Clinical trial NCT03817853
Conditions: Advanced Follicular Lymphoma
Sponsor: Hoffmann-La Roche
Start date: 2019-02-26; Completion date: 2023-01-25
Enrollment: 114 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This open-label, single arm study will evaluate the safety of obinutuzumab administered as a short duration infusion (SDI; target 90-minute infusion) during cycle 2 and from cycle 2 onwards in combination with chemotherapy in participants with previously untreated advanced follicular lymphoma (FL). The study has two phases: in the first phase, participants will receive the first cycle of obinutuzumab-based chemotherapy (G-chemo) induction therapy as usual with the first three infusions of obinutuzumab (1000 mg) administered at the regular infusion rate on Day 1, 8, and 15 of cycle 1. Phase 2 starts when participants who do not experience any Grade ≥ 3 infusion related reactions during the first cycle receive their first obintuzumab infusion given at the faster infusion rate in Cycle 2. For Cycle 2, Day 1 and all other following infusions (including maintenance), obinutuzumab will be administered at a faster infusion of 90-minute SDI, as long as the participant does not experience any Grade ≥ 3 infusion related reactions. The investigator is free to choose the chemotherapy for each participant (bendamustine, CHOP \[cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone/methylprednisolone\], or CVP \[cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone\]). The total number of cycles of G-chemo induction therapy and the cycles length depends on the chemotherapy chosen for each participant.

Detailed description:

Arms: arm 1: Participants received 6-8 cycles of obinutuzumab, combined with 6 or 8 cycles of standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone/methylprednisolone \[CHOP - 21-day cycle) or bendamustine (28-day cycle), or cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone \[CVP - 21-day cycle\]). Participants received an additional two doses of obinutuzumab on Days 8 and 15 of Cycle 1. The investigator is free to choose the chemotherapy for each patient. Obinutuzumab and chemotherapy is administered during induction phase and obinutuzumab monotherapy is administered during maintenance phase.
Interventions: intervention 1: Obinutuzumab intervention 2: Bendamustine intervention 3: Cyclophosphamide intervention 4: Doxorubicin intervention 5: Prednisone/Prednisolone/Methylprednisolone intervention 6: Vincristine
Intervention descriptions: intervention 1: Obinutuzumab 1000 mg IV infusion, administered on Day 1, 8 and 15 during Cycle 1, and on Day 1 of subsequent cycles, for 6-8 cycles. Each cycle is 21 or 28 days long depending on the chemotherapy regimen allocated. Maintenance obinutuzumab monotherapy in patients who achieve at least a partial response, after induction therapy will be administered a dose of 1000 mg once every 8 weeks for 2 years or until disease progression (whichever occurs first). intervention 2: Bendamustine will be administered on Days 1 and 2 for Cycles 1-6 at a dose of 90 mg/m2/day, for six 28-day cycles. intervention 3: Cyclophosphamide 750 milligrams per square metre (mg/m\^2), administered intravenously (IV) on Day 1 of each 21-day cycle, for six cycles for CHOP treatment or eight cycles for CVP treatment. intervention 4: Doxorubicin 50 mg/m\^2 IV, administered on Day 1 of each 21-day cycle, for six cycles. intervention 5: Prednisone 100 mg (or equivalent prednisolone or methylprednisolone), administered orally on Days 1-5 of each 21-day cycle, for six cycles for CHOP treatment or eight cycles for CVP treatment. intervention 6: Vincristine 1.4 mg/m\^2 (maximum 2 mg) IV, administered on Day 1 of each 21-day cycle, for six cycles for CHOP treatment or eight cycles for CVP treatment.

Protocol documents:
Prot_002.pdf: 
 
Official Title: A Multicentric, Open-Label, Single arm Study of Obinutuzumab Short 
Duration Infusion (SDI) in Patients With Previously Untreated 
Advanced Follicular Lymphoma 
NCT Number: NCT03817853 
Document Dates: Protocol Version 5: 30-June-2021 
 
 
 


PROTOCOL AMENDMENT APPROVAL 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
Protocol MO40597, Version 5 
PROTOCOL 
TITLE: 
A MULTICENTRIC, OPEN-LABEL, SINGLE ARM 
STUDY OF OBINUTUZUMAB SHORT DURATION 
INFUSION (SDI) IN PATIENTS WITH PREVIOUSLY 
UNTREATED ADVANCED FOLLICULAR 
LYMPHOMA 
PROTOCOL NUMBER: MO40597 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2018-003255-38 
IND NUMBER: 
104405 
TEST PRODUCT: 
Obinutuzumab (GA101, RO5072759) 
MEDICAL MONITOR: 
SPONSOR: 
F. Hoffmann-La Roche Ltd
APPROVAL DATE:  
See electronic date stamp below
Company Signatory
Approver's Name
Title
Date and Time (UTC)
30-Jun-2021 07:42:13


 
 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
2/Protocol MO40597, Version 5 
PROTOCOL HISTORY 
 
Protocol 
Version 
Date Final 
5 
See electronic date 
stamp on title page 
4 
21 September 2019 
3 
18 December 2018 
2 
06 December 2018 
1 
17 October 2018 
 


 
 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
3/Protocol MO40597, Version 5 
PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol MO40597 has been amended to provide guidance on the use of COVID-19 
vaccines in study patients and to add in the time windows allowed for completing the 
regular infusion and short duration infusion. Changes to the protocol, along with a 
rationale for each change, are summarized below: 
• 
Section 4.4.1 (Permitted Therapy) has been updated to indicate that patients are 
permitted to use COVID-19 vaccines that have been granted emergency use 
authorization or equivalent.  The vaccine should be captured in the eCRF as a 
concomitant medication and the brand/trade name or company manufacturer should 
be reported, if available. 
• 
Section 5.1.1.7 (Risks Associated with Obinutuzumab: Immunizations) has also 
been updated accordingly to describe the anticipated risk that the efficacy of 
COVID-19 vaccines may be diminished in patients receiving obinutuzumab. 
• 
Table 1 (Obinutuzumab Infusion Rates at Induction and Maintenance) has been 
updated to include the time windows allowed for completing the short duration 
infusion (93 [± 5] minutes) and regular rate infusion (195 [± 10] minutes). 
• 
An error in Figure 1 has been corrected: Patients with stable disease or progressive 
disease as best response after induction therapy will discontinue study treatment 
(and not discontinue the study); these patients have a safety follow-up visit 90 days 
(± 10 days) from the time of the last dose of study treatment. 
  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.  
 
 


 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND .......................................................................................... 24 
1.1 
Background on Follicular Lymphoma .................................... 24 
1.1.1 
Non-Hodgkin Lymphoma ....................................................... 24 
1.1.1.1 
Follicular Lymphoma ............................................................. 24 
1.2 
Background on Obinutuzumab .............................................. 25 
1.2.1 
Obinutuzumab (RO5072759, GA101) Structure 
and Mechanism of Action ...................................................... 25 
1.2.2 
Nonclinical Efficacy with Obinutuzumab ................................ 25 
1.2.3 
Clinical Experience with Obinutuzumab................................. 26 
1.2.3.1 
Clinical Efficacy in Previously Untreated Follicular 
Lymphoma (Study BO21223 [GALLIUM]).............................. 26 
1.2.3.2 
Clinical Efficacy in Follicular Lymphoma 
Relapsed or Refractory to Rituximab (Study 
GAO4753g [GADOLIN]) ........................................................ 27 
1.2.3.3 
Previous obinutuzumab SDI experience (Study 
GAO4915g [GATHER]). ......................................................... 28 
1.2.4 
Summary of Clinical Safety of Obinutuzumab ....................... 29 
1.2.5 
Pharmacokinetic and Pharmacodynamic Data for 
Obinutuzumab ....................................................................... 30 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 31 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 33 
2.1 
Safety Objectives ................................................................... 33 
2.2 
Secondary Efficacy Objective ................................................ 34 
2.3 
Exploratory Objectives ........................................................... 34 
2.4 
Pharmacokinetic Objective .................................................... 36 
2.5 
Immunogenicity Objective ...................................................... 36 
2.6 
Biomarker Objective .............................................................. 36 
3. 
STUDY DESIGN ......................................................................................... 36 
3.1 
Description of the Study......................................................... 36 


 
 
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3.2 
End of Study and Length of Study ......................................... 40 
3.3 
Rationale for Study Design .................................................... 40 
3.3.1 
Rationale for Obinutuzumab Dose and Schedule .................. 40 
3.3.2 
Rationale for Patient Population ............................................ 41 
3.3.3 
Rationale for Combination Therapies .................................... 41 
3.3.4 
Rationale for Provider- and Patient-Reported 
Outcomes .............................................................................. 41 
4. 
MATERIALS AND METHODS .................................................................... 42 
4.1 
Patients .................................................................................. 42 
4.1.1 
Inclusion Criteria .................................................................... 42 
4.1.2 
Exclusion Criteria ................................................................... 43 
4.2 
Method of Treatment Assignment and Blinding ..................... 46 
4.3 
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 46 
4.3.1 
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 46 
4.3.1.1 
Obinutuzumab ....................................................................... 46 
4.3.1.2 
CHOP Chemotherapy ............................................................ 46 
4.3.1.3 
CVP Chemotherapy ............................................................... 46 
4.3.1.4 
Bendamustine ........................................................................ 46 
4.3.2 
Study Treatment Dosage, Administration, and 
Compliance ............................................................................ 47 
4.3.2.1 
Obinutuzumab ....................................................................... 47 
4.3.2.2 
Combination Chemotherapy .................................................. 47 
4.3.3 
Premedication ........................................................................ 49 
4.3.3.1 
Premedication for infusion-related reactions .......................... 49 
4.3.3.2 
Premedication for tumor lysis syndrome (TLS) ...................... 50 
4.3.4 
Investigational Medicinal Product Accountability ................... 50 
4.3.5 
Continued Access to Obinutuzumab ..................................... 50 
4.4 
Concomitant Therapy and Additional Restrictions ................. 50 
4.4.1 
Permitted Therapy ................................................................. 51 
4.4.2 
Prohibited Therapy ................................................................ 51 
4.5 
Study Assessments ............................................................... 52 


 
 
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4.5.1 
Informed Consent Forms and Screening Log ........................ 52 
4.5.2 
Medical History, Concomitant Medication, and 
Demographic Data ................................................................. 52 
4.5.3 
Physical Examinations ........................................................... 53 
4.5.4 
Vital Signs .............................................................................. 54 
4.5.5 
Tumor and Response Evaluations ......................................... 54 
4.5.6 
Laboratory, Biomarker, and Other Biological 
Samples ................................................................................. 54 
4.5.7 
Electrocardiograms ................................................................ 55 
4.5.8 
Echocardiogram or MUGA ..................................................... 55 
4.5.9 
Clinical Outcome Assessments ............................................. 55 
4.5.9.1 
Data Collection Methods for Clinical Outcome 
Assessments ......................................................................... 56 
4.5.9.2 
Description of Clinical Outcome Assessment 
Instruments ............................................................................ 57 
4.6 
Treatment, Patient, Study, and Site 
Discontinuation ...................................................................... 57 
4.6.1 
Study Treatment Discontinuation ........................................... 57 
4.6.2 
Patient Discontinuation from the Study .................................. 58 
4.6.3 
Study Discontinuation ............................................................ 58 
4.6.4 
Site Discontinuation ............................................................... 58 
5. 
ASSESSMENT OF SAFETY ....................................................................... 59 
5.1 
Safety Plan ............................................................................ 59 
5.1.1 
Risks Associated With Obinutuzumab ................................... 59 
5.1.1.1 
Infusion-Related Reactions and Hypersensitivity 
Reactions ............................................................................... 59 
5.1.1.2 
Tumor Lysis Syndrome .......................................................... 60 
5.1.1.3 
Neutropenia ........................................................................... 60 
5.1.1.4 
Prolonged B-cell depletion ..................................................... 61 
5.1.1.5 
Thrombocytopenia ................................................................. 61 
5.1.1.6 
Infections ............................................................................... 61 
5.1.1.7 
Immunizations ....................................................................... 62 
5.1.1.8 
Worsening of Preexisting Cardiac Condition ......................... 63 


 
 
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5.1.1.9 
Gastrointestinal Perforation ................................................... 63 
5.1.1.10 
Secondary Malignancies........................................................ 63 
5.1.2 
Risks Associated With Bendamustine ................................... 63 
5.1.3 
Risks Associated With CHOP ................................................ 63 
5.1.4 
Risks Associated With CVP ................................................... 63 
5.1.5 
Management of Patients Who Experience 
Adverse Events ..................................................................... 64 
5.1.5.1 
Management Guidelines ........................................................ 64 
5.2 
Safety Parameters and Definitions ........................................ 68 
5.2.1 
Adverse Events ..................................................................... 68 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 69 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 70 
5.2.4 
Selected Adverse Events ....................................................... 70 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 71 
5.3.1 
Adverse Event Reporting Period ........................................... 71 
5.3.2 
Eliciting Adverse Event Information ....................................... 71 
5.3.3 
Assessment of Severity of Adverse Events ........................... 72 
5.3.4 
Assessment of Causality of Adverse Events ......................... 72 
5.3.5 
Procedures for Recording Adverse Events ............................ 73 
5.3.5.1 
Infusion-Related Reactions .................................................... 73 
5.3.5.2 
Diagnosis versus Signs and Symptoms................................. 73 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 74 
5.3.5.4 
Persistent or Recurrent Adverse Events ................................ 74 
5.3.5.5 
Abnormal Laboratory Values ................................................. 74 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 75 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 76 
5.3.5.8 
Deaths ................................................................................... 76 
5.3.5.9 
Preexisting Medical Conditions .............................................. 77 
5.3.5.10 
Lack of Efficacy or Worsening of Follicular 
Lymphoma ............................................................................. 77 


 
 
