the sum of the products (SPD) of the GTD, 3) Enlarged spleen regressed in size and not palpable, 4) Absence of macroscopic nodules, 5) Enlarged organs decreased in size, and 6) If the bone marrow (BM) was involved, the infiltrate must be cleared on repeat BM aspirate and biopsy. CRu included those participants who met CR Criteria 1 and 3, but with 1 or more of the following features: a) A residual LN mass \>1.5 cm in GTD that has regressed by more than 75% in their SPD, and b) Indeterminate BM (increased \[Inc\] number or size of aggregates). |
| Percentage of Participants With Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | 1 month after the last dose (received on Day 148) of study drug | PR: 1) ≥50% decrease in SPD of the 6 largest dominant nodes/nodal masses. These nodes or masses selected according to the following features: a) clearly measurable in ≥2 perpendicular dimensions, b) from as disparate regions of the body as possible, and c) included mediastinal and retroperitoneal areas of disease. 2) No increase in size of other nodes (liver/spleen). 3) Splenic and hepatic nodules regressed by ≥50% in SPD. 4) With exception of splenic and hepatic nodules, involvement of other organs was considered assessable and not measurable disease. 5) BM assessment is irrelevant for determination of a PR because it was assessable and not measurable disease; however, if positive, the cell type was specified. 6) No new sites of disease. PD requires the following: 1) ≥50% increase from nadir in the SPD of any previously identified abnormal node for PRs or nonresponders. 2) Appearance of any new lesion during or at the end of therapy. SD is defined as less than a PR but not PD. |
| Percentage of Participants With Best Overall Response (BOR) of CR, CRu at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | From screening to up to 1 month after the last dose (received on Day 148) of study drug | CR: 1) Disappearance of clinical and radiographic evidence of disease, related symptoms and normalization of biochemical abnormalities definitely assignable to NHL, 2) LN and nodal masses regressed to normal size AT (≤1.5 cm\] in their GTD for LN \>1.5 cm BT). LN that were 1.1 to 1.5 cm in their GTD BT decreased to ≤1 cm in GTD AT, or \>75% in the SPD of the GTD, 3) Enlarged spleen regressed in size and not palpable, 4) Absence of macroscopic nodules in any organs, 5) Enlarged organs decreased in size, and 6) If the BM was involved, the infiltrate must be cleared on repeat BM aspirate and biopsy. CRu included those participants who met CR Criteria 1 and 3, but with 1 or more of the following features: a) A residual LN mass \>1.5 cm in GTD that has regressed by more than 75% in their SPD, b) Indeterminate BM (increased number or size of aggregates). |
| Percentage of Participants With BOR of PR, SD, and PD at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | From screening to up to 1 month after the last dose (received on Day 148) of study drug | PR: 1) ≥50% decrease in SPD of the 6 largest dominant nodes/nodal masses. These nodes or masses selected according to the following features: a) clearly measurable in ≥2 perpendicular dimensions, b) from as disparate regions of the body as possible, and c) included mediastinal and retroperitoneal areas of disease. 2) No increase in size of other nodes (liver/spleen). 3) Splenic and hepatic nodules regressed by ≥50% in SPD. 4) With exception of splenic and hepatic nodules, involvement of other organs was considered assessable and not measurable disease. 5) BM assessment is irrelevant for determination of a PR because it was assessable and not measurable disease; however, if positive, the cell type was specified. 6) No new sites of disease. PD requires the following: 1) ≥50% increase from nadir in the SPD of any previously identified abnormal node for PRs or nonresponders. 2) Appearance of any new lesion during or at the end of therapy. SD is defined as less than a PR but not PD. |
| Percentage of Participants With Complete Remission (CRe), CRe With Incomplete BM Recovery (CRi) at End of Treatment (1 Month After Cycle 8) in CLL Participants According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Guidelines | 2 months after the last dose (received on Day 148) of study drug | CRe required the following criteria as assessed, at least 2 months from completing therapy: a) peripheral blood lymphocytes (PBL) less than (\<) 4 x 10\^9/L, b) Absence of significant lymphadenopathy (LD) by physical examination (PE), c) No hepatomegaly/splenomegaly (HM/SM) by PE, d) Absence of constitutional symptoms and e) Blood counts above the following values (i. Neutrophils \[Neu\] \>1.5 x 10\^9/L without the need for exogenous growth factors \[EGF\], ii. Platelets (Plt) \>100 x 10\^9/L without the need for EGF, and iii. Hemoglobin (Hb) \>11.0 g/dL without blood transfusion or need for erythropoietin), and d) Once clinical and laboratory reports demonstrated CRe, a BM aspirate and biopsy was performed at least 2 months after the last treatment; to define a CRe, BM sample should be normocellular for age, \<30% of the cells being PBL and lymphoid nodules absent. CRi: CRe but persistent anemia/thrombocytopenia/neutropenia unrelated to CLL, but related to drug toxicity. |
| Percentage of Participants With PR, SD, and PD at End of Treatment (1 Month After Cycle 8) in CLL Participants According to IWCLL 2008 Guidelines | 2 months after the last dose (received on Day 148) of study drug | Group A: a)Dec LN size by ≥50% either in SPD of 6 LN or largest diameter of enlarged LN (ELN) detected BT, b)Reduction (Red) in BT enlargement of liver, c)Red in BT enlargement of spleen, d)Dec in PBL by ≥50% from baseline, e)A 50% Red in BM infiltrate or B-lymphoid nodules in BM and f)No Inc in any LN and no new ELN. Group B: a)Plt count=100,000/µL or Inc of ≥50% over baseline, b)Hb \>11 g/dL or ≥50% Inc over baseline, c)Neu \> 1500/µL or \> 50% Inc over baseline. PR is considered as achieved if 2 of Group A criteria and 1 of Group B criteria were met for ≥2 months. PD is defined as LD (appearance of new lesion \[ELN\], SM, HM or other organ infiltrates) or Inc by ≥50% in greatest determined diameter of any previous site or Inc in previously noted enlargement of liver/spleen by ≥50% or new appearance of HM/SM or an Inc in number of PBL ≥50% or transformation to a more aggressive histology or occurrence of cytopenia attributable to CLL. SD is defined as less than a PR but is not PD. |
