A Study of Obinutuzumab [RO5072759 (GA101)] in Combination With CHOP Chemotherapy in Patients With Previously Untreated Advanced Diffuse Large B-Cell Lymphoma (GATHER)

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01414855
• Collaborator: (none)
• Enrollment: 100
• Locations: 38
• Arm: 1
• Actual Duration (Months): 63.8
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This open-label, multicenter study will evaluate the efficacy and safety of obinutuzumab [RO5072759 (GA101)] in combination with CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) chemotherapy in patients with advanced diffuse large B-cell lymphoma. Patients will receive 8 cycles of obinutuzumab (1000 mg intravenously on Day 1 of each 21-day cycle, during Cycle 1 obinutuzumab will also be infused on Days 8 and 15) in combination with CHOP chemotherapy on Day 1 of cycles 1 to 6. A substudy will investigate the drug-drug interaction of obinutuzumab with CHOP chemotherapy agents. For the substudy, an additional cohort of approximately 15 patients are planned to be enrolled at a subset of investigational sites.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, B-Cell	Drug: obinutuzumab; Drug: cyclophosphamide; Drug: doxorubicin; Drug: prednisone; Drug: vincristine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Open-Label, Multicenter Study of Efficacy, Safety, and Biomarkers in Patients With Previously Untreated Advanced Diffuse Large B-Cell Lymphoma Treated With GA101 (RO5072759) in Combination With CHOP Chemotherapy
• Actual Study Start Date: Aug 31, 2011
• Actual Primary Completion Date: Dec 31, 2013
• Actual Study Completion Date: Dec 23, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: obinutuzumab + CHOP Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy (cyclophosphamide, doxorubicin, vincristine and prednisone) for 6 cycles.

Drug: obinutuzumab; 1000 mg intravenously on Day 1 of each 21-day cycle, 8 cycles; during Cycle 1 administration also on Days 8 and 15.; Drug: cyclophosphamide; 750 mg/m^2 intravenous (IV), Day 1 of each 21-day cycle, 6 cycles.; Drug: doxorubicin; 50 mg/m^2 IV, Day 1 of each 21-cycle, 6 cycles.; Drug: prednisone; 100 mg/day, Days 1 through 5 of each 21-day cycle, 6 cycles.; Drug: vincristine; 1.4 mg/m^2 IV, Day 1 of each 21-day cycle, 6 cycles.

Outcome Measures

Primary Outcome Measures

1. Complete Response (CR) Rate as Assessed by the Investigator at the End of Treatment [From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)]

   Complete response rate is defined as the percentage of participants with Complete Response (CR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the investigator using regular clinical and laboratory examinations, fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT). CR is the disappearance of all evidence of disease.

2. Overall Response Rate (ORR) as Assessed by the Investigator at the End of Treatment [From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)]

   Overall response rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the investigator using regular clinical and laboratory examinations, FDG-PET and computed tomography (CT). CR is the disappearance of all evidence of disease. PR is at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.

Secondary Outcome Measures

1. Complete Response (CR) Rate as Assessed by the Independent Review Facility (IRF) at the End of Treatment [From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)]

   Complete response rate is defined as the percentage of participants with Complete Response (CR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the IRF using CT scans, PET scans and pertinent clinical information. CR is the disappearance of all evidence of disease.

2. Overall Response Rate (ORR) as Assessed by the IRF at the End of Treatment [From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)]

   Overall response rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the IRF using CT scans, PET scans and pertinent clinical information. CR is the disappearance of all evidence of disease. PR is at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.

3. Progression-Free Survival (PFS) as Assessed by the Investigator [From the first dose of study treatment to PFS assessment (up to 64 months)]

   PFS was defined as the time from the date of the first dose of study treatment until the date of disease progression, relapse, or death from any cause.

4. Duration of Response (DOR) [From the response assessment to relapse, progression, or death (up to 64 months)]

   DOR is defined as first occurrence of documented response (CR or PR) until the first occurrence of relapse or progression or death of any cause. CR: disappearance of all evidence of disease. PR: at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.

