A Study Comparing Obinutuzumab (RO5072759; GA101) 1000 Milligram (mg) Versus 2000 mg in Participants With Previously Untreated Chronic Lymphocytic Leukemia (CLL) (GAGE)

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01414205
• Collaborator: (none)
• Enrollment: 80
• Locations: 31
• Arms: 2
• Actual Duration (Months): 53
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphocytic Leukemia, Chronic	Drug: Obinutuzumab; Drug: Corticosteroids	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multicenter, Randomized Phase II Trial Comparing the Efficacy, Safety, and Pharmacokinetics of GA101 1000 mg Versus 2000 mg in Patients With Previously Untreated Chronic Lymphocytic Leukemia
• Actual Study Start Date: Oct 31, 2011
• Actual Primary Completion Date: Mar 31, 2013
• Actual Study Completion Date: Mar 31, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Obinutuzumab; 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.; Other Names: RO5072759; GA101 ; Drug: Corticosteroids; Participants were administered corticosteroids IV prior to the initial dose.
Experimental: 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.	Drug: Obinutuzumab; 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.; Other Names: RO5072759; GA101 ; Drug: Corticosteroids; Participants were administered corticosteroids IV prior to the initial dose.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. Duration of Response [Up to 4 years, 5 months]

3. Number of Participants Surviving at End-of-Study [Up to 4 years, 5 months]

4. 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.

5. 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.

6. 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.

7. 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).

8. 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).

9. 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).

10. 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.

11. 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.

12. 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).

13. 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.

14. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Univ of Alabama at Birmingham; UAB Comprehensive Cancer Ctr	Birmingham	Alabama	United States	35291-3300
2	Arizona Oncology	Tucson	Arizona	United States	85704
3	Arizona Clinical Research Ctr	Tucson	Arizona	United States	85715
4	University of California; Moores Cancer Center	La Jolla	California	United States	92093
5	USC Norris Cancer Center	Los Angeles	California	United States	90033
6	USC/Norris Can Ctr; IDS Pharm	Los Angeles	California	United States	90033
7	Ventura County Hematology-Oncology Specialists	Oxnard	California	United States	93030
8	Wilshire Oncology Medical Group	Pasadena	California	United States	91750
9	Univ of Colorado Canc Ctr	Aurora	Colorado	United States	80045
10	Rocky Mountain Cancer Center; Medical Oncology	Denver	Colorado	United States	80218
11	Kootenai Cancer Center	Post Falls	Idaho	United States	83854
12	Goshen Hlth Sys Ctr Can Care	Goshen	Indiana	United States	46526
13	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
14	Horizon Oncology Research, Inc.	Lafayette	Indiana	United States	47905
15	Purchase Cancer Group	Paducah	Kentucky	United States	42001
16	Hem Onc Assoc of Northern NJ; Carol G. Simon Canc Ctr	Morristown	New Jersey	United States	07962
17	Columbia University Medical Center	New York	New York	United States	10032
18	Ohio State University	Columbus	Ohio	United States	43210
19	Mark H. Zangmeister Center	Columbus	Ohio	United States	43219
20	Kettering Medical Center	Kettering	Ohio	United States	45429
21	INTEGRIS Cancer Inst of OK	Oklahoma City	Oklahoma	United States	73142
22	Willamette Valley Cancer Ctr - 520 Country Club	Eugene	Oregon	United States	97401-8122
23	Texas Oncology-Medical City Dallas	Dallas	Texas	United States	75230
24	Texas Oncology - Dallas Presbyterian Hospital	Dallas	Texas	United States	75231
25	US Oncology Research Pharm.	Fort Worth	Texas	United States	76177
26	Texas Cancer Center - Sherman	Sherman	Texas	United States	75090-0504
27	Virginia Cancer Specialists, PC	Fairfax	Virginia	United States	22031
28	SW Virginia Hem Onc	Roanoke	Virginia	United States	24014
29	Shenandoah Oncology Associates	Winchester	Virginia	United States	22601
30	Northwest Cancer Specialists - Vancouver	Vancouver	Washington	United States	98684
31	Yakima Valley Memorial Hospital/North Star Lodge	Yakima	Washington	United States	98902

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT01414205
• Other Study ID Numbers: GAO4768g; GO25677
• First Posted: Aug 11, 2011
• Last Update Posted: Apr 17, 2017
• Last Verified: Mar 1, 2017

• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Obinutuzumab

Study Results

Participant Flow

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	41	39
Received Study Drug	40	38
COMPLETED	34	32
NOT COMPLETED	7	7

Baseline Characteristics

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	41	39	80
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.0 (10.0)	64.3 (12.4)	65.7 (11.2)
Sex: Female, Male (Count of Participants)
Female	16 39%	13 33.3%	29 36.3%
Male	25 61%	26 66.7%	51 63.8%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR)
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants.