| Time to Maximum Observed Serum Concentration (Tmax) of Obinutuzumab at Cycle 8 | Cycle 8: within 2 h Pr-D, EoI, 4, 24, 72, 120, 168, 336 (Day 15), and 504 (Day 22) h Po-I on Day 1 | — |
| Percentage of Participants With BOR of PR, SD, and PD at Anytime During Study in CLL Participants According to IWCLL 2008 Guidelines | From screening to up to 2 months after the last dose (received on Day 148) of study drug | Group A: a)Dec LN size by ≥50% either in SPD of 6 LN or largest diameter of ELN detected BT, b)Red in BT enlargement of liver, c)Red in BT enlargement of spleen, d)Dec in PBL by ≥50% from baseline, e)A 50% Red in BM infiltrate or B-lymphoid nodules in BM and f)No Inc in any LN and no new ELN. Group B: a)Plt count=100,000/µL or Inc of ≥50% over baseline, b)Hb \>11 g/dL or ≥50% Inc over baseline, c)Neu \> 1500/µL or \> 50% Inc over baseline. PR is considered as achieved if 2 of Group A criteria and 1 of Group B criteria were met for ≥2 months. PD is defined as LD (appearance of new lesion \[ELN\], SM, HM or other organ infiltrates) or Inc by ≥50% in greatest determined diameter of any previous site or Inc in previously noted enlargement of liver/spleen by ≥50% or new appearance of HM/SM or an Inc in number of PBL ≥50% or transformation to a more aggressive histology or occurrence of cytopenia attributable to CLL. SD is defined as less than a PR but is not PD. |
| Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | Cycle 1 (Day 1), Cycle 4 (Day 1), 4-week follow-up, 3 and 6 month follow-up | For the detection of HAHA, serum samples were initially analyzed using a validated enzyme linked immunosorbent assay (ELISA) method (screening assay, tier 1). The lower limit of quantification (LLOQ) in undiluted serum was 18.4 nanograms per milliliter (ng/mL). The precision ranged from 4.85 percent (%) to 16.0%. In serum samples found positive, the presence of specific anti-obinutuzumab antibodies was confirmed or excluded using the same ELISA method with an appropriate immunocompetition step (addition of excess obinutuzumab, confirmation assay, tier 2). Samples were confirmed as containing specific anti-obinutuzumab antibodies if there was a signal reduction ≥85.7% in the presence of obinutuzumab. |
| Number of Participants With Positive Human Anti-Chimeric Antibodies (HACA) | Cycle 1, Day 1 | Serum concentrations of HACA against rituximab were determined by ELISA. The LLOQ in undiluted serum was 5.00 relative units per milliliter (RU/mL). The precision and accuracy of the assay, as determined from the analysis of quality control samples, were satisfactory throughout the study; precision ranged from 6.4% to 13.6% and accuracy ranged from 88.2% to 94.8%. |
| Number of Participants With B-cell Depletion or Recovery | Screening, Cycle 1 (Days 1,8), Cycle 2 (Day 1), Cycle 4 (Day 1), Cycle 6 (Day 1), Cycle 8 (Day 1), 4 weeks after last dose of study drug and every 3 months after last dose of study drug up to 1 year | Depletion is defined as cluster of differentiation (CD) 19+ B-cell count \<0.07 x10\^9/L.Recovery is defined as CD19+ B-cell equal to or greater than 0.07 x 10\^9/L. |
| Duration of Depletion of CD19+ B-cell | Screening, Cycle 1 (Days 1,8), Cycle 2 (Day 1), Cycle 4 (Day 1), Cycle 6 (Day 1), Cycle 8 (Day 1), 4 weeks after last dose of study drug and every 3 months after last dose of study drug up to 1 year | Depletion is defined as CD19+ B-cell count \< 0.07 x 10\^9/L. The duration of depletion is defined as the number of days between first assessment of B-cell depletion and the first assessment where CD19+ cell count returned to at least the depletion level from baseline and not followed by any further B-cell depletion. If participant did not return to above depletion level, then the cut off is at the time of last assessment. |
| Time to Recovery of CD19+ B-cell | Screening, Cycle 1 (Days 1,8), Cycle 2 (Day 1), Cycle 4 (Day 1), Cycle 6 (Day 1), Cycle 8 (Day 1), 4 weeks after last dose of study drug and every 3 months after last dose of study drug up to 1 year | Recovery is defined as CD19+ B-cell equal to or greater than 0.07 x 10\^9/L. Time to recovery is defined as time between the beginning of depletion and first value after end of treatment that is equal or above 0.07x10\^9/L and not exclusively followed by depleted values only. If participant did not return to above recovery level then set to Null. |
| Percentage of Participants With BOR of CRe, CRi at Anytime During the Study in CLL Participants According to IWCLL 2008 Guidelines | From screening to up to 2 months after the last dose (received on Day 148) of study drug | CRe required the following criteria as assessed, at least 2 months from completing therapy: a) PBL \<4 x 10\^9/L, b) Absence of significant LD by PE, c) No HM/SM by PE, d) Absence of constitutional symptoms and e) Blood counts above the following values (i. Neu \>1.5 x 10\^9/L without the need for EGF, ii. Plt \>100 x 10\^9/L without the need for EGF, and iii. Hb \>11.0 g/dL without blood transfusion or need for EGF, and d) Once clinical and laboratory reports demonstrated CRe, a BM aspirate and biopsy was performed at least 2 months after the last treatment; to define a CRe, BM sample should be normocellular for age, \<30% of the cells being PBL and lymphoid nodules absent. CRi: CRe but persistent anemia/thrombocytopenia/neutropenia unrelated to CLL, but related to drug toxicity. |