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5.3.5.11 
Hospitalization or Prolonged Hospitalization .......................... 77 
5.3.5.12 
Cases of Accidental Overdose and Medication 
Error....................................................................................... 78 
5.3.5.13 
Patient-Reported Outcome Data ........................................... 79 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 79 
5.4.1 
Emergency Medical Contacts ................................................ 80 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ..................... 80 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 80 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 80 
5.4.3 
Reporting Requirements for Pregnancies .............................. 81 
5.4.3.1 
Pregnancies in Female Patients ............................................ 81 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 81 
5.4.3.3 
Abortions ............................................................................... 82 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 82 
5.5 
Follow-Up of Patients after Adverse Events .......................... 82 
5.5.1 
Investigator Follow-Up ........................................................... 82 
5.5.2 
Sponsor Follow-Up ................................................................ 83 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 83 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 83 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 84 
6.1 
Determination of Sample Size ............................................... 84 
6.2 
Summaries of Conduct of Study ............................................ 85 
6.3 
Summaries of Demographic and Baseline 
Characteristics ....................................................................... 85 
6.4 
Safety Analyses ..................................................................... 86 
6.5 
Secondary Efficacy Analyses ................................................ 87 
6.6 
Exploratory Analyses ............................................................. 88 
6.6.1 
Exploratory Safety Analyses .................................................. 88 
6.6.2 
Exploratory Efficacy Analyses ............................................... 88 


 
 
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6.6.3 
Exploratory Provider and Patient-reported 
Analyses ................................................................................ 89 
6.7 
Interim Analysis ..................................................................... 89 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 90 
7.1 
Data Quality Assurance ......................................................... 90 
7.2 
Electronic Case Report Forms ............................................... 90 
7.3 
Source Data Documentation .................................................. 90 
7.4 
Use of Computerized Systems .............................................. 91 
7.5 
Retention of Records ............................................................. 91 
8. 
ETHICAL CONSIDERATIONS .................................................................... 92 
8.1 
Compliance with Laws and Regulations ................................ 92 
8.2 
Informed Consent .................................................................. 92 
8.3 
Institutional Review Board or Ethics Committee .................... 93 
8.4 
Confidentiality ........................................................................ 94 
8.5 
Financial Disclosure .............................................................. 94 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 94 
9.1 
Study Documentation ............................................................ 94 
9.2 
Protocol Deviations ................................................................ 95 
9.3 
Site Inspections ..................................................................... 95 
9.4 
Administrative Structure......................................................... 95 
9.5 
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 95 
9.6 
Protocol Amendments ........................................................... 96 
10. REFERENCES ........................................................................................... 97 
 
 
 
 
 


 
 
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LIST OF TABLES 
Table 1 
Obinutuzumab Infusion Rates at Induction and Maintenance ..... 38 
Table 2 
Premedication to be Administered Before Obinutuzumab 
Infusion to Reduce the Risk of IRRs ........................................... 49 
Table 3 
Guidelines for Management of Patients who Experience 
Adverse Events During Induction Treatment............................... 64 
Table 4 
Guidelines for Management of Patients Who Experience 
Adverse Events during Maintenance Treatment ......................... 68 
Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 72 
Table 6 
Relationship Between the Sample Size, the Number of 
Observed ≥G3 IRRs and the Upper Bound of the 
Corresponding Two-sided 95% Clopper-Pearson Confidence 
Interval ........................................................................................ 85 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 39 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 100 
Appendix 2 
Provider and Patient-reported Measures .................................. 103 
Appendix 3 
Eastern Cooperative Oncology Group Performance Status 
Scale ......................................................................................... 107 
Appendix 4 
Ann Arbor Staging ..................................................................... 108 
Appendix 5 
Follicular Lymphoma International Prognostic Index ................. 109 
Appendix 6 
Management of Infusion-Related Reactions ............................. 111 
Appendix 7 
Anaphylaxis Precautions ........................................................... 115 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
11/Protocol MO40597, Version 5 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A MULTICENTRIC, OPEN-LABEL, SINGLE ARM 
STUDY OF OBINUTUZUMAB SHORT DURATION 
INFUSION (SDI) IN PATIENTS WITH PREVIOUSLY 
UNTREATED ADVANCED FOLLICULAR 
LYMPHOMA 
PROTOCOL NUMBER: MO40597 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2018-003255-38 
IND NUMBER: 
104405 
TEST PRODUCT: 
Obinutuzumab (GA101, RO5072759) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by the Sponsor. 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
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PROTOCOL SYNOPSIS 
TITLE: 
A MULTICENTRIC, OPEN-LABEL, SINGLE ARM STUDY OF 
OBINUTUZUMAB SHORT DURATION INFUSION (SDI) IN 
PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED 
FOLLICULAR LYMPHOMA 
PROTOCOL NUMBER: 
MO40597 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2018-003255-38 
IND NUMBER: 
104405 
TEST PRODUCT: 
Obinutuzumab (GA101, RO5072759) 
PHASE: 
Phase IV 
INDICATION: 
Follicular lymphoma 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
The primary objective of this study is to evaluate the safety of administering obinutuzumab as a 
short duration infusion (SDI; target 90-minute infusion) during cycle 2 and from cycle 2 onwards 
in combination with chemotherapy in patients with previously untreated advanced follicular 
lymphoma (FL) on the basis of the following endpoints: 
Primary endpoint:  
• 
The incidence of Grade ≥3 infusion-related reactions (IRRs*) during cycle 2 in patients who 
had previously received obinutuzumab at the standard infusion rate during cycle 1 without 
experiencing a Grade 3 or 4 IRR, with severity determined according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. 
* IRRs are defined as all adverse events (AEs) that occur during or within 24 hours from the 
end of study treatment infusion and are judged as related to infusion of study treatment 
components (obinutuzumab and chemotherapy during induction and obinutuzumab alone 
during maintenance) by the investigator. 
Secondary safety endpoints: 
• 
Incidence, nature, and severity of all AEs during cycle 1 and from cycle 1 onwards 
(including maintenance) 
• 
Incidence of IRRs regardless of grade by cycle (separately) 
• 
Time to IRR (in hours) from infusion to onset of the IRR during cycle 2 
• 
Duration (in minutes) of obinutuzumab administration by cycle (all cycles including 
maintenance) 
• 
Type and duration of Grade ≥3 IRRs, during all cycles, where obinutuzumab was 
administered as an SDI. 
Secondary efficacy objective: 
The secondary efficacy objective for this study is to evaluate the efficacy of obinutuzumab 
administered as an SDI from cycle 2 in patients with previously untreated advanced FL on the 
basis of the following endpoints: 


 
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• 
Objective response rate at the end of induction (EOI) therapy as determined by the 
investigator and according to the guidelines used at the site (Lugano [Cheson et al 2014], 
Cheson et al 2007, or Cheson et al 1999) 
• 
Progression-free survival rate at the end of the study 
• 
Overall survival at the end of the study 
• 
Complete response (CR) rate at 30 months (CR30), as assessed by the investigator and 
according to the guidelines used at the site. 
Exploratory objectives:  
The exploratory safety objectives for this study are to further evaluate the safety of 
obinutuzumab administered in patients with previously untreated advanced FL on the basis of 
the following endpoints to evaluate the impact of time to IRR: 
• 
The incidence of Grade ≥3 IRRs* (with severity determined according to NCI CTCAE 
Version 5.0) during the first SDI cycle:  
o 
cycle 2 in patients who received obinutuzumab at the standard infusion rate without 
experiencing a Grade 3 IRR in cycle 1  
o 
cycle 3 in patients who experienced a Grade 3 IRR when administered obinutuzumab 
at the standard infusion rate in cycle 1 and subsequently received obinutuzumab at 
the standard infusion rate in cycle 2 without experiencing a Grade 3 IRR 
• 
Time to IRR (in hours) from infusion to onset of the IRR in cycle 1 or cycle 3 
* IRRs are defined as all adverse events (AEs) that occur during or within 24 hours from the 
end of study treatment infusion and are judged as related to infusion of study treatment 
components (obinutuzumab and chemotherapy during induction and obinutuzumab alone 
during maintenance) by the investigator. 
The exploratory efficacy objectives for this study are to evaluate patients with a partial response 
(PR) at the end of induction treatment who convert to CR during maintenance treatment and to 
evaluate and compare the objective response and CR rate after the end of induction treatment 
with and without 18F-fluorodeoxyglucose positron emission tomography (FDG-PET): 
• 
Proportion of patients with a PR at the end of induction treatment who convert to CR during 
maintenance treatment, as assessed by the investigator and according to the guidelines 
used at the site (see above) 
• 
Objective response rate and CR rate after the end of induction treatment, as assessed by 
the investigator and according to the guidelines used at the site (see above), for those with 
and those without 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) 
separately. 
The exploratory patient-reported objective for this study is to evaluate the severity and 
interference of disease- and treatment-related symptoms in patients with previously untreated 
advanced FL treated with obinutuzumab administered as an SDI from cycle 2. 
• 
Severity of disease symptoms experienced by patients and the interference with daily living 
caused by these symptoms, as assessed through use of the MD Anderson Symptom 
Inventory (MDASI; Appendix 2). 
The exploratory provider-reported objective is to evaluate the site experience with the SDI, 
specifically: 
• 
Physician / nurse experience on time savings with obinutuzumab SDI compared with 
obinutuzumab at the regular infusion rate 
• 
Physician / nurse experience on the convenience of and preference for obinutuzumab SDI 
compared with obinutuzumab at the regular infusion rate. 
Study Design 
Description of Study 
This is an open-label, international, multicenter, single arm Phase IV study to investigate the 
safety and efficacy of the short duration infusion (SDI; target 90-minute infusion) obinutuzumab 
in patients with previously untreated advanced FL. 


 
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The study has two phases: in the first phase patients will receive the first cycle of 
obinutuzumab-based chemotherapy (G-chemo) induction therapy as usual with the first three 
infusions of obinutuzumab (1000 mg) administered at the regular infusion rate (Table 1) on Day 
1, 8, and 15 of cycle 1. The investigator is free to choose the chemotherapy for each patient 
(bendamustine, CHOP [cyclophosphamide, doxorubicin, vincristine, 
prednisone/prednisolone/methylprednisolone], or CVP [cyclophosphamide, vincristine, and 
prednisone/prednisolone/methylprednisolone]). The total number of cycles of G-chemo 
induction therapy and the cycles length depends on the chemotherapy chosen for each patient 
(see Section 4.3.1). 
Study treatment in this protocol refers to obinutuzumab and chemotherapy during the induction 
phase and obinutuzumab monotherapy during the maintenance phase. 
For the purpose of this study IRRs are defined as all AEs that occur during or within 24 hours 
from the end of study treatment infusion and are judged as related to infusion of study treatment 
components (obinutuzumab and chemotherapy during induction and obinutuzumab alone 
during maintenance) by the investigator.  
Patients who do not experience any Grade ≥3 IRRs during the first cycle will enter into the 
second, faster infusion, phase from Cycle 2 onwards. These patients will receive obinutuzumab 
at the SDI rate, starting on Cycle 2, Day 1 (Table 1).  
Patients who experience a Grade 3 IRR during the first cycle will remain on the study but cycle 
2 of obinutuzumab must be administered at the regular infusion rate. If these patients do not 
experience a Grade ≥3 IRR during cycle 2 at the regular infusion rate, then they will be eligible 
to receive SDI dosing from cycle 3 onwards, according to investigator judgement. 
Patients who experience a first occurrence of a Grade 3 IRR during any SDI administration of 
obinutuzumab may continue to receive SDI dosing during the current infusion, and in the next 
cycle, as long as the Grade 3 IRR resolves after the infusion is interrupted and symptoms are 
treated, and no further IRR symptoms reoccur after restarting the SDI. Guidance on IRR 
management during both regular and SDI infusions is given in Appendix 6.  
The obinutuzumab infusion must be stopped, and obinutuzumab must be permanently 
discontinued, in any patient who experiences a second occurrence of any Grade 3 IRR, 
regardless of the rate of infusion. 
Patients who experience a Grade 4 IRR at any time during the study will permanently 
discontinue obinutuzumab treatment. 
 


 
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Table 1 Obinutuzumab Infusion Rates at Induction and Maintenance 
Regular infusion rate a 
SDI (approximately 
90 minutes) a 
First Infusion 
(Cycle 1, Day 1) 
Second and Third Infusions 
(Cycle 1, Days 8 and 15)  
Cycle 2, Day 1 and All Other 
following Infusions 
(including maintenance) b 
50 mg/hr 
Rate increased by 
50 mg/hr every 30 min 
400 mg/hr max rate 
Refer to Appendix 6a 
for guidance on 
management of IRRs 
during regular 
infusion 
If no IRR, or an IRR of Grade 1 
occurred during the previous 
infusion and the final infusion rate 
was 100 mg/hr or faster:  
Start at a rate of 100 mg/hr 
Increase rate by 100 mg/hr  
every 30 min 
400 mg/hr max rate  
If an IRR of Grade 2–3 occurred 
during the previous infusion, start at 
50 mg/hr. The rate of the infusion 
can be escalated in increments of 
50 mg/hr every 30 min to a 
maximum rate of 400 mg/hr 
Refer to Appendix 6b  
for guidance on  
management of IRRs  
during regular infusion 
100 mg/hr for 30 min, then 
900 mg/hr for 60 min 
Refer to Appendix 6c  
for guidance on  
management of IRRs  
during SDI infusion 
If an IRR of Grade 1–2, or a 
first occurrence of Grade 3, 
occurred during the previous 
SDI infusion and the patient 
has ongoing symptoms until 
the time of the next cycle, then 
the next administration of 
obinutuzumab should be given 
at the regular infusion rate 
as per Cycle 1, Days 8 and 15.  
If the IRR in the previous 
infusion resolved, then the 
next cycle can be administered 
at the SDI rate. 
IRR=infusion-related reaction; Max=maximum; SDI=short duration infusion 
a. To deliver the full dose of 1000 mg, the whole contents of the bag should be administered in 
195 (± 10) minutes for the regular infusion rate and 93 (± 5) minutes for the SDI. 
b. Patients should only start the SDI infusion in Cycle 2 if they did not experience any Grade ≥3 
IRRs during Cycle 1 (on Day 1, 8, or 15). If they did experience a Grade ≥3 IRR during Cycle 1 
(on Day 1, 8, or 15), then the infusion on Day 1 of Cycle 2 should be given at the regular 
infusion rate. 
 
All patients will be assessed for disease response by the investigator at the end of induction 
therapy and end of maintenance therapy according to local practice and according to the 
guidelines used at the site (Lugano [Cheson et al 2014], Cheson et al 2007, or Cheson et al 
1999). No central confirmation of disease response will be conducted. 
Patients who achieve at least a partial response following the completion of induction therapy 
will receive obinutuzumab maintenance therapy (1000 mg as single agent administered as an 
SDI every 8 weeks (± 10 days) for 2 years or until disease progression).  
The first administration of obinutuzumab maintenance therapy is expected to start 8 weeks ± 10 
days from Day 1 of the last induction cycle. 
Patients with stable disease or progressive disease as best response after induction therapy will 
discontinue study treatment and undergo a safety follow-up visit at 3 months (90 days (± 10 
days)). 
All patients will be followed up at 3 months (90 days (± 10 days)) from the time of the last dose 
of study treatment. 