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	41	39
Number [Percentage of participants]	48.8 119%	66.7 171%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab 1000 mg, Obinutuzumab 2000 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0779
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-values based on stratified Cochran-Mantel-Haenszel test by the randomization stratification factors as supportive analyses.
Method of Estimation	Estimation Parameter	Difference (Hauck-Anderson)
	Estimated Value	17.89
	Confidence Interval	(2-Sided) 95%; -4.95 to 40.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants.

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	41	39
Median (95% Confidence Interval) [Months]	25.2	26.0

3. Secondary Outcome

Title	Duration of Response
Time Frame	Up to 4 years, 5 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Number of Participants Surviving at End-of-Study
Time Frame	Up to 4 years, 5 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants.

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	41	39
Number [Participants]	35 85.4%	37 94.9%

5. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Description	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

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	40	38
Adverse Events	100.0 243.9%	100.0 256.4%
Serious Adverse Events	20.0 48.8%	21.1 54.1%

6. Secondary Outcome

Title	Percentage of Participants With Adverse Events of Interest
Description	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

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	40	38
Serious Infusion-Related Reactions (IRR)	7.5 18.3%	5.3 13.6%
Serious Neutropenia	5.0 12.2%	5.3 13.6%
Serious Infection	5.0 12.2%	5.3 13.6%
Tumor Lysis Syndrome	0.0 0%	2.6 6.7%
Hepatitis B Reactivation	0.0 0%	0.0 0%

7. Secondary Outcome

Title	Percentage of Participants With Adverse Events Leading to Study Discontinuation
Description	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

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	40	38
Number [Percentage of participants]	0 0%	0 0%

8. Secondary Outcome

Title	PK Parameter: Maximum Serum Concentration (Cmax)
Description	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)

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug with PK data available for analysis.

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	37	33
Geometric Mean (Geometric Coefficient of Variation) [μg/mL]	600 (45.6)	1190 (34.9)

9. Secondary Outcome

Title	PK Parameter: Area Under the Serum Concentration-Time Curve Between Dosing Interval Tau (AUCt )
Description	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)

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug with PK data available for analysis. Participants with insufficient data points for PK estimation were excluded.

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	26	25
Geometric Mean (Geometric Coefficient of Variation) [day*μg/mL]	8230 (58.3)	16500 (50.3)

10. Secondary Outcome

Title	PK Parameter: Clearance at Steady State (CLss)
Description	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)

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug with PK data available for analysis. Participants with insufficient data points for PK estimation were excluded.

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	26	25
Geometric Mean (Geometric Coefficient of Variation) [mL/day]	121 (58.3)	122 (50.3)

11. Secondary Outcome

Title	PK Parameter: Volume of Distribution at Steady State (Vss)
Description	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)

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug with PK data available for analysis. Participants with insufficient data points for PK estimation were excluded.

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	24	23
Geometric Mean (Geometric Coefficient of Variation) [Liters]	7.08 (73.2)	6.68 (74.7)

12. Secondary Outcome

Title	PK Parameter: Terminal Half-Life (t1/2)
Description	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)

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug with PK data available for analysis. Participants with insufficient data points for PK estimation were excluded.

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	24	23
Geometric Mean (Geometric Coefficient of Variation) [Days]	30.6 (87.1)	26.3 (80.1)

13. Secondary Outcome

Title	PK: Serum Concentrations of Obinutuzumab (Follow-Up Visits)
Description	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

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug with PK data available for analysis. Participants with insufficient data points for PK estimation were excluded.

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	37	33
Month 3 (n=14, 10)	41.2 (63.3)	98.9 (88.9)
Month 6 (n=19, 15)	15 (21.4)	12.6 (17.7)
Month 9 (n=24, 23)	2.63 (4.4)	4.09 (9.42)
Month 12 (n=16, 18)	0.633 (1.11)	0.857 (1.74)

14. Secondary Outcome

Title	Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	40	38
At Last Antibody Administration (n=40, 38)	31 75.6%	31 79.5%
Up to 6 Months of Follow-Up (FU) (n=30, 31)	28 68.3%	28 71.8%
Within 6-12 Months of Follow-up (n=24, 24)	16 39%	17 43.6%
Within 12-18 Months of Follow-up (n=17, 17)	11 26.8%	9 23.1%
Within 18-24 Months of Follow-up (n=10, 9)	5 12.2%	8 20.5%
Within 24-30 Months of Follow-up (n=4, 6)	2 4.9%	5 12.8%
Within 30-36 Months of Follow-up (n=1, 3)	1 2.4%	3 7.7%
Within 36-42 Months of Follow-up (n=0, 0)	0 0%	0 0%
After 42 Months of Follow-up (n=0, 0)	0 0%	0 0%

15. Secondary Outcome

Title	Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery
Description	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

Outcome Measure Data

Analysis Population Description

Participants from the Safety Evaluable Population, all randomized participants who received at least one dose of study drug, with B-Cell depletion.