| Apparent Terminal Half-life (t1/2) | Cycle 8: within 2 h Pr-D, EoI, 4, 24, 72, 120, 168, 336 (Day 15), and 504 (Day 22) h Po-I on Day 1, 4-week follow-up (Day 29), 3 and 6 months after Cycle 8 dosing | Half-life is the time measured for the serum concentration of study drug to decrease (Dec) by one half. |
| Volume of Distribution at Steady State (Vss) of Obinutuzumab at Cycle 8 | Cycle 8: within 2 h Pr-D, EoI, 4, 24, 72, 120, 168, 336 (Day 15), and 504 (Day 22) h Po-I on Day 1 | Vss reflects the actual blood and tissue volume into which a drug is distributed and the relative binding of drug to protein in these spaces. |
| Total Systemic Clearance at Steady State (CLss) of Obinutuzumab at Cycle 8 | Cycle 8: within 2 h Pr-D, EoI, 4, 24, 72, 120, 168, 336 (Day 15), and 504 (Day 22) h Po-I on Day 1 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CLL: 1000 mg Obinutuzumab Participants with CLL received 1000 mg obinutuzumab as an IV infusion, on Day 1 of each 21-day cycle for a maximum of 8 cycles. Additional doses of obinutuzumab were administered on Cycle 1 Day 8 and Day 15. The first infusion on Cycle 1 Day 1 was given over two days: Day 1- 100 mg and Day 2- 900 mg. | 12 |
| DLBCL: 1000 mg Obinutuzumab Participants with DLBCL received 1000 mg obinutuzumab as an IV infusion, on Day 1 of each 21-day cycle for a maximum of 8 cycles. Additional doses of obinutuzumab were administered on Cycle 1 Day 8 and Day 15. | 23 |
| FL: 1000 mg Obinutuzumab Participants with FL received 1000 mg obinutuzumab as an IV infusion, on Day 1 of each 21-day cycle for a maximum of 8 cycles. Additional doses of obinutuzumab were administered on Cycle 1 Day 8 and Day 15. | 13 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Bad physical condition | 0 | 0 | 1 |
| Overall Study | Death | 1 | 0 | 1 |
| Overall Study | PD confirmed in other hospital | 1 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 7 | 2 |
| Overall Study | Progressive disease (PD) | 0 | 10 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 1 | 0 |
Baseline characteristics
| Characteristic | CLL: 1000 mg Obinutuzumab | DLBCL: 1000 mg Obinutuzumab | FL: 1000 mg Obinutuzumab | Total |
|---|---|---|---|---|
| Age, Continuous | 60.7 years STANDARD_DEVIATION 12 | 53.3 years STANDARD_DEVIATION 15.8 | 55.1 years STANDARD_DEVIATION 8.8 | 55.6 years STANDARD_DEVIATION 13.4 |
| Sex: Female, Male Female | 5 Participants | 12 Participants | 5 Participants | 22 Participants |
| Sex: Female, Male Male | 7 Participants | 11 Participants | 8 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 12 | 17 / 23 | 7 / 13 |
| serious Total, serious adverse events | 5 / 12 | 3 / 23 | 1 / 13 |
Outcome results
Primary
Area Under the Serum Concentration Time Curve From Zero to Day 7 (AUC0-7) of Obinutuzumab on Day 1, Cycle 1
DLBCL and FL are sub-types of Non-Hodgkin's Lymphoma (NHL) and time frame for these 2 groups was presented under NHL. For CLL, pharmacokinetic (PK) parameters were from Cycle 1 Day 1 and Day 2 dosing, due to split dosing.
Time frame: Cycle 1-NHL: within 2 hours (h) pre-dose (Pr-D), end of infusion (EoI), 4, 24, 72 and 120 h post-infusion (Po-I) on Day 1; CLL: within 2 h Pr-D, EoI on Days 1,2; 4, 24, 72 and 120 h Po-I on Day 2. NHL and CLL: within 2 h Pr-D on Day 8
Population: PK analysis population included all participants who received at least 1 dose of study drug and had serum concentrations available. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Area Under the Serum Concentration Time Curve From Zero to Day 7 (AUC0-7) of Obinutuzumab on Day 1, Cycle 1 | 1458 day*micrograms per milliliter | Geometric Coefficient of Variation 34.8 |
| DLBCL: 1000 mg Obinutuzumab | Area Under the Serum Concentration Time Curve From Zero to Day 7 (AUC0-7) of Obinutuzumab on Day 1, Cycle 1 | 1750 day*micrograms per milliliter | Geometric Coefficient of Variation 20.5 |
| FL: 1000 mg Obinutuzumab | Area Under the Serum Concentration Time Curve From Zero to Day 7 (AUC0-7) of Obinutuzumab on Day 1, Cycle 1 | 1647 day*micrograms per milliliter | Geometric Coefficient of Variation 20.7 |
Primary
Area Under the Serum Concentration Versus Time Curve From 0 to Day 21 (AUC0-21) of Obinutuzumab at Cycle 8
Time frame: Cycle 8: within 2 h Pr-D, EoI, 4, 24, 72, 120, 168, 336 (Day 15), and 504 (Day 22) h Po-I on Day 1
Population: PK analysis population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Area Under the Serum Concentration Versus Time Curve From 0 to Day 21 (AUC0-21) of Obinutuzumab at Cycle 8 | 12289 day*mcg/mL | Geometric Coefficient of Variation 42.7 |
| DLBCL: 1000 mg Obinutuzumab | Area Under the Serum Concentration Versus Time Curve From 0 to Day 21 (AUC0-21) of Obinutuzumab at Cycle 8 | 13000 day*mcg/mL | Geometric Coefficient of Variation 37.3 |
| FL: 1000 mg Obinutuzumab | Area Under the Serum Concentration Versus Time Curve From 0 to Day 21 (AUC0-21) of Obinutuzumab at Cycle 8 | 11285 day*mcg/mL | Geometric Coefficient of Variation 26.7 |
Primary
Cmax of Obinutuzumab at Cycle 8
Time frame: Cycle 8: within 2 h Pr-D, EoI, 4, 24, 72, 120, 168, 336 (Day 15), and 504 (Day 22) h Po-I on Day 1
Population: PK analysis population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Cmax of Obinutuzumab at Cycle 8 | 1050 mcg/mL | Geometric Coefficient of Variation 32.6 |
| DLBCL: 1000 mg Obinutuzumab | Cmax of Obinutuzumab at Cycle 8 | 966 mcg/mL | Geometric Coefficient of Variation 28.3 |
| FL: 1000 mg Obinutuzumab | Cmax of Obinutuzumab at Cycle 8 | 867 mcg/mL | Geometric Coefficient of Variation 19.6 |
Primary
Maximum Observed Serum Concentration (Cmax) of Obinutuzumab on Day 1, Cycle 1
DLBCL and FL are sub-types of NHL and time frame for these 2 groups was presented under NHL. For CLL, PK parameters were from Cycle 1 Day 1 and Day 2 dosing, due to split dosing.