 
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The first scheduled Internal Monitoring committee (IMC) data review will take place after the first 
10 patients have completed the first SDI infusion (i.e. cycle 2). The second IMC data review will 
happen after 50 patients have completed the first SDI infusion (i.e. cycle 2) or at 6 months after 
the first IMC, whichever occurs first. Furthermore, the IMC will review results obtained for the 
primary analysis, end of induction analysis, and final analysis. Further meetings will be 
scheduled as deemed necessary. Further details will be specified in the IMC charter. 
Safety will be evaluated by monitoring dose delays and dose intensity, adverse events, serious 
adverse events, and deaths. These will be graded using the NCI CTCAE, Version 5.0. 
Laboratory safety assessments will include regular monitoring of hematology and blood 
chemistry. 
Provider and patient-reported outcome data will be collected via questionnaires to document the 
severity of disease and treatment-related symptoms experienced by patients and the 
interference with daily living caused by these symptoms, as assessed through use of the MD 
Anderson Symptom Inventory (MDASI; Appendix 2); and to evaluate the site experience with 
the SDI and standard infusions of obinutuzumab. 
Number of Patients 
A total of 100 patients is needed in the SDI population. Allowing for drop-outs this means that 
approximately 112 patients will be enrolled in this study. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Signed Informed Consent Form 
2. Age ≥ 18 years at time of signing Informed Consent Form 
3. Able and willing to comply with all study related procedures including completion of 
patient-reported outcome (PRO) endpoints 
4. Ability to comply with the study protocol, in the investigator's judgment 
5. Patients with previously untreated Stage III or IV FL or Stage II bulky disease scheduled 
to receive obinutuzumab and chemotherapy due to at least one of the following criteria: 
a. Bulky disease, defined as a nodal or extranodal (except spleen) mass ≥ 7 cm in 
the greatest diameter 
b. Local symptoms or compromise of normal organ function due to progressive nodal 
disease or extranodal tumor mass 
c. Presence of B symptoms (fever [> 38ºC], drenching night sweats, or unintentional 
weight loss of > 10% of normal body weight over a period of 6 months or less) 
d. Presence of symptomatic extranodal disease (e.g., pleural effusions, peritoneal 
ascites) 
e. Cytopenias due to underlying lymphoma (i.e., absolute neutrophil count < 1.0 × 
109/L, hemoglobin < 10 g/dL, and/or platelet count < 100 × 109/L) 
f. 
Involvement of ≥ 3 nodal sites, each with a diameter of ≥ 3 cm 
g. Symptomatic splenic enlargement 
6. Histologically documented CD-20-positive FL, as determined by the local laboratory 
7. Eastern Cooperative Oncology Group (ECOG) performance status 0−2 
8. Adequate hematologic function (unless abnormalities are related to FL), defined as 
follows: 
a. Hemoglobin ≥ 9.0 g/dL 
b. Absolute neutrophil count ≥ 1.5 × 109/L 


 
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c. Platelet count ≥ 75 × 109/L 
9. Life expectancy of ≥ 12 months 
10. For women who are not postmenopausal (≥ 12 consecutive months of non-therapy-
induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement 
to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods 
that result in a failure rate of < 1% per year during the treatment period and for at least 18 
months after the last dose of obinutuzumab, for at least 3 months after the last dose of 
bendamustine or according to institutional guidelines for CHOP or CVP chemotherapy, 
whichever is longer 
a. Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of progestogen-
only hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices (IUDs), and copper IUDs 
b. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception 
Barrier methods must always be supplemented with the use of a spermicide 
11. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined 
below: 
a. With female partners of childbearing potential, men must remain abstinent or use 
a condom plus an additional contraceptive method that together result in a failure 
rate of < 1% per year during the treatment period and for at least 3 months after 
the last dose of study treatment. Men must refrain from donating sperm for the 
same period 
b. With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 3 months after the last dose of study 
treatment 
c. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Relapsed / refractory FL 
2. Prior treatment for FL with chemotherapy, radiotherapy, or immunotherapy 
3. Grade IIIb FL 
4. Histological evidence of transformation of FL into high-grade B-cell NHL 
5. Treatment with systemic immunosuppressive medications, including, but not limited to, 
prednisone/prednisolone/methylprednisolone (at a dose equivalent to >30 mg/day 
prednisone), azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor 
agents within 2 weeks prior to Day 1 of Cycle 1  
a. Treatment with inhaled corticosteroids and mineralocorticoids is permitted 


 
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b. Patients receiving corticosteroid treatment with ≤30 mg/day of prednisone or 
equivalent must be documented to be on a stable dose of at least 4 weeks' 
duration prior to enrolment 
c. If glucocorticoid treatment is urgently required for medical reasons (e.g., 
complications imminent if not treated at least with glucocorticoids; strong 
discomfort/pain of the patient due to lymphoma), prednisone 100 mg or equivalent 
can be given for a maximum of 5 sequential days, but all tumor assessments must 
be completed prior to the start of glucocorticoid treatment. Glucocorticoid 
treatment must be stopped prior to enrolment 
d. In cases when a glucocorticoid pre-treatment/pre-phase was done externally prior 
to considering the patient for study inclusion, glucocorticoids must be stopped for 
at least 7 days before screening assessments can begin 
6. History of solid organ transplantation 
7. History of anti-CD20 antibody therapy 
8. History of severe allergic or anaphylactic reaction to humanized, chimeric, or murine 
monoclonal antibodies 
9. Known sensitivity or allergy to murine products 
10. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells 
or any of the study drugs 
11. Active bacterial, viral, fungal, or other infection or any major episode of infection requiring 
treatment with intravenous (IV) antibiotics within 4 weeks of Day 1 of Cycle 1 
a. Caution should be exercised when considering the use of obinutuzumab in 
patients with a history of recurring or chronic infections 
12. Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive 
HBsAg serology) 
a. Patients with occult or prior HBV infection (defined as negative HBsAg and 
positive total HBcAb) may be included if HBV DNA is undetectable, provided that 
they are willing to undergo DNA testing at least every 3 months (during the study 
and for at least 1 year after completion of lymphoma treatment). Patients who 
have protective titers of hepatitis B surface antibody (HBsAb) after vaccination or 
prior but cured hepatitis B are eligible 
13. Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing) 
a. Patients positive for HCV antibody are eligible only if the polymerase chain 
reaction (PCR) is negative for HCV RNA 
14. Known history of human immunodeficiency virus (HIV) positive status 
a. For patients with unknown HIV status, HIV testing will be performed at screening if 
required by local regulations 
15. History of progressive multifocal leukoencephalopathy (PML) 
16. Vaccination with a live virus vaccine within 28 days prior to Day 1 of Cycle 1 or 
anticipation that such a live, attenuated vaccine will be required during the study 
17. History of prior other malignancy with the exception of: 
a. Curatively treated carcinoma in situ of the cervix, good-prognosis ductal 
carcinoma in situ of the breast, basal- or squamous-cell skin cancer, Stage I 
melanoma, or low-grade, early-stage localized prostate cancer 


 
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b. Any previously treated malignancy that has been in remission without treatment 
for ≥ 2 years prior to enrollment 
18. Evidence of any significant, uncontrolled concomitant disease that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV cardiac 
disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or 
unstable angina) or significant pulmonary disease (such as obstructive pulmonary 
disease or history of bronchospasm)  
19. Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle 
1, Day 1, or anticipation of a major surgical procedure during the course of the study 
20. For patients who will be receiving CHOP: left ventricular ejection fraction (LVEF) < 50% 
by multigated acquisition (MUGA) scan or echocardiogram  
21. Any of the following abnormal laboratory values: 
a. Creatinine > 1.5 × the upper limit of normal (ULN) (unless creatinine clearance 
normal) or creatinine clearance < 40 mL/min 
b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN 
c. Total bilirubin ≥ 1.5 × the ULN: Patients with documented Gilbert disease may be 
enrolled if total bilirubin is ≤ 3.0 × the ULN. 
d. International normalized ratio (INR) > 1.5 in the absence of therapeutic 
anticoagulation 
e. Partial thromboplastin time or activated partial thromboplastin time > 1.5 × ULN in 
the absence of a lupus anticoagulant 
22. Pregnant or lactating, or intending to become pregnant during the study 
a. Women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test 
result within 7 days prior to Day 1 of Cycle 1 
23. Any investigational therapy within 28 days prior to the start of Cycle 1 
24. Positive test results for human T-lymphotropic virus 1 (HTLV-1) 
a. HTLV testing is required in patients from endemic countries 
 
Patients who meet the following criteria will be excluded from further study participation after 
Cycle 1: 
• 
Development of a Grade 4 IRR during Cycle 1. 
 
End of Study 
The end of the study is defined as the Last Patient, Last Visit (LPLV) which will occur when the 
last patient to discontinue participation in the study has completed the safety follow-up visit or at 
the time that one of the following is documented: 
• 
Patient has withdrawn consent 
 
OR 
• 
Patient is lost to follow-up 
 
OR 
• 
Patient death. 
In addition, the Sponsor may decide to terminate the study at any time. 


 
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Length of Study 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4 years. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
Obinutuzumab will be administered intravenously at a flat dose of 1000 mg on Day 1, 8 and 15 
during Cycle 1, and on Day 1 of subsequent cycles, according to the infusion rates shown in 
Table 1. Splitting of the obinutuzumab dose (i.e. 100 mg + 900 mg) will not be permitted in this 
study. The cycle length and number of cycles depends on the chemotherapy combination (see 
below). 
Following induction obinutuzumab and chemotherapy, maintenance obinutuzumab 
monotherapy will be administered at a dose of 1000 mg once every 8 weeks (± 10 days) for 
2 years or until disease progression (whichever occurs first). 
Non-Investigational Medicinal Products 
Combination chemotherapy 
Obinutuzumab will be administered in combination with one of the following chemotherapy 
regimens: 
• 
Six 28-day cycles in combination with bendamustine 
• 
Six 21-day cycles in combination with CHOP, followed by two additional cycles of 
obinutuzumab alone 
• 
Eight 21-day cycles in combination with CVP. 
Chemotherapy combinations will be administered according to the standard preparation and 
infusion procedures of each site. Body surface area (BSA) may be capped at 2 m2 per 
institutional standards. 
Premedication 
Premedication to reduce the risk of IRRs is mandatory for the first standard infusion of 
obinutuzumab (Cycle 1, Day 1) and the first infusion of obinutuzumab given as an SDI and will 
comprise IV corticosteroid, oral analgesic/anti-pyretic, and antihistamine (e.g. 50 mg 
diphenhydramine) administered according to local guidelines. 
For subsequent cycles, premedication will depend on whether the patient experienced an IRR 
with the previous infusion. 
Patients with a high tumor burden, a circulating lymphocyte count (>25 × 109/L), or renal 
impairment (CrCL <70 mL/min) will receive premedication for TLS comprising hydration and 
uricostatics or urate oxidase 12–24 hours before infusion of obinutuzumab according to 
standard practice. 
Statistical Methods 
The primary analysis will be analyzed and reported based on all patients’ data up to the time 
when all patients have completed 2 cycles of obinutuzumab treatment. The End of Induction 
analysis will be analyzed and reported once all patients have completed the induction period. 
The final analysis will be performed at the end of the study and include PFS and OS rates. 
The analysis populations are defined as follows: 
• 
The SDI population includes all patients who received obinutuzumab as an SDI at cycle 2 
and who did not experience a Grade 3 or 4 IRR during the infusion of obinutuzumab given 
at the standard rate during cycle 1. This population will be used for the analysis of the 
primary endpoint and one of the secondary endpoints (time to IRR during cycle 2).  
• 
The safety population includes all patients who received at least one dose of obinutuzumab. 
This population will be used for all remaining analyses. 
No formal statistical hypothesis tests will be performed, and all analyses are considered 
descriptive. 


 
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Primary Analysis 
The primary objective for this study is to evaluate the safety of obinutuzumab administered as 
an SDI in patients with previously untreated advanced FL on the basis of the following endpoint: 
• 
The incidence of Grade ≥3 IRRs* during cycle 2 in patients who had previously received 
obinutuzumab at the standard infusion rate without experiencing a Grade 3 or 4 IRR, with 
severity determined according to NCI CTCAE v 5.0 
* IRRs are defined as all adverse events (AEs) that occur during or within 24 hours from the 
end of study treatment infusion and are judged as related to infusion of study treatment 
components (obinutuzumab and chemotherapy during induction and obinutuzumab alone 
during maintenance) by the investigator. 
Determination of Sample Size  
A sample size of approximately 112 patients is planned for this study.  
The incidence of Grade ≥3 IRRs during cycle 2 was chosen as the safety endpoint of primary 
interest and used to justify the sample size. Based on experience from previous studies 
(BO21223/GALLIUM, GAO4915g/GATHER), it is assumed to have an incidence rate of only 1% 
or 2%, and hence to observe only a few events. 
Observing two Grade ≥3 IRRs during cycle 2 would yield an upper bound (of the Corresponding 
Two-sided 95% Clopper-Pearson Confidence Interval [CI]) of 7.0% in an SDI population of 100 
patients and of 7.8% in an SDI population of 90 patients. Not observing any Grade ≥3 IRRs 
during cycle 2 would yield upper bounds of 3.6% and 4.0%, respectively.  
There will be no formal hypothesis test for the primary endpoint.  
Taking into account an estimated drop-out rate of 10%, a total of approximately 112 patients will 
be enrolled in this study to have 100 patients in the SDI population. If the drop-out rate would be 
lower, accrual would be stopped after 100 patients in the SDI population. If the drop-out rate 
would be higher, with 112 patients enrolled into the study a drop-out rate of 19.7% would still 
leave 90 patients in the SDI population which would result in a reasonable precision for the CI. If 
there would be less than 90 patients in the SDI population at the end of the planned enrolment 
phase, the IMC would decide whether to continue enrolment or not. 
Interim Analyses  
No formal Interim analysis is planned for this study. There will be three reporting events: the 
primary analysis, the end of induction analysis, and the final analysis. 
In addition, the data will be monitored by an Internal Monitoring Committee (IMC). The first IMC 
data review will take place after the first 10 patients have completed the first SDI infusion (i.e. 
cycle 2). The second IMC data review will happen after 50 patients have completed the first SDI 
infusion (i.e. cycle 2) or at 6 months after the first IMC, whichever occurs first. Furthermore, the 
IMC will review results obtained for the primary analysis, end of induction analysis, and final 
analysis. Further meetings will be scheduled as deemed necessary. See the IMC charter for 
details. 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
(a)PTT 
(activated) partial thromboplastin time 
ADCC 
antibody-dependent cellular cytotoxicity 
AE 
adverse events 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and 
prednisone/prednisolone/methylprednisolone 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
CrCL 
creatinine clearance 
CR 
complete response 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVP 
cyclophosphamide, vincristine, and 
prednisone/prednisolone/methylprednisolone 
DLBCL 
diffuse large B-cell lymphoma 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EOI 
end of induction 
FC 
fludarabine plus cyclophosphamide 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FL 
follicular lymphoma 
G-chemo 
obinutuzumab-based chemotherapy 
GI 
gastrointestinal 
HBV/HCV 
hepatitis B/C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 