Arm/Group Title	Obinutuzumab 1000 mg	Obinutuzumab 2000 mg
Arm/Group Description	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.	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.
Measure Participants	40	38
Up to 6 Months FU: Recovery with PD (n=30, 31)	0 0%	0 0%
Up to 6 Months FU: Recovery without PD (n=30, 31)	2 4.9%	3 7.7%
6-12 Months FU: Recovery with PD (n=24, 24)	1 2.4%	0 0%
6-12 Months FU: Recovery without PD (n=24, 24)	7 17.1%	7 17.9%
12-18 Months FU: Recovery with PD (n=17, 17)	0 0%	0 0%
12-18 Months FU: Recovery without PD (n=17, 17)	6 14.6%	8 20.5%
18-24 Months FU: Recovery with PD (n=10, 9)	0 0%	0 0%
18-24 Months FU: Recovery without PD (n=10, 9)	5 12.2%	1 2.6%
24-30 Months FU: Recovery with PD (n=4, 6)	0 0%	0 0%
24-30 Months FU: Recovery without PD (n=4, 6)	2 4.9%	1 2.6%
30-36 Months FU: Recovery with PD (n=1, 3)	0 0%	0 0%
30-36 Months FU: Recovery without PD (n=1, 3)	0 0%	0 0%
36-42 Months FU: Recovery with PD (n=0, 0)	0 0%	0 0%
36-42 Months FU: Recovery without PD (n=0, 0)	0 0%	0 0%
After 42 Months FU: Recovery with PD (n=0, 0)	0 0%	0 0%
After 42 Months FU: Recovery without PD (n=0, 0)	0 0%	0 0%