Time frame: Cycle 1-NHL: within 2 h Pr-D, EoI, 4, 24, 72 and 120 h Po-I on Day 1; CLL: within 2 h Pr-D, EoI on Days 1,2; 4, 24, 72 and 120 h Po-I on Day 2. NHL and CLL: within 2 h Pr-D on Day 8
Population: PK analysis population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Maximum Observed Serum Concentration (Cmax) of Obinutuzumab on Day 1, Cycle 1 | 369 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 31.8 |
| DLBCL: 1000 mg Obinutuzumab | Maximum Observed Serum Concentration (Cmax) of Obinutuzumab on Day 1, Cycle 1 | 442 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 21.1 |
| FL: 1000 mg Obinutuzumab | Maximum Observed Serum Concentration (Cmax) of Obinutuzumab on Day 1, Cycle 1 | 437 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 16.7 |
Secondary
Apparent Terminal Half-life (t1/2)
Half-life is the time measured for the serum concentration of study drug to decrease (Dec) by one half.
Time frame: Cycle 8: within 2 h Pr-D, EoI, 4, 24, 72, 120, 168, 336 (Day 15), and 504 (Day 22) h Po-I on Day 1, 4-week follow-up (Day 29), 3 and 6 months after Cycle 8 dosing
Population: PK analysis population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Apparent Terminal Half-life (t1/2) | 21.5 day | Geometric Coefficient of Variation 71.8 |
| DLBCL: 1000 mg Obinutuzumab | Apparent Terminal Half-life (t1/2) | 33.3 day | Geometric Coefficient of Variation 68.6 |
| FL: 1000 mg Obinutuzumab | Apparent Terminal Half-life (t1/2) | 26.7 day | Geometric Coefficient of Variation 49.6 |
Secondary
Duration of Depletion of CD19+ B-cell
Depletion is defined as CD19+ B-cell count \< 0.07 x 10\^9/L. The duration of depletion is defined as the number of days between first assessment of B-cell depletion and the first assessment where CD19+ cell count returned to at least the depletion level from baseline and not followed by any further B-cell depletion. If participant did not return to above depletion level, then the cut off is at the time of last assessment.
Time frame: Screening, Cycle 1 (Days 1,8), Cycle 2 (Day 1), Cycle 4 (Day 1), Cycle 6 (Day 1), Cycle 8 (Day 1), 4 weeks after last dose of study drug and every 3 months after last dose of study drug up to 1 year
Population: Safety analysis population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Duration of Depletion of CD19+ B-cell | 238.7 days | Standard Deviation 182.5 |
| DLBCL: 1000 mg Obinutuzumab | Duration of Depletion of CD19+ B-cell | 141.0 days | Standard Deviation 167.5 |
| FL: 1000 mg Obinutuzumab | Duration of Depletion of CD19+ B-cell | 386.0 days | Standard Deviation 176 |
Secondary
Minimum Observed Serum Concentration of Obinutuzumab
Time frame: Within 2 hours Pr-D on Day 1 of Cycles 2-8 and on Days 8,15 of Cycle 1
Population: PK population. Here, number of participants analyzed = participants who were evaluable for this outcome and n is the number of participants evaluable at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 8 (n=9,8,11) | 403 mcg/mL | Geometric Coefficient of Variation 85.3 |
| CLL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 5 (n=9,11,11) | 299 mcg/mL | Geometric Coefficient of Variation 91.2 |
| CLL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 3 (n=10,18,13) | 260 mcg/mL | Geometric Coefficient of Variation 246 |
| CLL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 4 (n=10,14,13) | 232 mcg/mL | Geometric Coefficient of Variation 279.7 |
| CLL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 7 (n=9,10,11) | 358 mcg/mL | Geometric Coefficient of Variation 80.6 |
| CLL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 1-Day 15 (n=11,22,13) | 282 mcg/mL | Geometric Coefficient of Variation 69.4 |
| CLL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 1-Day 8 (n=11,22,13) | 156 mcg/mL | Geometric Coefficient of Variation 57.2 |
| CLL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 6 (n=9,10,11) | 317 mcg/mL | Geometric Coefficient of Variation 93.5 |
| CLL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 2 (n=11,21,13) | 389 mcg/mL | Geometric Coefficient of Variation 71.2 |
| DLBCL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 3 (n=10,18,13) | 367 mcg/mL | Geometric Coefficient of Variation 49.6 |
| DLBCL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 1-Day 8 (n=11,22,13) | 186 mcg/mL | Geometric Coefficient of Variation 25.2 |
| DLBCL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 1-Day 15 (n=11,22,13) | 350 mcg/mL | Geometric Coefficient of Variation 23.7 |
| DLBCL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 2 (n=11,21,13) | 458 mcg/mL | Geometric Coefficient of Variation 26.3 |
| DLBCL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 4 (n=10,14,13) | 370 mcg/mL | Geometric Coefficient of Variation 49.2 |
| DLBCL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 5 (n=9,11,11) | 412 mcg/mL | Geometric Coefficient of Variation 42 |
| DLBCL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 6 (n=9,10,11) | 425 mcg/mL | Geometric Coefficient of Variation 38.2 |
| DLBCL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 7 (n=9,10,11) | 367 mcg/mL | Geometric Coefficient of Variation 40.3 |
| DLBCL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 8 (n=9,8,11) | 455 mcg/mL | Geometric Coefficient of Variation 45.4 |
| FL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 1-Day 15 (n=11,22,13) | 284 mcg/mL | Geometric Coefficient of Variation 26.5 |
| FL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 3 (n=10,18,13) | 346 mcg/mL | Geometric Coefficient of Variation 31 |
| FL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 6 (n=9,10,11) | 361 mcg/mL | Geometric Coefficient of Variation 40.6 |
| FL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 1-Day 8 (n=11,22,13) | 148 mcg/mL | Geometric Coefficient of Variation 39.2 |
| FL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 8 (n=9,8,11) | 352 mcg/mL | Geometric Coefficient of Variation 38.4 |
| FL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 4 (n=10,14,13) | 346 mcg/mL | Geometric Coefficient of Variation 31 |
| FL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 2 (n=11,21,13) | 433 mcg/mL | Geometric Coefficient of Variation 31.2 |
| FL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 7 (n=9,10,11) | 375 mcg/mL | Geometric Coefficient of Variation 41.3 |
| FL: 1000 mg Obinutuzumab | Minimum Observed Serum Concentration of Obinutuzumab | Cycle 5 (n=9,11,11) | 396 mcg/mL | Geometric Coefficient of Variation 44.8 |
Secondary
Number of Participants With B-cell Depletion or Recovery
Depletion is defined as cluster of differentiation (CD) 19+ B-cell count \<0.07 x10\^9/L.Recovery is defined as CD19+ B-cell equal to or greater than 0.07 x 10\^9/L.