 
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HR 
hazard ratio 
ICH 
International Council for Harmonisation 
HTLV-1 
human T-lymphotropic virus 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
infusion-related reactions 
IUD 
intrauterine devices 
IV 
intravenous 
IxRS 
interactive voice or Web-based response system 
LDH 
lactate dehydrogenase 
LPLV 
last patient, last visit 
LVEF 
left ventricular ejection fraction  
MDASI 
MD Anderson Symptom Inventory 
MUGA 
multigated acquisition (scan) 
MZL 
marginal zone lymphoma 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin lymphoma 
OS 
overall survival 
PCR 
polymerase chain reaction 
PFS 
progression-free survival 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response 
PRO 
patient-reported outcome 
PT 
prothrombin time 
RBC 
red blood cell 
SD 
stable disease 
SDI 
short duration infusion 
SLL 
small lymphocytic lymphoma 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
WBC 
white blood cell 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON FOLLICULAR LYMPHOMA  
 
1.1.1 
Non-Hodgkin Lymphoma 
Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in adults. 
In 2018, there were estimated to be 74,680 new cases and 19,910 deaths due to the 
disease in the United States (Siegel et al. 2018). In Europe, there were an estimated 
97,400 new cases and 39,500 deaths in 2018 (Ferlay et al. 2018).  
Most NHLs (also known as malignant lymphoma) are of B-cell origin and are 
characterized by the expression of a membrane antigen, CD20, which is important in cell 
cycle initiation and differentiation (Anderson et al. 1984). NHLs encompass many 
different histological sub-types, including the most common subtypes, diffuse large B-cell 
lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL). NHL 
can be broadly divided into indolent and aggressive lymphomas, each with unique 
characteristics. 
1.1.1.1 
Follicular Lymphoma 
Indolent NHLs (iNHLs) are a heterogeneous group of malignant lymphomas and account 
for approximately one third of all NHLs. Follicular lymphoma is the most common 
subtype of iNHL, accounting for about 22% of all newly diagnosed cases of NHL 
(Armitage and Weisenburger 1998). Approximately 90% of the cases have a t(14;18) 
translocation, which juxtaposes BCL2 gene with the IgH locus and results in deregulated 
expression of BCL2. 
Follicular lymphoma remains an incurable disease with the currently available therapies. 
The addition of rituximab, an anti-CD20 monoclonal antibody, to commonly used 
induction chemotherapy, including cyclophosphamide, doxorubicin, vincristine, and 
prednisone/prednisolone/methylprednisolone (CHOP); cyclophosphamide, vincristine, 
and prednisone/prednisolone/methylprednisolone (CVP); fludarabine; or bendamustine 
(Marcus et al. 2005; Hiddemann et al. 2005), followed by rituximab maintenance therapy 
led to prolonged response and improved patient outcomes. Long-term follow-up from 
Study MO18264 (PRIMA trial) confirmed the benefit of 2-year rituximab maintenance in 
patients responding to first-line immunotherapy, with a 6-year progression-free survival 
(PFS) of 59.2% compared with 42.7% in the observation arm (p<0.0001) (Salles et al. 
2013). Rituximab in combination with chemotherapy for newly diagnosed patients with 
advanced Stage III and IV disease requiring treatment continues to be strongly 
recommended by both the 2016 European Society for Medical Oncology (ESMO) 
Guidelines Working Group recommendations (Dreyling et al. 2016) and the 2018 
National Comprehensive Cancer Network (NCCN) guidelines (NCCN 2018). 


 
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Despite significant therapeutic progress with the use of chemoimmunotherapy as first-
line treatment, most patients will eventually experience disease relapse. Relapses are 
characterized by increasing refractoriness and decreasing duration of response to 
subsequent lines of therapy. Thus, new treatments are needed to improve the outcome 
for these patients. One such candidate is obinutuzumab (RO5072759, GA101), a novel 
glyco-engineered anti-CD20 monoclonal antibody that has shown efficacy with an 
acceptable toxicity profile in clinical trials.  
1.2 
BACKGROUND ON OBINUTUZUMAB 
1.2.1 
Obinutuzumab (RO5072759, GA101) Structure and Mechanism 
of Action 
Obinutuzumab is a humanized and glyco-engineered monoclonal antibody, derived by 
humanization of the parental B-Ly1 mouse antibody and subsequent glyco-engineering 
leading to the following characteristics (Beers et al. 2010; Mössner et al. 2010): 
• 
High-affinity binding to CD20 
• 
Type II binding to the CD20 epitope, leading to low complement-dependent 
cytotoxicity (CDC) related to the recognition of the CD20 epitope and the lack of 
CD20 localization into lipid rafts after binding of the monoclonal antibody to CD20 
• 
Compared with the chimeric Type I anti-CD20 antibody rituximab, increased 
antibody-dependent cellular cytotoxicity (ADCC) related to an improved binding of 
obinutuzumab to the different allotypes of FcγRIIIa expressed by natural killer cells 
and monocytes 
• 
Compared with rituximab, increased direct cell-death induction related to an elbow 
hinge amino exchange of the Fab region and Type II binding of the CD20 epitope  
Given the significantly greater ADCC and direct cell-death induction, it is possible that 
obinutuzumab may have greater efficacy than rituximab, particularly in the 80%−85% of 
patients who are carriers of the FcγRIIIa low-affinity receptor polymorphism (FF/FV 
genotype), since such patients may have decreased overall survival compared with 
patients with the high-affinity (V/V) polymorphism who demonstrate improved survival 
following therapy with chemotherapy plus either rituximab or I-131 tositumomab (Persky 
et al. 2009).  
1.2.2 
Nonclinical Efficacy with Obinutuzumab 
In nonclinical studies, obinutuzumab demonstrated superior depletion of normal B cells 
(measured as CD19+ depletion) from the blood of healthy volunteers (Mössner et al. 
2010) as well as malignant B cells from the blood of patients with chronic lymphocytic 
leukemia (CLL; Patz et al. 2011). Nonclinical xenograft experiments performed with 
obinutuzumab as monotherapy and in combination with chemotherapy have consistently 
showed promising anti-tumor activity of obinutuzumab (Mössner et al. 2010; 


 
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2011) and superiority of obinutuzumab over rituximab (Herting et al. 2014; Herter et al. 
2013). 
For more detailed nonclinical information on obinutuzumab, please refer to the current 
version of the obinutuzumab Investigator’s Brochure.  
1.2.3 
Clinical Experience with Obinutuzumab 
As of 26 April 2018, clinical data from 18 company-sponsored clinical studies on 
obinutuzumab as monotherapy or combination therapy in patients with NHL or CLL are 
summarized in the current obinutuzumab Investigator’s Brochure. These include 13 
Phase I/II or Phase II studies (BO29448 [GALACTA], GAO4779g [GALTON], BO21000 
[GAUDI], GAO4915g [GATHER], BO29561, BO29562, BO29563, JO29737 [GATS], 
GAO4768g [GAGE], BO20999 [GAUGUIN], BO21003 [GAUSS], YP25623 
[GERSHWIN], JO21900) and five Phase III studies (Studies BO21004 [CLL-11], 
BO21223 [GALLIUM], BO21005 [GOYA], GAO4753g [GADOLIN], MO28543 [GREEN]).  
As of 26th April 2018, obinutuzumab has been administered to an estimated 3745 study 
patients with CLL or NHL, from doses ranging from 50 mg to 2000 mg in monotherapy or 
in combination with CHOP, fludarabine plus cyclophosphamide (FC), bendamustine, 
CVP, atezolizumab or chlorambucil. An estimated 2359 patients have been observed for 
over 1 year, 2016 patients have been observed for ≥ 2.5 years and 1440 patients have 
been observed for ≥ 4 years since receiving the first administration of obinutuzumab. 
Results from the Phase III trials involving patients with FL, and previous experience with 
obinutuzumab SDI administration in DLBCL, are described below. For details on Phase 
I/II studies, and clinical studies in patients with other NHL subtypes or CLL, please refer 
to the current version of the obinutuzumab Investigator’s Brochure. 
1.2.3.1 
Clinical Efficacy in Previously Untreated Follicular Lymphoma 
(Study BO21223 [GALLIUM]) 
In a Phase III, open label, multicentre, randomised clinical study (BO21223/GALLIUM), 
1202 patients with previously untreated Grade 1–3a advanced (stage II bulky disease, 
stage III/IV) FL were randomized to 1:1 to receive either obinutuzumab (n=601 patients) 
or rituximab (n=601 patients) combined with chemotherapy (bendamustine, CHOP or 
CVP), followed by obinutuzumab or rituximab maintenance in patients achieving a 
complete or partial response (Marcus et al. 2017). Intravenous obinutuzumab (1,000 mg) 
was given by regular infusion on Days 1, 8 and 15 of Cycle 1, on Day 1 of subsequent 
cycles for 6–8 cycles. 
At a pre-planned interim analysis (20th May 2016), after a median follow-up of 34.5 
months, the IDMC recommended to unblind and fully analyze the study. The results 
showed that obinutuzumab-based chemotherapy significantly reduced the risk of 
disease progression or death (PFS, as assessed by investigator) compared to rituximab-


 
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based treatment in patients with previously untreated advanced FL (stratified hazard 
ratio [HR] 0.66, 95% confidence interval [CI] 0.51,0.85; log-rank p-value = 0.0012). 
Consistent results were observed in the analysis of PFS as assessed by the 
Independent Review Committee (IRC; stratified HR 0.71, 95% CI 0.54, 0.93; log-rank p-
value = 0.0138). Interim overall survival (OS) data and other secondary time-to-event 
endpoints (including event-free survival, disease-free survival, duration of response, and 
time to next anti-lymphoma treatment) were consistent with the primary efficacy endpoint 
(HRs range from 0.65–0.81) and supportive of clinical benefit for the obinutuzumab and 
chemotherapy regimen in patients with FL. 
An updated analysis (cut-off date 10th September 2016) reported treatment with 
obinutuzumab-based chemotherapy resulted in a 32% reduction in the risk of an 
investigator-assessed PFS compared with rituximab-based chemotherapy (stratified HR 
0.68, 95% CI 0.54, 0.87; log-rank p-value = 0.0016). Results of IRC-assessed PFS were 
consistent with the analysis of Investigator-assessed PFS (stratified HR 0.72, 95% CI 
0.56, 0.93; log-rank p-value = 0.0118). 
On the basis of these results, obinutuzumab was granted approval for use in patients 
with previously untreated FL in the European Union, United States, and elsewhere. 
1.2.3.2 
Clinical Efficacy in Follicular Lymphoma Relapsed or 
Refractory to Rituximab (Study GAO4753g [GADOLIN]) 
In a Phase III, open label, multicentre, randomized clinical study (GAO4753g/GADOLIN), 
396 patients with iNHL who had no response during treatment or who progressed within 
6 months following the last dose of rituximab or a rituximab-containing regimen were 
randomized 1:1 to receive either obinutuzumab plus bendamustine (n=194) or 
bendamustine alone (n=202) (Sehn et al. 2016). A total of 81.1% of patients had FL. 
MZL was present in 11.6% of patients, and 7.1% had small lymphocytic lymphoma 
(SLL). Intravenous obinutuzumab (1,000 mg) was given by regular infusion on Days 1, 8 
and 15 of Cycle 1, on Day 1 of subsequent cycles for 6 cycles. Patients in the 
obinutuzumab treatment group who had not experienced disease progression at the end 
of induction therapy received obinutuzumab monotherapy every 2 months for up to 2 
years.  
At a pre-planned interim analysis after a median follow-up of 20.3–21.9 months, the 
study met its primary objective of showing a difference in IRC-assessed PFS 
(progression or death) between treatment arms. Treatment with obinutuzumab plus 
bendamustine resulted in a clinically meaningful and statistically significant reduction by 
45% in the risk of IRC-assessed PFS compared with bendamustine alone (stratified 
analysis: HR 0.55, 95% CI 0.40, 0.74; log rank p-value = 0.0001). 
At the second efficacy analysis (cut-off date 1st April 2016), this improvement in PFS with 
obinutuzumab plus bendamustine compared with bendamustine alone was maintained 