5. Percentage of Participants With Adverse Events as a Measure of Safety [From the first dose of study treatment to end of study (up to 5 years 4 months)]

   An adverse event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug or other protocol-imposed intervention. Preexisting conditions that worsened during the study were reported as adverse events.

6. Number of Participants With Grade 3 to 4 Infusion-Related (IRR) Adverse Events (AE) in Participants Receiving Shorter Duration Infusion (SDI) [From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)]

   SDI 120 is a shorter duration infusion of 120 minutes and SDI 90 is shorter duration infusion of 90 minutes. Grade 3 IRR AE: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae. Grade 4 IRR AE: Life-threatening consequences; urgent intervention indicated.

7. Pharmacokinetics (PK): Maximum Concentration Observed (Cmax) for Obinutuzumab [Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12]

   Blood was collected for PK Parameters. 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. Pharmacokinetics: Terminal Half-Life (t1/2) for Obinutuzumab [Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12]

   T1/2 is the time required for the concentration of the drug to reach half of its original value. Blood was collected for PK Parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in days

9. Pharmacokinetics: Clearance (Cl) for Obinutuzumab [Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12]

   Cl is the volume of serum cleared of the drug per unit of time. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in milliliters/day (mL/day).

10. Pharmacokinetics: Volume of Distribution (V) for Obinutuzumab [Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12]

    V is the apparent volume in which a drug is distributed in the body. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in milliliters (mL).

11. Pharmacokinetics: Area Under the Concentration-Time Curve 7 Day (AUC7day) [Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12]

    Blood was collected for PK parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in in day times micrograms per milliliter (day*μg/mL).

12. Pharmacodynamics: Peripheral Blood CD19-positive B-cell Count [Up to approximately 24 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult patients, ≥18 years of age

• Previously untreated cluster of differentiation antigen 20 (CD20)-positive diffuse large B-cell lymphoma

• Ann Arbour Stage III/IV and bulky II (mass >10 cm)

• At least one bi-dimensionally measurable lesion defined as >1.5 cm in its largest dimension by CT scan

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2

• Left ventricular ejection fraction ≥50%

• Adequate hematologic function

Exclusion Criteria:

• Transformed lymphoma (follicular IIIB) if previously treated with chemotherapy or immunotherapy

• Prior therapy for diffuse large B-cell lymphoma except for nodal biopsy or local irradiation

• Central nervous system (CNS) lymphoma, primary mediastinal large cell lymphoma, primary cutaneous lymphoma, primary effusion lymphoma

• Patients who received cytotoxic drugs or rituximab as part of their treatment for another condition (e.g. rheumatoid arthritis) or prior use of an anti-CD20 antibody

• Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1

• Contraindication to any of the individual components of CHOP, including prior receipt of anthracyclines

• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy

• History of other malignancy, except for curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix, or malignancy treated with or without curative intent and in remission without treatment for ≥2 years prior to enrolment

• Positive for hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or human T-cell leukemia virus (HTLV-1) infection