Time frame: Screening, Cycle 1 (Days 1,8), Cycle 2 (Day 1), Cycle 4 (Day 1), Cycle 6 (Day 1), Cycle 8 (Day 1), 4 weeks after last dose of study drug and every 3 months after last dose of study drug up to 1 year
Population: Safety analysis population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Number of Participants With B-cell Depletion or Recovery | B-cell Depletion | 9 participants |
| CLL: 1000 mg Obinutuzumab | Number of Participants With B-cell Depletion or Recovery | B-cell Recovery | 4 participants |
| DLBCL: 1000 mg Obinutuzumab | Number of Participants With B-cell Depletion or Recovery | B-cell Depletion | 23 participants |
| DLBCL: 1000 mg Obinutuzumab | Number of Participants With B-cell Depletion or Recovery | B-cell Recovery | 1 participants |
| FL: 1000 mg Obinutuzumab | Number of Participants With B-cell Depletion or Recovery | B-cell Depletion | 13 participants |
| FL: 1000 mg Obinutuzumab | Number of Participants With B-cell Depletion or Recovery | B-cell Recovery | 1 participants |
Secondary
Number of Participants With Positive Human Anti-Chimeric Antibodies (HACA)
Serum concentrations of HACA against rituximab were determined by ELISA. The LLOQ in undiluted serum was 5.00 relative units per milliliter (RU/mL). The precision and accuracy of the assay, as determined from the analysis of quality control samples, were satisfactory throughout the study; precision ranged from 6.4% to 13.6% and accuracy ranged from 88.2% to 94.8%.
Time frame: Cycle 1, Day 1
Population: Safety analysis population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CLL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Chimeric Antibodies (HACA) | 2 participants |
| DLBCL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Chimeric Antibodies (HACA) | 1 participants |
| FL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Chimeric Antibodies (HACA) | 0 participants |
Secondary
Number of Participants With Positive Human Anti-Human Antibodies (HAHA)
For the detection of HAHA, serum samples were initially analyzed using a validated enzyme linked immunosorbent assay (ELISA) method (screening assay, tier 1). The lower limit of quantification (LLOQ) in undiluted serum was 18.4 nanograms per milliliter (ng/mL). The precision ranged from 4.85 percent (%) to 16.0%. In serum samples found positive, the presence of specific anti-obinutuzumab antibodies was confirmed or excluded using the same ELISA method with an appropriate immunocompetition step (addition of excess obinutuzumab, confirmation assay, tier 2). Samples were confirmed as containing specific anti-obinutuzumab antibodies if there was a signal reduction ≥85.7% in the presence of obinutuzumab.
Time frame: Cycle 1 (Day 1), Cycle 4 (Day 1), 4-week follow-up, 3 and 6 month follow-up
Population: Safety analysis population. n represents the number of participants who were evaluable at the specified time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | 3 month follow-up (n=8,4,11) | 0 participants |
| CLL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | 6 month follow-up (n=7,4,11) | 0 participants |
| CLL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | Cycle 4, Day 1 (n=11,14,13) | 0 participants |
| CLL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | 4 week follow-up (n=10,10,11) | 0 participants |
| CLL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | Cycle 1, Day 1 (n=12,23,13) | 0 participants |
| DLBCL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | Cycle 4, Day 1 (n=11,14,13) | 0 participants |
| DLBCL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | Cycle 1, Day 1 (n=12,23,13) | 0 participants |
| DLBCL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | 3 month follow-up (n=8,4,11) | 0 participants |
| DLBCL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | 6 month follow-up (n=7,4,11) | 0 participants |
| DLBCL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | 4 week follow-up (n=10,10,11) | 0 participants |
| FL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | 6 month follow-up (n=7,4,11) | 1 participants |
| FL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | Cycle 4, Day 1 (n=11,14,13) | 0 participants |
| FL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | 4 week follow-up (n=10,10,11) | 0 participants |
| FL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | 3 month follow-up (n=8,4,11) | 0 participants |
| FL: 1000 mg Obinutuzumab | Number of Participants With Positive Human Anti-Human Antibodies (HAHA) | Cycle 1, Day 1 (n=12,23,13) | 0 participants |
Secondary
Percentage of Participants With Best Overall Response (BOR) of CR, CRu at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria
CR: 1) Disappearance of clinical and radiographic evidence of disease, related symptoms and normalization of biochemical abnormalities definitely assignable to NHL, 2) LN and nodal masses regressed to normal size AT (≤1.5 cm\] in their GTD for LN \>1.5 cm BT). LN that were 1.1 to 1.5 cm in their GTD BT decreased to ≤1 cm in GTD AT, or \>75% in the SPD of the GTD, 3) Enlarged spleen regressed in size and not palpable, 4) Absence of macroscopic nodules in any organs, 5) Enlarged organs decreased in size, and 6) If the BM was involved, the infiltrate must be cleared on repeat BM aspirate and biopsy. CRu included those participants who met CR Criteria 1 and 3, but with 1 or more of the following features: a) A residual LN mass \>1.5 cm in GTD that has regressed by more than 75% in their SPD, b) Indeterminate BM (increased number or size of aggregates).