 
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(stratified analysis: HR 0.57, 95% CI [0.44, 0.73]; log-rank p-value = 0.0001). At the cut-
off date for the primary efficacy endpoint (1st May 2015), the median IRC-assessed PFS 
was 14.1 (95% CI: 11.7, 16.6) months in the bendamustine arm vs. 29.2 (95% CI: 20.5, 
NE) months in the obinutuzumab plus bendamustine arm (HR 0.53, 95% CI 0.40, 0.70; 
log-rank test p-value = 0.0001). 
The reduction in the risk of disease progression or death seen in the iNHL population 
was driven by the subset of patients with FL (81.1% of patients). No conclusions could 
be drawn on efficacy in the MZL and SLL subgroups due to the small sample size in this 
sub population.  
At the time of the second efficacy analysis (cut-off date 1st April 2016), 64/171 (37.4%) 
patients in the bendamustine arm and 39/164 (23.8%) patients in the obinutuzumab plus 
bendamustine arm had died. Median OS for the bendamustine arm was 53.9 months but 
was not yet reached for the obinutuzumab plus bendamustine arm. The stratified HR for 
OS in just the patients with FL was 0.58 (95% CI: 0.39, 0.86). 
On the basis of these positive results obinutuzumab in combination with bendamustine 
was granted approval for use in patients with FL who did not respond or who progressed 
during or up to 6 months after treatment with rituximab or a rituximab-containing 
regimen. 
The data cut-off for the final analysis of the study was 30-Nov-2018, and the data are 
currently under assessment. 
1.2.3.3 
Previous obinutuzumab SDI experience (Study GAO4915g 
[GATHER]). 
Study GAO4915g was a Phase II, open-label, multicenter study of efficacy, safety, and 
biomarkers in patients with previously untreated advanced DLBCL treated with 
obinutuzumab in combination with CHOP chemotherapy (Sharman et al. 2019). The 
secondary safety objective of this study was to evaluate the safety and tolerability of a 
shorter duration of infusion (SDI) of obinutuzumab, as measured by the incidence of 
Grade 3 or 4 infusion-related AEs, in patients who receive an SDI of obinutuzumab.  
Once safety of obinutuzumab in combination with CHOP was established in the first 20 
patients, two SDI infusion times (120 minutes and then 90 minutes) were then tested 
(see Table S1 for infusion rates). Patients were treated with SDI if they had received ≥3 
obinutuzumab doses at the regular infusion rate without any grade ≥3 IRRs and had a 
lymphocyte count <5 × 109/L. SDI safety was assessed based on the incidence of Grade 
3/4 IRRs. 
Obinutuzumab-related IRRs were reported in 60% of patients (60/100) administered 
obinutuzumab at the regular infusion rate, in 20% of patients (1/5) who received 


 
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SDI 120, and in 2.9% of patients (2/70) who received SDI 90. Three patients 
administered obinutuzumab at the regular infusion rate experienced Grade ≥3 AEs (of 
any type); none of the patients administered obinutuzumab at the SDI 120 or SDI 90 
infusion rates experience Grade ≥3 AEs. 
Seventy-one patients received corticosteroids for IRR prophylaxis. The safety of SDI 
after cycle 1 was evaluated. Twenty patients received obinutuzumab at the standard rate 
to establish baseline safety. Thereafter, three patients who had not experienced an IRR 
Grade 3 in prior infusions were treated with SDI 120 as an initial test of SDI; none 
experienced an IRR Grade 3 and thus SDI 90 was tested. Once declared safe, 
remaining patients were treated with SDI 90 after three infusions at the standard rate. 
Overall, 69 patients (69%) experienced 244 IRRs. The majority occurred in cycle 1 
(187/244) and were predominantly Grade 2 in intensity (129/244). One Grade 4 IRR was 
reported (febrile neutropenia) and there were no Grade 5 IRRs. IRRs of all grades 
affected 60% of patients infused at the standard rate. No patients receiving SDI 90 
experienced IRRs Grade 3; 3% (2/70) experienced Grade 1 to 2 IRRs. No patients 
withdrew from obinutuzumab treatment as a result of IRRs. Obinutuzumab concentration 
at the end of infusion was summarized by infusion duration and was as expected, 
slightly higher for SDI 90 compared with the regular rate. However, when data variability 
was taken into account, the difference was not marked. 
1.2.4 
Summary of Clinical Safety of Obinutuzumab 
Overall, the safety of monotherapy obinutuzumab, or obinutuzumab combination therapy 
was clinically manageable. Adverse events of particular interest include infusion-related 
reactions (IRRs), tumor lysis syndrome (TLS), thrombocytopenia (including acute 
thrombocytopenia), neutropenia (including late onset and prolonged neutropenia), 
prolonged B-cell depletion, infections including progressive multifocal 
leukoencephalopathy (PML) and hepatitis B virus (HBV) reactivation, worsening of pre-
existing cardiac conditions, gastrointestinal (GI) perforation, and secondary 
malignancies. The important identified risks associated with obinutuzumab are 
presented in detail in Section 5.1.1 of this protocol. Appropriate risk minimization and 
mitigation actions are provided in the obinutuzumab Investigator’s Brochure (Section 6). 
The most frequent causes of death in studies of obinutuzumab were disease 
progression and adverse events associated with infectious diseases. This is consistent 
with the study population and the disease under treatment. The incidence of fatal 
adverse events was similar across all completed studies. In Study GAO4768g 
(obinutuzumab 1000 versus 2000 mg), the incidence of deaths did not increase with 
increased obinutuzumab dose (7.5% and 2.6%, respectively).  
A high incidence of IRRs was observed consistently in all obinutuzumab trials. IRRs 
appear to be linked to the release of cytokines and/or other chemical mediators from B-


 
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cells targeted by obinutuzumab. Due to the pharmacological class of obinutuzumab, as 
well as the evidence from clinical trials, the Sponsor considers IRRs as related to 
obinutuzumab. To reduce investigator bias and to generate better comparability across 
trials, IRRs in studies of obinutuzumab have typically been defined as any study 
treatment-related AEs (as assessed by the investigator) that occur during infusion or 
within 24 hours of completing the infusion. 
The reported incidence of IRRs varied across studies. In the pivotal studies, BO21004 
(CLL-11) and BO21223 (GALLIUM), the incidence of IRRs was comparable (~71%), but 
Grade 3–5 IRRs were higher in CLL indication (26.8%) as compared to FL indication 
(12.3%). In study GAO4753g (GATHER), 66.7% of patients experienced IRRs including 
11.3% with Grade 3–5 IRRs (Sharman et al. 2019). In DLBCL (aggressive NHL) in 
BO21005, the incidence of Grade 3–5 IRRs (9.8%) was comparable with the one 
observed in FL patients in BO21223 and GAO4753g.  
The incidence of IRR observed with combination therapy (FC, CHOP and 
bendamustine) appears similar to that observed with monotherapy across indications. 
Furthermore, the incidence of IRRs appears to be higher in obinutuzumab compared 
with rituximab-exposed patients based on evidence from studies BO21003 and 
BO20999. There is no clear relationship between obinutuzumab dose and the incidence 
of IRRs based on data from Study GAO4768g. The incidence and severity of IRRs are 
highest with the first infusion of obinutuzumab and decrease with subsequent infusions. 
In the pivotal trials, a higher incidence of IRR was observed in CLL obinutuzumab 
exposed patients compared to iNHL obinutuzumab exposed patients as per the 
summary below:   
 
1.2.5 
Pharmacokinetic and Pharmacodynamic Data for 
Obinutuzumab 
A population PK (PopPK) model was fitted to data from Phase I/Phase II clinical studies 
(Studies BO20999 and BO21003) and Phase III studies (BO21004, GAO4753g, and 
BO21223). Obinutuzumab concentration-time course is well described by a two-
compartment PK model with total clearance being the sum of time-independent and 
time-dependent clearance pathways. The non-linear clearance pathway (dependent on 
the number of CD20+ tumor cells) had a high contribution to total clearance at the start 
of treatment, decreased with repeated treatment, and was consistent with target-


 
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mediated drug disposition (TMDD). The linear (time-independent) clearance of 
obinutuzumab is not dependent on the number of CD20+ tumor cells and remained 
constant during the course of treatment. For a drug exhibiting TMDD, like obinutuzumab, 
the PK can be used as a surrogate marker of target occupancy, i.e., the obinutuzumab 
PK represents the binding to CD20+ malignant cells. 
Consequently, the underlying rationale in selecting an appropriate obinutuzumab dose 
and schedule was to saturate the target as early and quickly as possible and to maintain 
this saturation over the complete treatment period in all patients, while minimizing AEs. 
A loading dose strategy was applied in order to decrease the number of unbound CD20 
malignant cells rapidly; this was achieved by administering a fixed dose of 1000 mg of 
obinutuzumab on Day 1, Day 8, and Day 15 during Cycle 1 and then every 21 or 28 
days on Day 1 of subsequent cycles. 
As is typical for monoclonal antibodies, the population PK analysis of obinutuzumab has 
shown that obinutuzumab time-independent clearance (linear pathway) and central 
volume increased with body size, thus affecting the exposure to obinutuzumab. 
However, the non-linear clearance was found independent of body weight as expected 
and the loading dose strategy used in Cycle 1 was found to maximize the target 
occupancy across the whole range of body weights (median [range]: 75 kg [35.3–163]) 
The doubling of the systemic exposure in patients weighing less than 60 kg compare 
with patients weighing more than 90 kg is due to the body size effect on the linear 
clearance of obinutuzumab, however, it does not impact the saturation of the CD20 
target as the serum concentrations remain high enough across the body weight range to 
maintain the saturation of the CD20 target. This is consistent with the lack of exposure-
efficacy (PFS) relationship determined by Cox regression analysis. 
Treatment with obinutuzumab resulted in extensive B-cell depletion, with all patients 
showing a reduction in cell count to absolute zero at some stage of their treatment cycle. 
Overall, there has been no notable increase in complement levels before or after 
infusion, but changes have been observed in the levels of interleukin-6 and interleukin-8 
before and after infusion. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Despite significant therapeutic progress with the use of chemoimmunotherapy as first-
line treatment, FL remains essentially an incurable disease for which more effective 
treatments in addition to rituximab were needed. As described in Section 1.2.3, 
obinutuzumab-based chemotherapy is an effective treatment for patients with untreated 
FL and in patients with FL who did not respond or who progressed during or up to 6 
months after treatment with rituximab or a rituximab-containing regimen. Obinutuzumab 
is approved for use in these populations in the European Union, United States, and 
elsewhere.  


 
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In addition to developing more efficacious treatments for FL, there is also a need for 
more convenient treatments. The administration of obinutuzumab is associated with 
IRRs. In the GALLIUM study (BO21223), 71.6% of patients experienced an IRR, 
including 12.3% who experienced a Grade 3–5 IRR. The incidence of IRRs is greatest 
with the first infusion and decreases significantly with subsequent infusions. To reduce 
the risk of IRRs, the first dose of obinutuzumab is administered at a low rate initially 
(50 mg/hour) and gradually increased every 30 minutes in 50 mg/hour increments to a 
maximum of 400 mg/hour. If no IRR occurs during the first infusion, subsequent 
infusions start at 100 mg/hour and gradually increase every 30 minutes in 100 mg/hour 
increments to a maximum of 400 mg/hour. This means that a typical infusion of 
obinutuzumab can take around 4 hours  
Shorter infusion times would yield substantial time savings for patients and benefit 
outpatient infusion facilities by increasing both the number of infusion chairs available 
during clinic hours and nursing efficiencies.  
Infusion of rituximab, another monoclonal antibody that targets the CD20 antigen, is also 
associated with a high incidence of IRRs (Atmar et al. 2010). Standard rituximab 
administration involves a similarly cautious administration schedule to obinutuzumab 
with a slow initial infusion rate followed by increasing the rate in 30-minute increments if 
tolerated (Mabthera SmPC).  
To reduce the logistical challenges associated with rituximab administration, a 90-minute 
rapid-infusion protocol was developed (Sehn et al. 2007). This protocol administers 20% 
of the rituximab dose in the first 30 minutes, with the remaining 80% over the following 
60 minutes. In the original study by Sehn et al, no episodes of Grade ≥3 IRRs occurred 
in patients who received rituximab as a rapid-infusion (Sehn et al. 2007). Two patients 
experienced transient grade 1 toxicity, one of whom had not received rituximab 
previously with induction chemotherapy. The phase IIIb MAXIMA study investigated 
rituximab maintenance every 2 months for 2 years in 545 patients with first-line or 
relapsed FL who responded to 8 cycles of rituximab-based induction (Witzens-Harig et 
al. 2014). 82 patients received rituximab maintenance as a rapid infusion, 370 as a 
standard infusion, and 82 received both. The incidence of infusion-related AEs was 
similar among patients receiving all standard (5.4 %) or all rapid infusions (4.9 %).  
The results of other studies confirm that after the first dose of rituximab has been given in 
the standard manner, subsequent doses can safely be administered using a rapid infusion 
protocol (reviewed in Atmar et al. 2010). The RATE study (Dakhil et al. 2014) 
demonstrated a Safety Profile with a 90-minute infusion in cycles 2-8: 
• 
Of the 425 patients treated with rituximab in Cycle 1, 85% (n=363) were able to 
receive the 90-minute infusion of rituximab in Cycle 2 


 
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• 
Primary endpoint of the RATE trial was the incidence of Grade 3 or 4 IRRs the day 
of or the day after a 90-minute infusion of rituximab in Cycle 2 
• 
Incidence of Grade 3/4 IRRs in Days 1-2 of Cycle 2 was 1.1% 
• 
Incidence of Grade 3/4 IRRs was 2.8% cumulatively in Cycles 2-8 
• 
No fatal IRRs or fatal AEs on Days 1-2 of any cycle 
It is now widespread practice to administer subsequent doses as a rapid 90-minute 
infusion, if the first dose of rituximab is well-tolerated.  
In the phase 2 GAO4915g /GATHER study, in patients with previously untreated 
advanced DLBCL, the safety of shortening the duration of the obinutuzumab infusion to 
120 minutes (24 infusions) and 90 minutes (264 infusions) was also assessed by the 
incidence of Grade 3/4 infusion-related AEs (Sharman et al. 2019).  Fifty-three patients 
received at least one SDI. The SDIs were associated with three Grade 1/2 IRRs and no 
Grade ≥3 IRRs. In the phase 2 JO29737/GATS study evaluating obinutuzumab as a 
shorter duration of infusion (90 minutes) in Japanese patients with previously untreated 
NHL (DLBCL, FL, or MZL), there were no Grade ≥3 infusion-related reaction in 31 
patients who received a shorter duration of infusion of obinutuzumab over 90 minutes in 
Cycle 2. Steady-state pharmacokinetics of obinutuzumab were attained in Cycle 2 
despite the shorter duration of infusion (Ohmachi et al. 2018).   
The aim of this study is to evaluate whether a similar short duration infusion (SDI; target 
90 minute infusion) can be used for obinutuzumab induction therapy during cycle 2 and 
from cycle 2 onwards (including obinutuzumab maintenance therapy) in combination 
with chemotherapy in patients with previously untreated advanced FL. Risk mitigation 
measures in this study include the use of premedication to reduce the risk of IRRS as 
described in Section 4.3.3, safety monitoring as described in Section 5, and 
incorporation of a safety data review after the first patients receive the SDI, followed by 
periodic safety reviews.  
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety of administering obinutuzumab as a short duration 
infusion (SDI) during cycle 2 and from cycle 2 onwards in combination with 
chemotherapy in patients with previously untreated advanced FL.  
Specific objectives and corresponding endpoints for the study are outlined below. 
2.1 
SAFETY OBJECTIVES 
The primary objective of this study is to evaluate the safety of obinutuzumab 
administered as an SDI during cycle 2 and from cycle 2 onwards in patients with 
previously untreated advanced FL on the basis of the following endpoints: 


 
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Primary endpoint:  
• 
The incidence of Grade ≥3 IRRs* during cycle 2 in patients who had previously 
received obinutuzumab at the standard infusion rate during cycle 1 without 
experiencing a Grade 3 or 4 IRR, with severity determined according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 5.0. 
* IRRs are defined as all adverse events (AEs) that occur during or within 24 hours from the end 
of study treatment infusion and are judged as related to infusion of study treatment 
components (obinutuzumab and chemotherapy during induction and obinutuzumab alone 
during maintenance) by the investigator. 
Secondary safety endpoints: 
• 
Incidence, nature, and severity of all AEs during cycle 1 and from cycle 1 onwards 
(including maintenance) 
• 
Incidence of IRRs regardless of grade by cycle (separately) 
• 
Time to IRR (in hours) from infusion to onset of the IRR during cycle 2 
• 
Duration (in minutes) of obinutuzumab administration by cycle (all cycles including 
maintenance) 
• 
Type and duration of Grade ≥3 IRRs, during all cycles, where obinutuzumab was 
administered as an SDI. 
  
