A Study of Obinutuzumab in Chinese Participants With CD20+ Malignant Disease

Study Overview
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Brief Summary
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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.

Official Title
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A Multi-Center, Open Label, Single Arm, Multiple Dose Study to Assess the Pharmacokinetics of RO5072759 in Chinese Patients With CD20+ Malignant Disease

Conditions
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Lymphocytic Leukemia, Chronic, Diffuse Large B-cell Lymphoma, Follicular Lymphoma

Intervention / Treatment
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* Drug: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CLL: 1000 mg Obinutuzumab<br>Participants with chronic lymphocytic leukemia (CLL) will receive 1000 milligrams (mg) obinutuzumab as an intravenous (IV) infusion, on Day 1 of each 21-day cycle for a maximum of 8 cycles. The first infusion on Cycle 1 Day 1 will be given over two days: Day 1 and Day 2. Additional doses of obinutuzumab will be administered on Cycle 1 Day 8 and Day 15. | Drug: Obinutuzumab<br>* Multiple doses of obinutuzumab.<br>* Other names: GA101;|
| Experimental: DLBCL: 1000 mg Obinutuzumab<br>Participants with diffuse large B-cell lymphoma (DLBCL) will receive 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 will be administered on Cycle 1 Day 8 and Day 15. | Drug: Obinutuzumab<br>* Multiple doses of obinutuzumab.<br>* Other names: GA101;|
| Experimental: FL: 1000 mg Obinutuzumab<br>Participants with follicular lymphoma (FL) will receive 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 will be administered on Cycle 1 Day 8 and Day 15. | Drug: Obinutuzumab<br>* Multiple doses of obinutuzumab.<br>* Other names: GA101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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 | 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). | 1 month after the last dose (received on Day 148) of study drug | 
| 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. | 1 month after the last dose (received on Day 148) of study drug | 
| 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). | From screening to up to 1 month after the last dose (received on Day 148) of study drug | 
| 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. | From screening to up to 1 month after the last dose (received on Day 148) of study drug | 
| 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. | 2 months after the last dose (received on Day 148) of study drug | 
| 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. | 2 months after the last dose (received on Day 148) of study drug | 
| 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. | From screening to up to 2 months after the last dose (received on Day 148) of study drug | 
| 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. | From screening to up to 2 months after the last dose (received on Day 148) of study drug | 
| 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. | Cycle 1 (Day 1), Cycle 4 (Day 1), 4-week follow-up, 3 and 6 month follow-up | 
| 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%. | Cycle 1, Day 1 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 |