Time frame: From screening to up to 1 month after the last dose (received on Day 148) of study drug
Population: Safety analysis population. Data reported only for DLBCL and FL arm groups.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With Best Overall Response (BOR) of CR, CRu at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | CR | 0 percentage of participants |
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With Best Overall Response (BOR) of CR, CRu at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | CRu | 4.3 percentage of participants |
| DLBCL: 1000 mg Obinutuzumab | Percentage of Participants With Best Overall Response (BOR) of CR, CRu at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | CR | 0 percentage of participants |
| DLBCL: 1000 mg Obinutuzumab | Percentage of Participants With Best Overall Response (BOR) of CR, CRu at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | CRu | 0 percentage of participants |
Secondary
Percentage of Participants With BOR of CRe, CRi at Anytime During the Study in CLL Participants According to IWCLL 2008 Guidelines
CRe required the following criteria as assessed, at least 2 months from completing therapy: a) PBL \<4 x 10\^9/L, b) Absence of significant LD by PE, c) No HM/SM by PE, d) Absence of constitutional symptoms and e) Blood counts above the following values (i. Neu \>1.5 x 10\^9/L without the need for EGF, ii. Plt \>100 x 10\^9/L without the need for EGF, and iii. Hb \>11.0 g/dL without blood transfusion or need for EGF, and d) Once clinical and laboratory reports demonstrated CRe, a BM aspirate and biopsy was performed at least 2 months after the last treatment; to define a CRe, BM sample should be normocellular for age, \<30% of the cells being PBL and lymphoid nodules absent. CRi: CRe but persistent anemia/thrombocytopenia/neutropenia unrelated to CLL, but related to drug toxicity.
Time frame: From screening to up to 2 months after the last dose (received on Day 148) of study drug
Population: Safety analysis population. Data reported only for CLL participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With BOR of CRe, CRi at Anytime During the Study in CLL Participants According to IWCLL 2008 Guidelines | CRe | 0 percentage of participants |
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With BOR of CRe, CRi at Anytime During the Study in CLL Participants According to IWCLL 2008 Guidelines | CRi | 0 percentage of participants |
Secondary
Percentage of Participants With BOR of PR, SD, and PD at Anytime During Study in CLL Participants According to IWCLL 2008 Guidelines
Group A: a)Dec LN size by ≥50% either in SPD of 6 LN or largest diameter of ELN detected BT, b)Red in BT enlargement of liver, c)Red in BT enlargement of spleen, d)Dec in PBL by ≥50% from baseline, e)A 50% Red in BM infiltrate or B-lymphoid nodules in BM and f)No Inc in any LN and no new ELN. Group B: a)Plt count=100,000/µL or Inc of ≥50% over baseline, b)Hb \>11 g/dL or ≥50% Inc over baseline, c)Neu \> 1500/µL or \> 50% Inc over baseline. PR is considered as achieved if 2 of Group A criteria and 1 of Group B criteria were met for ≥2 months. PD is defined as LD (appearance of new lesion \[ELN\], SM, HM or other organ infiltrates) or Inc by ≥50% in greatest determined diameter of any previous site or Inc in previously noted enlargement of liver/spleen by ≥50% or new appearance of HM/SM or an Inc in number of PBL ≥50% or transformation to a more aggressive histology or occurrence of cytopenia attributable to CLL. SD is defined as less than a PR but is not PD.
Time frame: From screening to up to 2 months after the last dose (received on Day 148) of study drug
Population: Safety analysis population. Data reported only for CLL participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With BOR of PR, SD, and PD at Anytime During Study in CLL Participants According to IWCLL 2008 Guidelines | PR | 75.0 percentage of participants |
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With BOR of PR, SD, and PD at Anytime During Study in CLL Participants According to IWCLL 2008 Guidelines | SD | 8.3 percentage of participants |
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With BOR of PR, SD, and PD at Anytime During Study in CLL Participants According to IWCLL 2008 Guidelines | PD | 0 percentage of participants |
Secondary
Percentage of Participants With BOR of PR, SD, and PD at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria
PR: 1) ≥50% decrease in SPD of the 6 largest dominant nodes/nodal masses. These nodes or masses selected according to the following features: a) clearly measurable in ≥2 perpendicular dimensions, b) from as disparate regions of the body as possible, and c) included mediastinal and retroperitoneal areas of disease. 2) No increase in size of other nodes (liver/spleen). 3) Splenic and hepatic nodules regressed by ≥50% in SPD. 4) With exception of splenic and hepatic nodules, involvement of other organs was considered assessable and not measurable disease. 5) BM assessment is irrelevant for determination of a PR because it was assessable and not measurable disease; however, if positive, the cell type was specified. 6) No new sites of disease. PD requires the following: 1) ≥50% increase from nadir in the SPD of any previously identified abnormal node for PRs or nonresponders. 2) Appearance of any new lesion during or at the end of therapy. SD is defined as less than a PR but not PD.