2.2 
SECONDARY EFFICACY OBJECTIVE 
The secondary efficacy objective for this study is to evaluate the efficacy of 
obinutuzumab administered as an SDI from cycle 2 in patients with previously untreated 
advanced FL on the basis of the following endpoints: 
• 
Objective response rate at the end of induction therapy as determined by the 
investigator and according to the guidelines used at the site (Lugano [Cheson et al 
2014], Cheson et al 2007, or Cheson et al 1999) 
• 
Progression-free survival rate at the end of the study 
• 
Overall survival at the end of the study 
• 
Complete response (CR) rate at 30 months (CR30), as assessed by the investigator 
and according to the guidelines used at the site. 
 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory safety objectives for this study are to further evaluate the safety of 
obinutuzumab administered in patients with previously untreated advanced FL on the 
basis of the following endpoints to evaluate the impact of time to IRR: 


 
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• 
The incidence of Grade ≥3 IRRs* (with severity determined according to NCI 
CTCAE Version 5.0) during the first SDI cycle:  
– 
cycle 2 in patients who received obinutuzumab at the standard infusion rate 
without experiencing a Grade 3 IRR in cycle 1  
– 
cycle 3 in patients who experienced a Grade 3 IRR when administered 
obinutuzumab at the standard infusion rate in cycle 1 and subsequently 
received obinutuzumab at the standard infusion rate in cycle 2 without 
experiencing a Grade 3 IRR 
• 
Time to IRR (in hours) from infusion to onset of the IRR in cycle 1 or cycle 3 
* IRRs are defined as all adverse events (AEs) that occur during or within 24 hours from the end 
of study treatment infusion and are judged as related to infusion of study treatment 
components (obinutuzumab and chemotherapy during induction and obinutuzumab alone 
during maintenance) by the investigator. 
The exploratory efficacy objectives for this study are to evaluate patients with a partial 
response (PR) at the end of induction treatment who convert to complete response (CR) 
during maintenance treatment and to evaluate and compare the objective response and 
CR rate after the end of induction treatment with and without 18F-fluorodeoxyglucose 
positron emission tomography (FDG-PET): 
• 
Proportion of patients with a PR at the end of induction treatment who convert to CR 
during maintenance treatment, as assessed by the investigator and according to the 
guidelines used at the site (see above) 
• 
Objective response rate and CR rate after the end of induction treatment, as 
assessed by the investigator and according to the guidelines used at the site (see 
above), for those with and those without 18F-fluorodeoxyglucose positron emission 
tomography (FDG-PET) separately. 
 
The exploratory patient-reported objective for this study is to evaluate the severity and 
interference of disease- and treatment-related symptoms in patients with previously 
untreated advanced FL treated with obinutuzumab administered as an SDI from cycle 2. 
• 
Severity of disease symptoms experienced by patients and the interference with 
daily living caused by these symptoms, as assessed through use of the MD 
Anderson Symptom Inventory (MDASI; Appendix 2). 
The exploratory provider-reported objective is to evaluate the site experience with the 
SDI, specifically: 
• 
Physician / nurse experience on time savings with obinutuzumab SDI compared 
with obinutuzumab at the regular infusion rate 


 
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• 
Physician / nurse experience on the convenience of and preference for 
obinutuzumab SDI compared with obinutuzumab at the regular infusion rate. 
 
Questionnaires for provider and patient-reported outcomes (PROs) are shown in 
Appendix 2. 
2.4 
PHARMACOKINETIC OBJECTIVE 
None. 
 
2.5 
IMMUNOGENICITY OBJECTIVE 
None. 
 
2.6 
BIOMARKER OBJECTIVE 
None. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is an open-label, international, multicenter, single arm Phase IV study to investigate 
the safety and efficacy of the short duration infusion (SDI; target 90-minute infusion) 
obinutuzumab in patients with previously untreated advanced FL. 
A total of 100 patients is needed in the SDI population (see Section 6.1). Allowing for 
drop-outs this means that approximately 112 patients will be enrolled in this study. 
The study has two phases: in the first phase patients will receive the first cycle of 
obinutuzumab-based chemotherapy (G-chemo) induction therapy as usual with the first 
three infusions of obinutuzumab (1000 mg) administered at the regular infusion rate 
(Table 1) on Day 1, 8, and 15 of cycle 1. The investigator is free to choose the 
chemotherapy for each patient (bendamustine, CHOP [cyclophosphamide, doxorubicin, 
vincristine, prednisone/prednisolone/methylprednisolone], or CVP [cyclophosphamide, 
vincristine, and prednisone/prednisolone/methylprednisolone]). The total number of 
cycles of G-chemo induction therapy and the cycles length depends on the 
chemotherapy chosen for each patient (see Section 4.3.1). 
Study treatment in this protocol refers to obinutuzumab and chemotherapy during the 
induction phase and obinutuzumab monotherapy during the maintenance phase. 
For the purpose of this study IRRs are defined as all AEs that occur during or within 24 
hours from the end of study treatment infusion and are judged as related to infusion of 
study treatment components (obinutuzumab and chemotherapy during induction and 
obinutuzumab alone during maintenance) by the investigator.  


 
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Patients who do not experience any Grade ≥3 IRRs during the first cycle will enter into 
the second, faster infusion, phase from Cycle 2 onwards. These patients will receive 
obinutuzumab at the SDI rate, starting on Cycle 2, Day 1 (Table 1).  
Patients who experience a Grade 3 IRR during the first cycle will remain on the study 
but cycle 2 of obinutuzumab must be administered at the regular infusion rate. If these 
patients do not experience a Grade ≥3 IRR during cycle 2 at the regular infusion rate, 
then they will be eligible to receive SDI dosing from cycle 3 onwards, according to 
investigator judgement. 
Patients who experience a first occurrence of a Grade 3 IRR during any SDI 
administration of obinutuzumab may continue to receive SDI dosing during the current 
infusion, and in the next cycle, as long as the Grade 3 IRR resolves after the infusion is 
interrupted and symptoms are treated, and no further IRR symptoms reoccur after 
restarting the SDI. Guidance on IRR management during both regular and SDI infusions 
is given in Appendix 6.  
The obinutuzumab infusion must be stopped, and obinutuzumab must be permanently 
discontinued, in any patient who experiences a second occurrence of any Grade 3 IRR, 
regardless of the rate of infusion.  
Patients who experience a Grade 4 IRR at any time during the study will permanently 
discontinue obinutuzumab treatment. 
 


 
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Table 1 
Obinutuzumab Infusion Rates at Induction and Maintenance 
Regular infusion rate a 
SDI (approximately 
90 minutes) a 
First Infusion 
(Cycle 1, Day 1) 
Second and Third Infusions 
(Cycle 1, Days 8 and 15) 
Cycle 2, Day 1 and All Other 
following Infusions 
(including maintenance) b 
50 mg/hr 
Rate increased by 
50 mg/hr every 30 min 
400 mg/hr max rate 
Refer to Appendix 6a 
for guidance on 
management of IRRs 
during regular 
infusion 
If no IRR, or an IRR of Grade 1 
occurred during the previous 
infusion and the final infusion rate 
was 100 mg/hr or faster:  
Start at a rate of 100 mg/hr 
Increase rate by 100 mg/hr  
every 30 min 
400 mg/hr max rate  
If an IRR of Grade 2–3 occurred 
during the previous infusion, start at 
50 mg/hr. The rate of the infusion 
can be escalated in increments of 
50 mg/hr every 30 min to a 
maximum rate of 400 mg/hr 
Refer to Appendix 6b  
for guidance on  
management of IRRs  
during regular infusion 
100 mg/hr for 30 min, then 
900 mg/hr for 60 min 
Refer to Appendix 6c  
for guidance on  
management of IRRs  
during SDI infusion 
If an IRR of Grade 1–2, or a 
first occurrence of Grade 3, 
occurred during the previous 
SDI infusion and the patient 
has ongoing symptoms until 
the time of the next cycle, then 
the next administration of 
obinutuzumab should be given 
at the regular infusion rate 
as per Cycle 1, Days 8 and 15. 
If the IRR in the previous 
infusion resolved, then the 
next cycle can be administered 
at the SDI rate. 
IRR=infusion-related reaction; Max=maximum; SDI=short duration infusion 
a. To deliver the full dose of 1000 mg, the whole contents of the bag should be administered in 
195 (± 10) minutes for the regular infusion rate and 93 (± 5) minutes for the SDI. 
b. Patients should only start the SDI infusion in Cycle 2 if they did not experience any Grade ≥3 
IRRs during Cycle 1 (on Day 1, 8, or 15). If they did experience a Grade ≥3 IRR during Cycle 1 
(on Day 1, 8, or 15), then the infusion on Day 1 of Cycle 2 should be given at the regular 
infusion rate. 
 
Figure 1 presents an overview of the study design. A schedule of activities is provided in 
Appendix 1. 


 
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Figure 1 Study Schema 
 
CR=complete response; IRR=infusion related reaction; G-chemo=obinutuzumab (Gazyva)-
containing chemotherapy PD=progressive disease; PR=partial response; SD=stable disease; 
SDI=short duration infusion; SoC=standard of care. 
 
All patients will be assessed for disease response by the investigator at the end of 
induction therapy and end of maintenance therapy according to local practice and 
according to the guidelines used at the site (Lugano [Cheson et al 2014], Cheson et al 
2007, or Cheson et al 1999). No central confirmation of disease response will be 
conducted. 
Patients who achieve at least a partial response (PR) following the completion of 
induction therapy will receive obinutuzumab maintenance therapy (1000 mg as single 
agent administered as an SDI every 8 weeks (± 10 days) for 2 years or until disease 
progression).  
The first administration of obinutuzumab maintenance therapy is expected to start 
8 weeks ± 10 days from Day 1 of the last induction cycle. 
Patients with stable disease or progressive disease as best response after induction 
therapy will discontinue study treatment and undergo a safety follow-up visit at 3 months 
(90 days (± 10 days)).  
All patients will be followed up at 3 months (90 days (± 10 days)) from the time of the last 
dose of study treatment. 


 
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The first scheduled Internal Monitoring committee (IMC) data review will take place after 
the first 10 patients have completed the first SDI infusion (i.e. cycle 2). The second IMC 
data review will happen after 50 patients have completed the first SDI infusion (i.e. cycle 
2) or at 6 months after the first IMC, whichever occurs first. Furthermore, the IMC will 
review results obtained for the primary analysis, end of induction analysis, and final 
analysis. Further meetings will be scheduled as deemed necessary. Further details will 
be specified in the IMC charter. 
Safety will be evaluated by monitoring dose delays and dose intensity, adverse events, 
serious adverse events, and deaths. These will be graded using the NCI CTCAE, 
Version 5.0. Laboratory safety assessments will include regular monitoring of 
hematology and blood chemistry. 
Provider and patient-reported measures (Appendix 2) will be assessed throughout the 
study as outlined in Appendix 1. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of the study is defined as the Last Patient, Last Visit (LPLV) which will occur 
when the last patient to discontinue participation in the study has completed the safety 
follow-up visit or at the time that one of the following is documented: 
• 
Patient has withdrawn consent 
OR 
• 
Patient is lost to follow-up 
OR 
• 
Patient death. 
In addition, the Sponsor may decide to terminate the study at any time. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4 years. 
The total length of the study for an individual patient is up to approximately 2.75 years. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Obinutuzumab Dose and Schedule 
Obinutuzumab will be administered with the treatment route, dose, and dosing regimen 
approved for use in patients with FL, i.e. 1000 mg administered intravenously on Day 1, 
8 and 15 of cycle 1 followed by 1000 mg IV on Day 1 of subsequent cycles, for 6–8 
cycles depending on the chemotherapy regimen. Maintenance obinutuzumab in patients 
who achieve at least a partial response (PR) after induction therapy will also be 
administered according to the approved indication (1000 mg obinutuzumab as single-


 
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agent therapy once every 8 weeks [± 10 days] for 2 years or until disease progression 
[whichever occurs first]). 
3.3.2 
Rationale for Patient Population 
As stated in Section 3.3.1, the incidence of IRRs following obinutuzumab administration 
decreases substantially after the first infusion; therefore, to fully investigate the safety of 
obinutuzumab administered as an SDI during cycle 2 and from cycle 2 onwards in 
combination with chemotherapy in FL patients, the patient population should be 
treatment-naïve to obinutuzumab. 
To assess the safety and feasibility of SDI, and to guarantee the transposition to the 
general patient population, this study needs to investigate a population that closely 
reflects clinical practice and treated according to the existing label. Patients in need of 
first-line treatment for FL were also selected due to the high incidence of this population. 
3.3.3 
Rationale for Combination Therapies 
The chemotherapy combinations in this study are not limited - any approved 
obinutuzumab-based chemotherapy can be used at the discretion of the investigator.  
The rationale for allowing any approved chemotherapy combination is to investigate the 
safety of administering obinutuzumab as an SDI during cycle 2 and from cycle 2 
onwards in patients with previously untreated FL in chemotherapy combinations that 
reflect the real-world use of obinutuzumab. 
3.3.4 
Rationale for Provider- and Patient-Reported Outcomes 
Patients with previously untreated FL may experience disease-related symptoms (e.g., 
B-symptoms, fatigue), treatment-related symptoms (e.g., nausea, diarrhea), and 
subsequently may face interference in aspects of daily functioning (e.g., physical 
activities, emotional functioning) (Tholstrup et al. 2011; Pettengell et al. 2008, Jerkeman 
et al. 2001). Assessing this directly from patients is important to help fully understand the 
impact and benefit-risk assessment of a treatment. The severity of symptoms 
experienced by patients with cancer and the interference with daily living caused by 
these symptoms will be assessed directly from patients using the MD Anderson 
Symptom Inventory (MDASI). 
Given the length of time that some treatments take to administer, and the resulting 
impact that has on the number of patients that providers can treat, it is important to 
assess potential benefits that shorter duration infusions could have on providers. In this 
study, investigator physicians and nurses will be asked to answer questions based on 
their site experience with the SDI and standard infusions of obinutuzumab, across all 
patients enrolled in the study. The rationale for including provider-reported outcomes in 
this study is to see whether providers believe that adopting a 90-minute SDI at cycle 2 