• Pregnant or lactating women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294-3300
2	cCare	Encinitas	California	United States	92024
3	University of Colorado Cancer Center Department of Hematology	Aurora	Colorado	United States	80045
4	Rocky Mountain Cancer Ctr - Denver (Williams)	Denver	Colorado	United States	80218
5	Norwalk Hospital	Norwalk	Connecticut	United States	06856
6	Florida Cancer Specialists; Department of Oncology	Fort Myers	Florida	United States	33901-8101
7	Florida Cancer Specialists; Saint Petersburg	Saint Petersburg	Florida	United States	33719
8	Northwest Georgia Oncology Centers PC - Marietta	Marietta	Georgia	United States	30060
9	Kootenai Medical Center	Coeur d'Alene	Idaho	United States	83814
10	Northwestern University; Robert H. Lurie Comp Can Ctr	Chicago	Illinois	United States	60611
11	Onc Hem Assoc of Central IL	Peoria	Illinois	United States	61615-7828
12	McFarland Clinic	Ames	Iowa	United States	50010
13	Jewish Cancer Care	Louisville	Kentucky	United States	40245
14	University of Massachusetts Medical School	Worcester	Massachusetts	United States	01655
15	University of Michigan	Ann Arbor	Michigan	United States	48109-0934
16	MT Cancer Inst Fndtn; MT Can Spec	Missoula	Montana	United States	59802
17	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89128
18	MSKCC at Basking Ridge	Basking Ridge	New Jersey	United States	07920
19	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
20	San Juan Oncology Associates	Farmington	New Mexico	United States	87401
21	Memorial Sloan-Kettering; Cancer Center	Commack	New York	United States	11725
22	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
23	MSKCC at Mercy Med Ctr	Rockville Centre	New York	United States	11570
24	MSKCC at Sleepy Hollow	Sleepy Hollow	New York	United States	10591
25	Emerywood Hematology and Onc	High Point	North Carolina	United States	27262
26	Willamette Valley Cancer Insitute and Research Center	Springfield	Oregon	United States	97477
27	Medical University of SC (MUSC)	Charleston	South Carolina	United States	29425
28	SCRI-Tennessee Oncology	Nashville	Tennessee	United States	37203
29	Onc & Hem Assoc; USO Cent Pharm	Fort Worth	Texas	United States	76177
30	MD Anderson Cancer Center Department of Lymphoma & Myeloma	Houston	Texas	United States	77030
31	Methodist Hospital Research Institute	Houston	Texas	United States	77030
32	Cancer Therapy & Research Center	San Antonio	Texas	United States	78229
33	USO - Tyler Cancer Ctr	Tyler	Texas	United States	75702
34	Blue Ridge Cancer Care - Roanoke	Roanoke	Virginia	United States	24014
35	Medical Oncology Associates	Spokane	Washington	United States	99208
36	Northwest Cancer Specialists - Vancouver	Vancouver	Washington	United States	98684
37	Yakima Valley Memorial Hospital/North Star Lodge	Yakima	Washington	United States	98902
38	Aurora Bay Care Medical Center	Green Bay	Wisconsin	United States	54311

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Clinical Trials, Genentech, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT01414855
• Other Study ID Numbers: GAO4915g
• First Posted: Aug 11, 2011
• Last Update Posted: Apr 25, 2018
• Last Verified: Apr 1, 2018

• Additional relevant MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Prednisone; Cyclophosphamide; Doxorubicin; Vincristine; Obinutuzumab

Study Results

Participant Flow

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy (cyclophosphamide, doxorubicin, vincristine and prednisone) for 6 cycles.
Period Title: Overall Study
STARTED	100
COMPLETED	71
NOT COMPLETED	29

Baseline Characteristics

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Overall Participants	100
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.9 (14.4)
Sex: Female, Male (Count of Participants)
Female	43 43%
Male	57 57%

Outcome Measures

1. Primary Outcome

Title	Complete Response (CR) Rate as Assessed by the Investigator at the End of Treatment
Description	Complete response rate is defined as the percentage of participants with Complete Response (CR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the investigator using regular clinical and laboratory examinations, fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT). CR is the disappearance of all evidence of disease.
Time Frame	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)

Outcome Measure Data

Analysis Population Description

All participants.

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Measure Participants	100
Number (95% Confidence Interval) [percentage of participants]	55.0 55%

2. Primary Outcome

Title	Overall Response Rate (ORR) as Assessed by the Investigator at the End of Treatment
Description	Overall response rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the investigator using regular clinical and laboratory examinations, FDG-PET and computed tomography (CT). CR is the disappearance of all evidence of disease. PR is at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.
Time Frame	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Measure Participants	100
Number (95% Confidence Interval) [percentage of participants]	82.0 82%

3. Secondary Outcome

Title	Complete Response (CR) Rate as Assessed by the Independent Review Facility (IRF) at the End of Treatment
Description	Complete response rate is defined as the percentage of participants with Complete Response (CR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the IRF using CT scans, PET scans and pertinent clinical information. CR is the disappearance of all evidence of disease.
Time Frame	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)

Outcome Measure Data

Analysis Population Description

All participants.