Time frame: From screening to up to 1 month after the last dose (received on Day 148) of study drug
Population: Safety analysis population. Data reported only for DLBCL and FL arm groups.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With BOR of PR, SD, and PD at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | PR | 21.7 percentage of participants |
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With BOR of PR, SD, and PD at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | SD | 26.1 percentage of participants |
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With BOR of PR, SD, and PD at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | PD | 39.1 percentage of participants |
| DLBCL: 1000 mg Obinutuzumab | Percentage of Participants With BOR of PR, SD, and PD at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | SD | 30.8 percentage of participants |
| DLBCL: 1000 mg Obinutuzumab | Percentage of Participants With BOR of PR, SD, and PD at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | PR | 61.5 percentage of participants |
| DLBCL: 1000 mg Obinutuzumab | Percentage of Participants With BOR of PR, SD, and PD at Anytime During Study in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | PD | 7.7 percentage of participants |
Secondary
Percentage of Participants With Complete Remission (CRe), CRe With Incomplete BM Recovery (CRi) at End of Treatment (1 Month After Cycle 8) in CLL Participants According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Guidelines
CRe required the following criteria as assessed, at least 2 months from completing therapy: a) peripheral blood lymphocytes (PBL) less than (\<) 4 x 10\^9/L, b) Absence of significant lymphadenopathy (LD) by physical examination (PE), c) No hepatomegaly/splenomegaly (HM/SM) by PE, d) Absence of constitutional symptoms and e) Blood counts above the following values (i. Neutrophils \[Neu\] \>1.5 x 10\^9/L without the need for exogenous growth factors \[EGF\], ii. Platelets (Plt) \>100 x 10\^9/L without the need for EGF, and iii. Hemoglobin (Hb) \>11.0 g/dL without blood transfusion or need for erythropoietin), and d) Once clinical and laboratory reports demonstrated CRe, a BM aspirate and biopsy was performed at least 2 months after the last treatment; to define a CRe, BM sample should be normocellular for age, \<30% of the cells being PBL and lymphoid nodules absent. CRi: CRe but persistent anemia/thrombocytopenia/neutropenia unrelated to CLL, but related to drug toxicity.
Time frame: 2 months after the last dose (received on Day 148) of study drug
Population: Safety analysis population. Data reported only for CLL participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With Complete Remission (CRe), CRe With Incomplete BM Recovery (CRi) at End of Treatment (1 Month After Cycle 8) in CLL Participants According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Guidelines | CRe | 0 percentage of participants |
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With Complete Remission (CRe), CRe With Incomplete BM Recovery (CRi) at End of Treatment (1 Month After Cycle 8) in CLL Participants According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Guidelines | CRi | 0 percentage of participants |
Secondary
Percentage of Participants With Complete Response (CR), CR Unconfirmed (CRu) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria
CR: 1) Disappearance of clinical and radiographic evidence of disease, related symptoms and normalization of biochemical abnormalities definitely assignable to NHL, 2) Lymph nodes (LN) and nodal masses regressed to normal size after therapy (AT) (≤1.5 centimeters \[cm\] in their greatest transverse diameter \[GTD\] for LN greater than (\>) 1.5 cm before therapy \[BT\]). LN that were 1.1 to 1.5 cm in their GTD BT decreased to ≤1 cm in GTD AT, or \>75% in the sum of the products (SPD) of the GTD, 3) Enlarged spleen regressed in size and not palpable, 4) Absence of macroscopic nodules, 5) Enlarged organs decreased in size, and 6) If the bone marrow (BM) was involved, the infiltrate must be cleared on repeat BM aspirate and biopsy. CRu included those participants who met CR Criteria 1 and 3, but with 1 or more of the following features: a) A residual LN mass \>1.5 cm in GTD that has regressed by more than 75% in their SPD, and b) Indeterminate BM (increased \[Inc\] number or size of aggregates).
Time frame: 1 month after the last dose (received on Day 148) of study drug
Population: Safety analysis population. Data reported only for DLBCL and FL arm groups.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With Complete Response (CR), CR Unconfirmed (CRu) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | CR | 0 percentage of participants |
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With Complete Response (CR), CR Unconfirmed (CRu) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | CRu | 4.3 percentage of participants |
| DLBCL: 1000 mg Obinutuzumab | Percentage of Participants With Complete Response (CR), CR Unconfirmed (CRu) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | CR | 0 percentage of participants |
| DLBCL: 1000 mg Obinutuzumab | Percentage of Participants With Complete Response (CR), CR Unconfirmed (CRu) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | CRu | 0 percentage of participants |
Secondary
Percentage of Participants With Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria
PR: 1) ≥50% decrease in SPD of the 6 largest dominant nodes/nodal masses. These nodes or masses selected according to the following features: a) clearly measurable in ≥2 perpendicular dimensions, b) from as disparate regions of the body as possible, and c) included mediastinal and retroperitoneal areas of disease. 2) No increase in size of other nodes (liver/spleen). 3) Splenic and hepatic nodules regressed by ≥50% in SPD. 4) With exception of splenic and hepatic nodules, involvement of other organs was considered assessable and not measurable disease. 5) BM assessment is irrelevant for determination of a PR because it was assessable and not measurable disease; however, if positive, the cell type was specified. 6) No new sites of disease. PD requires the following: 1) ≥50% increase from nadir in the SPD of any previously identified abnormal node for PRs or nonresponders. 2) Appearance of any new lesion during or at the end of therapy. SD is defined as less than a PR but not PD.
Time frame: 1 month after the last dose (received on Day 148) of study drug
Population: Safety analysis population. Data reported only for DLBCL and FL arm groups.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | PR | 8.7 percentage of participants |
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | SD | 8.7 percentage of participants |
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | PD | 65.2 percentage of participants |
| DLBCL: 1000 mg Obinutuzumab | Percentage of Participants With Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | PR | 46.2 percentage of participants |
| DLBCL: 1000 mg Obinutuzumab | Percentage of Participants With Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | SD | 30.8 percentage of participants |
| DLBCL: 1000 mg Obinutuzumab | Percentage of Participants With Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) at End of Treatment (1 Month After Cycle 8) in NHL Participants (DLBCL and FL Participants) Per Cheson 1999 Criteria | PD | 23.1 percentage of participants |
Secondary
Percentage of Participants With PR, SD, and PD at End of Treatment (1 Month After Cycle 8) in CLL Participants According to IWCLL 2008 Guidelines
Group A: a)Dec LN size by ≥50% either in SPD of 6 LN or largest diameter of enlarged LN (ELN) detected BT, b)Reduction (Red) in BT enlargement of liver, c)Red in BT enlargement of spleen, d)Dec in PBL by ≥50% from baseline, e)A 50% Red in BM infiltrate or B-lymphoid nodules in BM and f)No Inc in any LN and no new ELN. Group B: a)Plt count=100,000/µL or Inc of ≥50% over baseline, b)Hb \>11 g/dL or ≥50% Inc over baseline, c)Neu \> 1500/µL or \> 50% Inc over baseline. PR is considered as achieved if 2 of Group A criteria and 1 of Group B criteria were met for ≥2 months. PD is defined as LD (appearance of new lesion \[ELN\], SM, HM or other organ infiltrates) or Inc by ≥50% in greatest determined diameter of any previous site or Inc in previously noted enlargement of liver/spleen by ≥50% or new appearance of HM/SM or an Inc in number of PBL ≥50% or transformation to a more aggressive histology or occurrence of cytopenia attributable to CLL. SD is defined as less than a PR but is not PD.