 
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and beyond helps increase practice efficiency with respect to infusion chair time, waiting 
time, and patient scheduling. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 112 patients with patients with previously untreated advanced FL who 
meet the eligibility criteria presented below will be enrolled in this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Signed Informed Consent Form 
2. Age ≥ 18 years at time of signing Informed Consent Form 
3. Able and willing to comply with all study related procedures including completion 
of patient-reported outcome (PRO) endpoints 
4. Ability to comply with the study protocol, in the investigator's judgment 
5. Patients with previously untreated Stage III or IV FL or Stage II bulky disease 
scheduled to receive obinutuzumab and chemotherapy due to at least one of the 
following criteria: 
a. Bulky disease, defined as a nodal or extranodal (except spleen) mass 
≥ 7 cm in the greatest diameter 
b. Local symptoms or compromise of normal organ function due to progressive 
nodal disease or extranodal tumor mass 
c. Presence of B symptoms (fever [> 38ºC], drenching night sweats, or 
unintentional weight loss of > 10% of normal body weight over a period of 6 
months or less) 
d. Presence of symptomatic extranodal disease (e.g., pleural effusions, 
peritoneal ascites) 
e. Cytopenias due to underlying lymphoma (i.e., absolute neutrophil count 
< 1.0 × 109/L, hemoglobin < 10 g/dL, and/or platelet count < 100 × 109/L) 
f. Involvement of ≥ 3 nodal sites, each with a diameter of ≥ 3 cm 
g. Symptomatic splenic enlargement 
6. Histologically documented CD-20-positive FL, as determined by the local 
laboratory 
7. Eastern Cooperative Oncology Group (ECOG) performance status 0−2 
8. Adequate hematologic function (unless abnormalities are related to FL), defined 
as follows: 
a. Hemoglobin ≥ 9.0 g/dL 


 
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b. Absolute neutrophil count ≥ 1.5 × 109/L 
c. Platelet count ≥ 75 × 109/L 
9. Life expectancy of ≥ 12 months 
10. For women who are not postmenopausal (≥ 12 consecutive months of non-
therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or 
uterus): agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive methods that result in a failure rate of < 1% per year during the 
treatment period and for at least 18 months after the last dose of obinutuzumab, 
for at least 3 months after the last dose of bendamustine or according to 
institutional guidelines for CHOP or CVP chemotherapy, whichever is longer 
a. Examples of contraceptive methods with a failure rate of < 1% per year 
include bilateral tubal ligation, male sterilization, established, proper use of 
progestogen-only hormonal contraceptives that inhibit ovulation, hormone-
releasing intrauterine devices (IUDs), and copper IUDs 
b. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception 
Barrier methods must always be supplemented with the use of a spermicide 
11. For men: agreement to remain abstinent (refrain from heterosexual intercourse) 
or use contraceptive measures and agreement to refrain from donating sperm, as 
defined below: 
a. With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in 
a failure rate of < 1% per year during the treatment period and for at least 3 
months after the last dose of study treatment. Men must refrain from 
donating sperm for the same period 
b. With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 3 months after the last dose of 
study treatment 
c. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Relapsed / refractory FL 


 
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2. Prior treatment for FL with chemotherapy, radiotherapy, or immunotherapy 
3. Grade IIIb FL 
4. Histological evidence of transformation of FL into high-grade B-cell NHL 
5. Treatment with systemic immunosuppressive medications, including, but not 
limited to, prednisone/prednisolone/methylprednisolone (at a dose equivalent 
to >30 mg/day prednisone), azathioprine, methotrexate, thalidomide, and anti-
tumor necrosis factor agents within 2 weeks prior to Day 1 of Cycle 1  
a. Treatment with inhaled corticosteroids and mineralocorticoids is permitted 
b. Patients receiving corticosteroid treatment with ≤30 mg/day of prednisone or 
equivalent must be documented to be on a stable dose of at least 4 weeks’ 
duration prior to enrolment 
c. If glucocorticoid treatment is urgently required for medical reasons (e.g., 
complications imminent if not treated at least with glucocorticoids; strong 
discomfort/pain of the patient due to lymphoma), prednisone 100 mg or 
equivalent can be given for a maximum of 5 sequential days, but all tumor 
assessments must be completed prior to the start of glucocorticoid 
treatment. Glucocorticoid treatment must be stopped prior to enrolment 
d. In cases when a glucocorticoid pre-treatment/pre-phase was done externally 
prior to considering the patient for study inclusion, glucocorticoids must be 
stopped for at least 7 days before screening assessments can begin 
6. History of solid organ transplantation 
7. History of anti-CD20 antibody therapy 
8. History of severe allergic or anaphylactic reaction to humanized, chimeric, or 
murine monoclonal antibodies 
9. Known sensitivity or allergy to murine products 
10. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster 
ovary cells or any of the study drugs 
11. Active bacterial, viral, fungal, or other infection or any major episode of infection 
requiring treatment with IV antibiotics within 4 weeks of Day 1 of Cycle 1 
a. Caution should be exercised when considering the use of obinutuzumab in 
patients with a history of recurring or chronic infections 
12. Positive test results for chronic HBV infection (defined as positive HBsAg 
serology) 
a. Patients with occult or prior HBV infection (defined as negative HBsAg and 
positive total HBcAb) may be included if HBV DNA is undetectable, provided 
that they are willing to undergo DNA testing at least every 3 months (during 
the study and for at least 1 year after completion of lymphoma treatment). 
Patients who have protective titers of hepatitis B surface antibody (HBsAb) 
after vaccination or prior but cured hepatitis B are eligible 


 
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13. Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology 
testing) 
a. Patients positive for HCV antibody are eligible only if PCR is negative for 
HCV RNA 
14. Known history of HIV positive status 
a. For patients with unknown HIV status, HIV testing will be performed at 
screening if required by local regulations 
15. History of progressive multifocal leukoencephalopathy (PML) 
16. Vaccination with a live virus vaccine within 28 days prior to Day 1 of Cycle 1 or 
anticipation that such a live, attenuated vaccine will be required during the study 
17. History of prior other malignancy with the exception of: 
a. Curatively treated carcinoma in situ of the cervix, good-prognosis ductal 
carcinoma in situ of the breast, basal- or squamous-cell skin cancer, Stage I 
melanoma, or low-grade, early-stage localized prostate cancer 
b. Any previously treated malignancy that has been in remission without 
treatment for ≥ 2 years prior to enrollment 
18. Evidence of any significant, uncontrolled concomitant disease that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV 
cardiac disease, myocardial infarction within the previous 6 months, unstable 
arrhythmia, or unstable angina) or significant pulmonary disease (such as 
obstructive pulmonary disease or history of bronchospasm)  
19. Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of 
Cycle 1, Day 1, or anticipation of a major surgical procedure during the course of 
the study 
20. For patients who will be receiving CHOP: left ventricular ejection fraction (LVEF) 
< 50% by multigated acquisition (MUGA) scan or echocardiogram  
21. Any of the following abnormal laboratory values: 
a. Creatinine > 1.5 × the upper limit of normal (ULN) (unless creatinine 
clearance normal) or creatinine clearance < 40 mL/min 
b. AST or ALT > 2.5 × ULN 
c. Total bilirubin ≥ 1.5 × the ULN: Patients with documented Gilbert disease 
may be enrolled if total bilirubin is ≤ 3.0 × the ULN. 
d. International normalized ratio (INR) > 1.5 in the absence of therapeutic 
anticoagulation 
e. Partial thromboplastin time or activated partial thromboplastin time > 1.5 × 
ULN in the absence of a lupus anticoagulant 
22. Pregnant or lactating, or intending to become pregnant during the study 


 
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a. Women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test 
result within 7 days prior to Day 1 of Cycle 1 
23. Any investigational therapy within 28 days prior to the start of Cycle 1 
24. Positive test results for human T-lymphotropic virus 1 (HTLV-1) 
a. HTLV testing is required in patients from endemic countries 
 
Patients who meet the following criteria will be excluded from further study participation 
after Cycle 1: 
• 
Development of a Grade 4 IRR during Cycle 1. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
Not applicable - this study is not a randomized study. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal product (IMP) for this study is obinutuzumab. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Obinutuzumab 
Obinutuzumab will be supplied by the Sponsor as an investigational medicinal product 
(IMP). Obinutuzumab will be provided as a single-dose, sterile liquid formulation in a 
50-mL glass vial containing 1000 mg/40 mL of obinutuzumab. In addition to the drug 
substance, the liquid is also composed of histidine, trehalose, and poloxamer 188. For 
information on the formulation and handling of obinutuzumab, see the obinutuzumab 
Investigator’s Brochure and the Pharmacy Manual.  
For further details, see the obinutuzumab Investigator's Brochure. 
4.3.1.2 
CHOP Chemotherapy 
For details on drug formulations, see the cyclophosphamide, vincristine, doxorubicin, or 
prednisone/prednisolone/methylprednisolone prescribing information. 
4.3.1.3 
CVP Chemotherapy 
For details on drug formulations, see the cyclophosphamide, vincristine, or 
prednisone/prednisolone/methylprednisolone prescribing information. 
4.3.1.4 
Bendamustine 
For information on the formulation, packaging, and handling of bendamustine, see the 
local prescribing information (for example Levact® / Treanda® / Treakisym® / 
Ribomustin®). 


 
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4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
4.3.2.1 
Obinutuzumab 
Obinutuzumab should be administered as an IV infusion through a dedicated line in an 
environment in which full resuscitation facilities are immediately available and under the 
close supervision of an experienced physician. 
Obinutuzumab will be administered intravenously at a flat dose of 1000 mg on Day 1, 8 
and 15 during Cycle 1, and on Day 1 of subsequent cycles, according to the infusion 
rates shown in Table 1. The cycle length and number of cycles depends on the 
chemotherapy combination (see Section 4.3.2.2). 
Following induction obinutuzumab and chemotherapy, maintenance obinutuzumab 
monotherapy will be administered at a dose of 1000 mg once every 8 weeks (± 10 days) 
for 2 years or until disease progression (whichever occurs first). 
Splitting of the obinutuzumab dose (i.e. 100 mg + 900 mg) will not be permitted in this 
study. The full dose (1000 mg) should be given in one day. No dose modification for 
obinutuzumab is allowed. Guidelines for treatment delays or discontinuation are 
provided in Section 5.1.5. 
Premedication to reduce the incidence and severity of IRRs and for patients at risk of 
TLS will be conducted according to local practice as described in Section 4.3.3. 
4.3.2.2 
Combination Chemotherapy 
Obinutuzumab will be administered in combination with one of the following 
chemotherapy regimens: 
• 
Six 28-day cycles in combination with bendamustine 
• 
Six 21-day cycles in combination with CHOP, followed by two additional cycles of 
obinutuzumab alone 
• 
Eight 21-day cycles in combination with CVP. 
Chemotherapy combinations will be administered according to the standard preparation 
and infusion procedures of each site. Body surface area (BSA) may be capped at 2 m2 
per institutional standards. 
If the duration of the obinutuzumab administration (i.e. at the regular infusion rate) does 
not allow time for day 1 of the chemotherapy to be administered on the same day, then 


 
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the chemotherapy can be started on the following day (i.e. Day 2). When obinutuzumab 
is given at the short duration infusion rate there should be sufficient time to administer 
both the obinutuzumab and chemotherapy on Day 1. 
Bendamustine 
Bendamustine will be administered on Days 1 and 2 for Cycles 1–6 at a dose of 
90 mg/m2/day. Obinutuzumab will be administered prior to bendamustine, and patients 
should be observed for 30 minutes prior to starting bendamustine. 
 
CHOP 
The doses and schedules of CHOP components are: 
• 
Cyclophosphamide 750 mg/m2 IV, Day 1 
• 
Doxorubicin 50 mg/m2 IV push, Day 1 
• 
Vincristine 1.4 mg/m2 IV push, Day 1 (dose cap at 2 mg) 
• 
Prednisone 100 mg/day po (or prednisolone/methylprednisolone*), Days 1 through 5 
* Equivalent doses of prednisolone or methylprednisolone may be administered according to 
local standard practice instead of prednisone. 
When obinutuzumab and CHOP are scheduled to be administered on the same day, 
prednisone (100 mg; or equivalent dose of prednisolone/methylprednisolone) will be 
given prior to the obinutuzumab infusion. Obinutuzumab will be administered prior to 
CHOP, and patients should be observed for 30 minutes prior to starting CHOP. 
During cycle 1, CHOP may be given on the day after obinutuzumab administration if the 
duration of the obinutuzumab infusion necessitates such administration. 
For patients aged ≥70 years, the vincristine dose may be capped at 1.5 mg. 
Primary prophylaxis with G-CSF is recommended according to American Society of 
Clinical Oncology, EORTC, and European Society for Medical Oncology guidelines 
(Smith et al 2015), or per each site’s institutional standards.  
CVP 
The doses and schedules of CVP components are: 
• 
Cyclophosphamide 750 mg/m2 IV, Day 1 
• 
Vincristine 1.4 mg/m2 IV push, Day 1 (dose cap at 2 mg) 
• 
Prednisone 100 mg po (or prednisolone/methylprednisolone*), Days 1 through 5 
* Equivalent doses of prednisolone or methylprednisolone may be administered according to 
local standard practice instead of prednisone. 