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Measure Participants	100
Number (95% Confidence Interval) [percentage of participants]	58.0 58%

4. Secondary Outcome

Title	Overall Response Rate (ORR) as Assessed by the IRF at the End of Treatment
Description	Overall response rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the IRF using CT scans, PET scans and pertinent clinical information. CR is the disappearance of all evidence of disease. PR is at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.
Time Frame	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Measure Participants	100
Number (95% Confidence Interval) [percentage of participants]	75.0 75%

5. Secondary Outcome

Title	Progression-Free Survival (PFS) as Assessed by the Investigator
Description	PFS was defined as the time from the date of the first dose of study treatment until the date of disease progression, relapse, or death from any cause.
Time Frame	From the first dose of study treatment to PFS assessment (up to 64 months)

Outcome Measure Data

Analysis Population Description

All participants. Patients who had not progressed, relapsed or died at the time of analysis were censored on the date of last valid disease assessment. If no tumor assessments were performed after the baseline visit, the patient was censored for PFS at the date after the first dose of study treatments.

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Measure Participants	100
Median (95% Confidence Interval) [months]	48.3

6. Secondary Outcome

Title	Duration of Response (DOR)
Description	DOR is defined as first occurrence of documented response (CR or PR) until the first occurrence of relapse or progression or death of any cause. CR: disappearance of all evidence of disease. PR: at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.
Time Frame	From the response assessment to relapse, progression, or death (up to 64 months)

Outcome Measure Data

Analysis Population Description

All participants with data available. Participants who had not progressed, relapsed, or died at the time of analysis were censored for duration of response at the date of the last valid response assessment.

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Measure Participants	96
Median (Full Range) [months]	45.6

7. Secondary Outcome

Title	Percentage of Participants With Adverse Events as a Measure of Safety
Description	An adverse event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug or other protocol-imposed intervention. Preexisting conditions that worsened during the study were reported as adverse events.
Time Frame	From the first dose of study treatment to end of study (up to 5 years 4 months)

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received study drug.

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Measure Participants	100
Number [percentage of participants]	100.0 100%

8. Secondary Outcome

Title	Number of Participants With Grade 3 to 4 Infusion-Related (IRR) Adverse Events (AE) in Participants Receiving Shorter Duration Infusion (SDI)
Description	SDI 120 is a shorter duration infusion of 120 minutes and SDI 90 is shorter duration infusion of 90 minutes. Grade 3 IRR AE: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae. Grade 4 IRR AE: Life-threatening consequences; urgent intervention indicated.
Time Frame	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)

Outcome Measure Data

Analysis Population Description

Participants from the Safety population, all randomized participants who received at least 1 dose of study drug, who received shorter duration infusions.

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Measure Participants	75
SDI 120 (n=5)	0 0%
SDI 90 (n=70)	0 0%

9. Secondary Outcome

Title	Pharmacokinetics (PK): Maximum Concentration Observed (Cmax) for Obinutuzumab
Description	Blood was collected for PK Parameters. 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	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12

Outcome Measure Data

Analysis Population Description

PK-Evaluable included all participants with viable PK data for analysis.

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Measure Participants	100
Cycle 1	297 (110)
Cycle 8 (n = 85)	574 (183)

10. Secondary Outcome

Title	Pharmacokinetics: Terminal Half-Life (t1/2) for Obinutuzumab
Description	T1/2 is the time required for the concentration of the drug to reach half of its original value. Blood was collected for PK Parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in days
Time Frame	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12

Outcome Measure Data

Analysis Population Description

PK-Evaluable included all participants with viable PK data for analysis.