Time frame: 2 months after the last dose (received on Day 148) of study drug
Population: Safety analysis population. Data reported only for CLL participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With PR, SD, and PD at End of Treatment (1 Month After Cycle 8) in CLL Participants According to IWCLL 2008 Guidelines | PR | 58.3 percentage of participants |
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With PR, SD, and PD at End of Treatment (1 Month After Cycle 8) in CLL Participants According to IWCLL 2008 Guidelines | SD | 8.3 percentage of participants |
| CLL: 1000 mg Obinutuzumab | Percentage of Participants With PR, SD, and PD at End of Treatment (1 Month After Cycle 8) in CLL Participants According to IWCLL 2008 Guidelines | PD | 16.7 percentage of participants |
Secondary
Time to Maximum Observed Serum Concentration (Tmax) of Obinutuzumab at Cycle 8
Time frame: Cycle 8: within 2 h Pr-D, EoI, 4, 24, 72, 120, 168, 336 (Day 15), and 504 (Day 22) h Po-I on Day 1
Population: PK analysis population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CLL: 1000 mg Obinutuzumab | Time to Maximum Observed Serum Concentration (Tmax) of Obinutuzumab at Cycle 8 | 3.5 hours |
| DLBCL: 1000 mg Obinutuzumab | Time to Maximum Observed Serum Concentration (Tmax) of Obinutuzumab at Cycle 8 | 7.25 hours |
| FL: 1000 mg Obinutuzumab | Time to Maximum Observed Serum Concentration (Tmax) of Obinutuzumab at Cycle 8 | 4.0 hours |
Secondary
Time to Recovery of CD19+ B-cell
Recovery is defined as CD19+ B-cell equal to or greater than 0.07 x 10\^9/L. Time to recovery is defined as time between the beginning of depletion and first value after end of treatment that is equal or above 0.07x10\^9/L and not exclusively followed by depleted values only. If participant did not return to above recovery level then set to Null.
Time frame: Screening, Cycle 1 (Days 1,8), Cycle 2 (Day 1), Cycle 4 (Day 1), Cycle 6 (Day 1), Cycle 8 (Day 1), 4 weeks after last dose of study drug and every 3 months after last dose of study drug up to 1 year
Population: Safety analysis population. Here, number of participants analyzed = participants who were evaluable for this outcome and n represents the number of participants evaluable for the specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Time to Recovery of CD19+ B-cell | Time to recovery with PD (n=1,0,1) | 419 days | — |
| CLL: 1000 mg Obinutuzumab | Time to Recovery of CD19+ B-cell | Time to recovery without PD (n=3,1,0) | 229.0 days | Standard Deviation 87.5 |
| DLBCL: 1000 mg Obinutuzumab | Time to Recovery of CD19+ B-cell | Time to recovery with PD (n=1,0,1) | NA days | — |
| DLBCL: 1000 mg Obinutuzumab | Time to Recovery of CD19+ B-cell | Time to recovery without PD (n=3,1,0) | 515.0 days | — |
| FL: 1000 mg Obinutuzumab | Time to Recovery of CD19+ B-cell | Time to recovery with PD (n=1,0,1) | 331.0 days | — |
| FL: 1000 mg Obinutuzumab | Time to Recovery of CD19+ B-cell | Time to recovery without PD (n=3,1,0) | NA days | — |
Secondary
Total Systemic Clearance at Steady State (CLss) of Obinutuzumab at Cycle 8
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Time frame: Cycle 8: within 2 h Pr-D, EoI, 4, 24, 72, 120, 168, 336 (Day 15), and 504 (Day 22) h Po-I on Day 1
Population: PK analysis population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Total Systemic Clearance at Steady State (CLss) of Obinutuzumab at Cycle 8 | 81.4 mL/day | Geometric Coefficient of Variation 42.7 |
| DLBCL: 1000 mg Obinutuzumab | Total Systemic Clearance at Steady State (CLss) of Obinutuzumab at Cycle 8 | 76.9 mL/day | Geometric Coefficient of Variation 37.3 |
| FL: 1000 mg Obinutuzumab | Total Systemic Clearance at Steady State (CLss) of Obinutuzumab at Cycle 8 | 88.6 mL/day | Geometric Coefficient of Variation 26.7 |
Secondary
Volume of Distribution at Steady State (Vss) of Obinutuzumab at Cycle 8
Vss reflects the actual blood and tissue volume into which a drug is distributed and the relative binding of drug to protein in these spaces.
Time frame: Cycle 8: within 2 h Pr-D, EoI, 4, 24, 72, 120, 168, 336 (Day 15), and 504 (Day 22) h Po-I on Day 1
Population: PK analysis population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CLL: 1000 mg Obinutuzumab | Volume of Distribution at Steady State (Vss) of Obinutuzumab at Cycle 8 | 3.32 Liter | Geometric Coefficient of Variation 27.9 |
| DLBCL: 1000 mg Obinutuzumab | Volume of Distribution at Steady State (Vss) of Obinutuzumab at Cycle 8 | 4.49 Liter | Geometric Coefficient of Variation 38.2 |
| FL: 1000 mg Obinutuzumab | Volume of Distribution at Steady State (Vss) of Obinutuzumab at Cycle 8 | 4.03 Liter | Geometric Coefficient of Variation 21.5 |