Adverse Events

Time Frame	Up to 4 years, 5 months
Arm/Group Title	Obinutuzumab 1000 mg		Obinutuzumab 2000 mg
Arm/Group Description	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.		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.
All Cause Mortality
	Obinutuzumab 1000 mg		Obinutuzumab 2000 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Obinutuzumab 1000 mg		Obinutuzumab 2000 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/40 (20%)		8/38 (21.1%)
Blood and lymphatic system disorders
Febrile neutropenia	2/40 (5%)		1/38 (2.6%)
Neutropenia	0/40 (0%)		1/38 (2.6%)
Thrombocytopenia	0/40 (0%)		1/38 (2.6%)
Cardiac disorders
Acute coronary syndrome	0/40 (0%)		1/38 (2.6%)
Myocardial infarction	1/40 (2.5%)		0/38 (0%)
Sinus bradycardia	0/40 (0%)		1/38 (2.6%)
General disorders
Chest pain	1/40 (2.5%)		0/38 (0%)
Pyrexia	1/40 (2.5%)		0/38 (0%)
Infections and infestations
Sepsis	0/40 (0%)		1/38 (2.6%)
Sinusitis	1/40 (2.5%)		0/38 (0%)
Urinary tract infection	1/40 (2.5%)		0/38 (0%)
Urosepsis	0/40 (0%)		1/38 (2.6%)
Injury, poisoning and procedural complications
Infusion related reaction	2/40 (5%)		0/38 (0%)
Fall	0/40 (0%)		1/38 (2.6%)
Rib fracture	0/40 (0%)		1/38 (2.6%)
Metabolism and nutrition disorders
Hypoglycaemia	0/40 (0%)		1/38 (2.6%)
Nervous system disorders
Depressed level of consciousness	1/40 (2.5%)		0/38 (0%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/40 (2.5%)		0/38 (0%)
Emphysema	0/40 (0%)		1/38 (2.6%)
Vascular disorders
Hypotension	1/40 (2.5%)		0/38 (0%)
Other (Not Including Serious) Adverse Events
	Obinutuzumab 1000 mg		Obinutuzumab 2000 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/40 (100%)		38/38 (100%)
Blood and lymphatic system disorders
Neutropenia	14/40 (35%)		12/38 (31.6%)
Thrombocytopenia	9/40 (22.5%)		7/38 (18.4%)
Anaemia	7/40 (17.5%)		3/38 (7.9%)
Febrile Neutropenia	2/40 (5%)		1/38 (2.6%)
Ear and labyrinth disorders
Vertigo	2/40 (5%)		1/38 (2.6%)
Eye disorders
Lacrimation increased	1/40 (2.5%)		2/38 (5.3%)
Visual impairment	1/40 (2.5%)		2/38 (5.3%)
Vision Blurred	0/40 (0%)		2/38 (5.3%)
Gastrointestinal disorders
Nausea	15/40 (37.5%)		10/38 (26.3%)
Vomiting	11/40 (27.5%)		5/38 (13.2%)
Diarrhoea	3/40 (7.5%)		7/38 (18.4%)
Constipation	3/40 (7.5%)		5/38 (13.2%)
Abdominal pain	3/40 (7.5%)		4/38 (10.5%)
Dyspepsia	1/40 (2.5%)		4/38 (10.5%)
Gastrooesophageal reflux disease	2/40 (5%)		2/38 (5.3%)
Abdominal discomfort	2/40 (5%)		0/38 (0%)
Dry mouth	0/40 (0%)		2/38 (5.3%)
General disorders
Pyrexia	16/40 (40%)		18/38 (47.4%)
Fatigue	16/40 (40%)		12/38 (31.6%)
Chills	8/40 (20%)		7/38 (18.4%)
Oedema peripheral	6/40 (15%)		6/38 (15.8%)
Chest discomfort	3/40 (7.5%)		4/38 (10.5%)
Asthenia	3/40 (7.5%)		0/38 (0%)
Influenza like illness	0/40 (0%)		2/38 (5.3%)
Chest Pain	2/40 (5%)		0/38 (0%)
Infections and infestations
Upper respiratory tract infection	5/40 (12.5%)		6/38 (15.8%)
Urinary tract infection	2/40 (5%)		3/38 (7.9%)
Sinusitis	2/40 (5%)		2/38 (5.3%)
Fungal skin infection	2/40 (5%)		0/38 (0%)
Rhinitis	2/40 (5%)		0/38 (0%)
Injury, poisoning and procedural complications
Infusion related reaction	30/40 (75%)		24/38 (63.2%)
Contusion	0/40 (0%)		3/38 (7.9%)
Laceration	2/40 (5%)		1/38 (2.6%)
Fall	1/40 (2.5%)		2/38 (5.3%)
Investigations
Blood magnesium decreased	0/40 (0%)		2/38 (5.3%)
Metabolism and nutrition disorders
Decreased appetite	4/40 (10%)		3/38 (7.9%)
Hyperglycaemia	2/40 (5%)		0/38 (0%)
Musculoskeletal and connective tissue disorders
Bone pain	2/40 (5%)		4/38 (10.5%)
Muscle spasms	2/40 (5%)		3/38 (7.9%)
Myalgia	3/40 (7.5%)		3/38 (7.9%)
Back pain	3/40 (7.5%)		3/38 (7.9%)
Musculoskeletal pain	4/40 (10%)		0/38 (0%)
Neck pain	3/40 (7.5%)		1/38 (2.6%)
Pain in extremity	2/40 (5%)		1/38 (2.6%)
Muscular weakness	0/40 (0%)		2/38 (5.3%)
Musculoskeletal chest pain	2/40 (5%)		0/38 (0%)
Arthralgia	3/40 (7.5%)		3/38 (7.9%)
Nervous system disorders
Dizziness	10/40 (25%)		7/38 (18.4%)
Headache	11/40 (27.5%)		4/38 (10.5%)
Dysgeusia	2/40 (5%)		3/38 (7.9%)
Tremor	2/40 (5%)		2/38 (5.3%)
Memory impairment	2/40 (5%)		0/38 (0%)
Peripheral sensory neuropathy	0/40 (0%)		2/38 (5.3%)
Somnolence	2/40 (5%)		0/38 (0%)
Syncope	2/40 (5%)		0/38 (0%)
Psychiatric disorders
Insomnia	6/40 (15%)		7/38 (18.4%)
Depression	2/40 (5%)		2/38 (5.3%)
Renal and urinary disorders
Nocturia	2/40 (5%)		0/38 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	6/40 (15%)		11/38 (28.9%)
Cough	6/40 (15%)		8/38 (21.1%)
Oropharyngeal pain	1/40 (2.5%)		2/38 (5.3%)
Dysphonia	0/40 (0%)		2/38 (5.3%)
Hiccups	0/40 (0%)		2/38 (5.3%)
Hypoxia	2/40 (5%)		0/38 (0%)
Skin and subcutaneous tissue disorders
Rash	3/40 (7.5%)		6/38 (15.8%)
Hyperhidrosis	3/40 (7.5%)		4/38 (10.5%)
Night sweats	2/40 (5%)		3/38 (7.9%)
Pruritus	3/40 (7.5%)		1/38 (2.6%)
Erythema	0/40 (0%)		3/38 (7.9%)
Alopecia	2/40 (5%)		0/38 (0%)
Skin ulcer	0/40 (0%)		2/38 (5.3%)
Vascular disorders
Flushing	8/40 (20%)		9/38 (23.7%)
Hypotension	6/40 (15%)		4/38 (10.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.