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Measure Participants	100
Cycle 1 (n = 37)	6.04 (1.54)
Cycle 8 (n = 21)	23 (15.9)

11. Secondary Outcome

Title	Pharmacokinetics: Clearance (Cl) for Obinutuzumab
Description	Cl is the volume of serum cleared of the drug per unit of time. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in milliliters/day (mL/day).
Time Frame	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12

Outcome Measure Data

Analysis Population Description

PK-Evaluable included all participants with viable PK data for analysis.

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Measure Participants	100
Cycle 1 (n = 54)	456 (254)
Cycle 8 (n = 37)	143 (59.8)

12. Secondary Outcome

Title	Pharmacokinetics: Volume of Distribution (V) for Obinutuzumab
Description	V is the apparent volume in which a drug is distributed in the body. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in milliliters (mL).
Time Frame	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12

Outcome Measure Data

Analysis Population Description

PK-Evaluable included all participants with viable PK data for analysis.

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Measure Participants	100
Cycle 1 (n = 54)	4580 (2450)
Cycle 8 (n = 37)	9210 (17000)

13. Secondary Outcome

Title	Pharmacokinetics: Area Under the Concentration-Time Curve 7 Day (AUC7day)
Description	Blood was collected for PK parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in in day times micrograms per milliliter (day*μg/mL).
Time Frame	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12

Outcome Measure Data

Analysis Population Description

PK-Evaluable included all participants with viable PK data for analysis.

Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
Measure Participants	100
Cycle 1 (n = 59)	1320 (440)
Cycle 8 (n = 74)	3300 (1130)

14. Secondary Outcome

Title	Pharmacodynamics: Peripheral Blood CD19-positive B-cell Count
Time Frame	Up to approximately 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From the first dose of study treatment to clinical data cut-off: 23 December 2016 (up to 5 years, 4 months)
Adverse Event Reporting Description	All participants who received at least 1 dose of study drug.
Arm/Group Title	Obinutuzumab + CHOP
Arm/Group Description	Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.
All Cause Mortality
	Obinutuzumab + CHOP
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Obinutuzumab + CHOP
	Affected / at Risk (%)	# Events
Total	38/100 (38%)
Blood and lymphatic system disorders
Febrile neutropenia	14/100 (14%)
Anaemia	1/100 (1%)
Neutropenia	1/100 (1%)
Pancytopenia	1/100 (1%)
Cardiac disorders
Cardiac failure congestive	1/100 (1%)
Acute left ventricular failure	1/100 (1%)
Cardiovascular disorder	1/100 (1%)
Left ventricular dysfunction	1/100 (1%)
Gastrointestinal disorders
Diarrhoea	2/100 (2%)
Abdominal pain	1/100 (1%)
Abdominal pain lower	1/100 (1%)
Intestinal perforation	1/100 (1%)
Intra-abdominal haemorrhage	1/100 (1%)
Rectal haemorrhage	1/100 (1%)
Small intestinal obstruction	1/100 (1%)
Upper gastrointestinal haemorrhage	1/100 (1%)
General disorders
Asthenia	1/100 (1%)
Chest pain	1/100 (1%)
Death	1/100 (1%)
Infections and infestations
Pneumonia	6/100 (6%)
Sepsis	2/100 (2%)
Catheter site cellulitis	1/100 (1%)
Cellulitis	1/100 (1%)
Clostridium difficile infection	1/100 (1%)
Pneumonia cytomegaloviral	1/100 (1%)
Device related infection	1/100 (1%)
Encephalitis	1/100 (1%)
Enterococcal infection	1/100 (1%)
Herpes zoster	1/100 (1%)
Herpes zoster disseminated	1/100 (1%)
Colonic abscess	1/100 (1%)
Localised infection	1/100 (1%)
Pneumonia legionella	1/100 (1%)
Septic shock	1/100 (1%)
Urinary tract infection	1/100 (1%)
Injury, poisoning and procedural complications
Femur fracture	1/100 (1%)
Hip fracture	1/100 (1%)
Metabolism and nutrition disorders
Dehydration	2/100 (2%)
Hyponatraemia	1/100 (1%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/100 (1%)
Pathological fracture	1/100 (1%)
Nervous system disorders
Cerebrovascular accident	1/100 (1%)
Hemiparesis	1/100 (1%)
Presyncope	1/100 (1%)
Spondylitic myelopathy	1/100 (1%)
Syncope	1/100 (1%)
Psychiatric disorders
Mental status changes	2/100 (2%)
Delirium	1/100 (1%)
Suicide attempt	1/100 (1%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	2/100 (2%)
Pulmonary embolism	2/100 (2%)
Dyspnoea	1/100 (1%)
Skin and subcutaneous tissue disorders
Ecchymosis	1/100 (1%)
Other (Not Including Serious) Adverse Events
	Obinutuzumab + CHOP
	Affected / at Risk (%)	# Events
Total	100/100 (100%)
Blood and lymphatic system disorders
Neutropenia	40/100 (40%)
Anaemia	18/100 (18%)
Thrombocytopenia	6/100 (6%)
Cardiac disorders
Tachycardia	9/100 (9%)
Eye disorders
Lacrimation increased	5/100 (5%)
Vision blurred	5/100 (5%)
Gastrointestinal disorders
Nausea	59/100 (59%)
Diarrhoea	38/100 (38%)
Vomiting	31/100 (31%)
Constipation	29/100 (29%)
Stomatitis	14/100 (14%)
Abdominal pain	12/100 (12%)
Dry mouth	9/100 (9%)
Gastrooesophageal reflux disease	8/100 (8%)
Dyspepsia	5/100 (5%)
Oral pain	6/100 (6%)
Haemorrhoids	5/100 (5%)
General disorders
Fatigue	48/100 (48%)
Chills	41/100 (41%)
Pyrexia	26/100 (26%)
Mucosal inflammation	10/100 (10%)
Oedema peripheral	9/100 (9%)
Chest pain	7/100 (7%)
Pain	6/100 (6%)
Asthenia	5/100 (5%)
Infections and infestations
Urinary tract infection	9/100 (9%)
Sinusitis	6/100 (6%)
Candida infection	5/100 (5%)
Upper respiratory tract infection	5/100 (5%)
Injury, poisoning and procedural complications
Infusion related reaction	56/100 (56%)
Skin abrasion	5/100 (5%)
Investigations
Weight decreased	12/100 (12%)
Ejection fraction decreased	5/100 (5%)
Metabolism and nutrition disorders
Decreased appetite	19/100 (19%)
Dehydration	15/100 (15%)
Hypokalaemia	10/100 (10%)
Hypomagnesaemia	5/100 (5%)
Musculoskeletal and connective tissue disorders
Back pain	14/100 (14%)
Bone pain	14/100 (14%)
Arthralgia	10/100 (10%)
Myalgia	8/100 (8%)
Pain in extremity	5/100 (5%)
Nervous system disorders
Neuropathy peripheral	24/100 (24%)
Headache	20/100 (20%)
Dizziness	17/100 (17%)
Dysgeusia	7/100 (7%)
Paraesthesia	5/100 (5%)
Peripheral sensory neuropathy	5/100 (5%)
Psychiatric disorders
Insomnia	14/100 (14%)
Anxiety	10/100 (10%)
Renal and urinary disorders
Dysuria	5/100 (5%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	28/100 (28%)
Cough	20/100 (20%)
Oropharyngeal pain	15/100 (15%)
Hiccups	6/100 (6%)
Skin and subcutaneous tissue disorders
Alopecia	40/100 (40%)
Rash	8/100 (8%)
Pruritus	7/100 (7%)
Night sweats	6/100 (6%)
Vascular disorders
Hypotension	15/100 (15%)

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.