 
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When obinutuzumab and CVP are scheduled to be administered on the same day, 
prednisone (100 mg; or equivalent dose of prednisolone/methylprednisolone) will be 
given prior to the obinutuzumab infusion.  Obinutuzumab will be administered prior to 
CVP, and patients should be observed for 30 minutes prior to starting CVP. 
For patients aged ≥70 years, the vincristine dose may be capped at 1.5 mg. 
4.3.3 
Premedication 
4.3.3.1 
Premedication for infusion-related reactions 
Premedication to reduce the risk of IRRs is mandatory for the first standard infusion of 
obinutuzumab (Cycle 1, Day 1) and for the first infusion of obinutuzumab given as a 
short duration infusion (Table 2). For subsequent cycles, premedication will depend on 
whether the patient experienced an IRR with the previous infusion. 
All premedication must be completed at least 30 minutes before the obinutuzumab 
infusion. 
Table 2 
Premedication to be Administered Before Obinutuzumab Infusion 
to Reduce the Risk of IRRs 
Infusion 
Premedication  
Administration  
First standard 
infusion (Cycle 
1, Day 1)  
AND  
First infusion 
given as an SDI 
IV corticosteroid 1,4 
Oral analgesic/anti-pyretic 2 
Anti-histaminic medicine 3 
• Mandatory 
All subsequent 
infusions 
IV corticosteroid 1,4 
• Mandatory if the patient had a Grade 3 IRR 
during the previous infusion 
• According to clinical judgement of the 
investigator for patients without a Grade 3 
IRR in the previous infusion 
Oral analgesic/anti-pyretic 2 
• Mandatory 
Anti-histaminic medicine 3 
• Mandatory for patients with a Grade 1–3 
IRR during the previous infusion 
• According to local guidelines or the clinical 
judgment of the investigator for patients 
without an IRR during the previous infusion 


 
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1. 
Maximum allowable dose: 100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 
mg methylprednisolone. Hydrocortisone should not be used as it has not been effective in 
reducing rates of IRR.  
2. 
e.g. 1,000 mg acetaminophen/paracetamol. 
3 
e.g. 50 mg diphenhydramine. 
4. 
For patients receiving CHOP and CVP chemotherapy, the corticosteroid can be 
administered as an oral medication if given at least 30 minutes prior to obinutuzumab and 
additional IV corticosteroid as premedication is not required. 
 
 
4.3.3.2 
Premedication for tumor lysis syndrome (TLS) 
Patients with a high tumor burden, a circulating lymphocyte count (>25 × 109/L), or renal 
impairment (CrCL <70 mL/min) will receive premedication for TLS comprising hydration 
and uricostatics or urate oxidase 12–24 hours before infusion of obinutuzumab 
according to standard practice. 
4.3.4 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (obinutuzumab) will be provided by the 
Sponsor. The study site will acknowledge receipt of IMPs supplied by the Sponsor using 
the IxRS to confirm the shipment condition and content. Any damaged shipments will be 
replaced. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation. The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor. The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.5 
Continued Access to Obinutuzumab 
Currently, the Sponsor does not have any plans to provide the Roche IMP 
(obinutuzumab) or any other study treatments to patients who have completed the study.  
4.4 
CONCOMITANT THERAPY AND ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 7 days prior to study entry 
to the end of the 3-month safety follow-up visit. All such medications should be reported 
to the investigator and recorded on the Concomitant Medications eCRF.  


 
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4.4.1 
Permitted Therapy  
Patients who use oral contraceptives or hormone-replacement therapy should continue 
their use. 
Premedication as described in Section 4.3.3 is allowed during the study, as is the use of 
G-CSF for the treatment of neutropenia (see Section 5.1.1.3) and transfusion of blood 
products for treatment of thrombocytopenia (see Section 5.1.1.4) or anemia. 
The use of antibiotic, anti-viral, and/or anti-fungal prophylaxis according to institutional 
guidelines is also allowed. 
COVID-19 vaccines that have been granted emergency use authorization or equivalent 
are permitted. The vaccine should be captured in the eCRF as a concomitant 
medication. The brand/trade name or company manufacturer should be reported if 
available (Examples: Pfizer COVID-19 vaccine, Moderna COVID-19 vaccine). If not 
available, report as “COVID-19 vaccine”. Please report each dose separately. See 
Section 5.1.1.7 for further information concerning COVID-19 vaccines. 
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per local standard practice. Patients who experience infusion-
associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or 
equivalent medications per local standard practice. Serious infusion-associated events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced 
oxygen saturation, or respiratory distress should be managed with supportive therapies 
as clinically indicated (e.g., supplemental oxygen and β2-adrenergic agonists). 
4.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study: 
• 
Cytotoxic chemotherapy (other than bendamustine, cyclophosphamide, doxorubicin, 
or vincristine) 
Although MTX is a chemotherapeutic agent, due to the low doses used in treating 
rheumatoid arthritis (typically 7.5 to a maximum of 20 mg/week) it is not considered 
chemotherapy for lymphoma. Therefore, patients treated before or during study 
conduct with MTX for rheumatoid arthritis are still eligible to participate in the study. 
It is recommended to stop MTX 2-3 weeks prior to starting immunochemotherapy 
since the combination of MTX and immunochemotherapy increases the risk of 
immunosuppression and the risk of infection, but MTX may be resumed during 
maintenance / follow-up, if clinically indicated 
• 
Radiotherapy 
• 
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• 
Hormone therapy (other than contraceptives, hormone-replacement therapy, or 
megestrol acetate) 
• 
Hormonal therapy (e.g., GnRH-agonists) for egg cell harvest/fertility preservation 
prior to enrolment is allowed in women of childbearing age 
• 
Any therapies intended for the treatment of NHL, whether FDA approved or 
experimental (outside of this study) 
• 
The safety of immunization with live virus vaccines following obinutuzumab therapy 
has not been studied. Vaccination with live virus vaccines is not recommended 
during treatment and until B-cell recovery 
Patients who require the use of any of these prohibited therapies will be discontinued 
from study treatment. The end of induction or end of maintenance response assessment 
should be performed before the therapy is started, unless a recent response assessment 
is already available. For the timing of the safety follow-up assessment please see 
Appendix 1. 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1. All 
activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study. 
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. 
Results from local laboratory assessments (hematology and biochemistry) must be 
reviewed, and the review documented, prior to study drug administration. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations). Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment. Re-screening is possible at any time. The 
investigator will maintain a screening log to record details of all patients screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
4.5.2 
Medical History, Concomitant Medication, and Demographic 
Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
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will be recorded at baseline. In addition, all medications (e.g., prescription drugs, over-
the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by the patient within 7 days prior to study entry will be recorded. At the time of each 
follow-up physical examination, an interval medical history should be obtained and any 
changes in medications and allergies should be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
The following clinical parameters relative to disease history, diagnosis, and prognostic 
indices will be recorded at screening: 
• 
Date of initial diagnosis 
• 
ECOG performance status (see Appendix 3) 
• 
B symptoms (unexplained fever >38ºC, night sweats, unexplained weight loss >10% 
of body weight over 6 months) 
• 
Ann Arbor staging (see Appendix 4) 
• 
Follicular Lymphoma International Prognostic Index (FLIPI) and FLIPI2 (see 
Appendix 5) 
 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems. Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF. 
As part of tumor assessment, the physical examination should include evaluation for the 
presence of enlarged nodes, palpable hepatomegaly, and splenomegaly. This 
information will be recorded on the appropriate tumor assessment eCRF. 
At the end of induction and end of maintenance visits, targeted (limited, symptom-
directed) physical examinations should be performed. Targeted physical examinations 
should be limited to systems of primary relevance (e.g., cardiovascular and respiratory 
systems), systems associated with symptoms (newly emergent or monitored from 
baseline), and areas associated with tumor assessment (lymph nodes, liver, spleen, and 
any other areas identified at baseline). Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
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4.5.4 
Vital Signs 
Vital signs will include measurements of blood pressure, pulse rate and temperature as 
outlined in the schedule of assessment (Appendix 1), but the associated data do not 
need to be recorded on the eCRF (except in the case of an adverse event as described 
in Section 5.3.5.6). 
For the first cycle (i.e., includes Day 1, Day 8, and Day 15), vital signs will be measured 
prior to the infusion, every 15 minutes for the first 90 minutes of the infusion, then every 
30 minutes until end of the infusion and approximately every 60 minutes until the 
infusion line is removed.  
In subsequent cycles, for patients who experienced a Grade 3 IRR in the previous cycle 
vital signs will be measured at the same frequency as for the first cycle. For patients 
without a Grade 3 IRR in the previous cycle (i.e., those with no IRR or Grade ≤2 IRR), 
vital signs will be measured prior to the infusion and every 30 minutes during the 
infusion. If any abnormal values are observed during any infusion, the site should 
continue to monitor vital signs until stabilization of the abnormal values. 
4.5.5 
Tumor and Response Evaluations 
All known sites of disease must be documented at screening within 28 days of Cycle 1, 
Day 1 (e.g. CT with or without FDG-PET) and re assessed at the end of induction 
therapy and end of maintenance therapy for disease response by the investigator 
according to local practice and the guidelines used at the site (including Lugano [Cheson 
et al 2014], Cheson et al 2007, or Cheson et al 1999).  
No central confirmation of disease response will be conducted. 
A bone marrow biopsy (trephine) with or without aspirate must be obtained at screening 
according to local practice and guidelines used at the site. If bone marrow data are 
available in the patient’s medical record that were obtained within 3 months prior to 
Cycle 1, Day 1, these data can be used instead, and the patient does not need to 
undergo a new bone marrow biopsy with or without aspirate. 
If there was bone marrow infiltration at screening, then a subsequent bone marrow 
biopsy with or without aspirate may be needed at the end of induction and/or end of 
maintenance visits to confirm response according to local practice. 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
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• 
Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells) 
• 
Serum or plasma chemistry: bicarbonate or total carbon dioxide (if considered 
standard of care for the region), sodium, potassium, chloride, glucose, blood urea 
nitrogen (BUN) or urea, creatinine, total protein, albumin, phosphorus, calcium, total 
and direct bilirubin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), uric acid, beta-2 microglobulin, and lactate 
dehydrogenase (LDH) 
• 
Coagulation: International normalized ratio (INR), activated partial thromboplastin 
time (aPTT) (or PTT), prothrombin time (PT) 
• 
Pregnancy test 
– 
All women who are not postmenopausal (≥12 months of non-therapy-induced 
amenorrhea) or surgically sterile will have a serum pregnancy test at screening 
(within 7 days of Day 1 of Cycle 1)  
• 
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and, if routinely performed, microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria) 
• 
HBV/HCV DNA PCR in patients with resolved HBV/HCV infection. 
• 
HTLV-1 serology (for patients from endemic countries only) 
 
No samples in this study will be sent to a central laboratory for analysis. 
4.5.7 
Electrocardiograms 
Single, resting, 12-lead ECG recordings will be obtained at screening (see Appendix 1), 
and may be obtained at unscheduled timepoints as clinically indicated. ECGs for each 
patient should be obtained using the same machine wherever possible. Interpretation of 
the ECG should be performed by the investigator. 
4.5.8 
Echocardiogram or MUGA 
For patients receiving CHOP, LVEF will be assessed by echocardiography or MUGA 
scan at screening (see Appendix 1). 
4.5.9 
Clinical Outcome Assessments 
A patient-reported outcome (PRO) instrument will be completed to assess the severity of 
disease, treatment-related symptoms, and how symptoms interfere with aspects of the 
patient’s life. PRO data will be collected using the MD Anderson Symptom Inventory 
(MDASI) instrument (Appendix 2). 


 
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Provider-reported outcome instruments will be completed to evaluate the site experience 
with the SDI and standard infusions of obinutuzumab. Provider-reported data will be 
collected using a questionnaire (Appendix 2). 
The MDASI and provider-reported questionnaires, translated into the local language as 
appropriate, will be provided by the sponsor. The sheets will be labeled with the 
timepoint of administration. 
4.5.9.1 
Data Collection Methods for Clinical Outcome Assessments 
 
Patient-Reported Outcomes  
To ensure instrument validity and that data standards meet health authority 
requirements, the MDASI will be self-administered at the clinic at specified timepoints 
during the study (see schedule of activities in Appendix 1). At the clinic, the instrument 
will be administered before the patient receives any information on disease status, prior 
to the performance of non-PRO assessments, and prior to the administration of study 
treatment, unless otherwise specified. 
During clinic visits, PRO instruments should be administered as outlined below: 
• 
Patients' health status should not be discussed prior to administration of the 
instruments. 
• 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
• 
Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 5 minutes at each specified visit. 
• 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
• 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers. 
• 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request. 
• 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
• 
Site staff should review all completed instruments and should ask the patient to 
rectify any response that is not clearly marked in the appropriate location.  If a 
response is missing, site staff should ask the patient to complete the item or confirm 
that the item was intentionally left blank. 
 
Provider-reported outcomes 
Provider-reported outcome instruments will be completed at the clinic at specified 
timepoints during the study (see schedule of activities in Appendix 1). Provider-reported 


 
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outcome instruments will be self-administered at the timepoints specified in Appendix 1. 
The instruments will be provided by the Sponsor. Physicians/nurses must complete the 
official version of each provider-reported outcome instrument, as provided by the 
Sponsor. Instruments must not be copied from the protocol. 
4.5.9.2 
Description of Clinical Outcome Assessment Instruments 
 
MD Anderson Symptom Inventory (MDASI) 
The MD Anderson Symptom Inventory (MDASI; Appendix 2) is a validated and reliable 
self-report measure (Cleeland et al., 2000) that was developed to assess symptom 
severity and interference.  Thirteen items (i.e., pain, fatigue, nausea, disturbed sleep, 
distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry 
mouth, sad, vomiting, and numbness or tingling) ask patients to rate how severe the 
symptoms were when “at their worst” in the last 24 hours.  An additional 6 items ask 
patients to rate how much the symptoms have interfered with 6 areas of function (i.e., 
general activity, walking, work, mood, relations with other people, and enjoyment of life) 
in the last 24 hours. It takes approximately 5 minutes to complete.  
Provider-Reported Outcomes Instrument 
Investigator physicians and nurses involved in this study will be asked to answer four 
questions (Appendix 2) based on their experience with administering both the SDI and 
standard infusions of obinutuzumab, to patients enrolled in the study. It should take 
approximately 5 minutes to complete. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment 
• 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
• 
Pregnancy 
• 
Symptomatic deterioration attributed to disease progression 
• 
Confirmed disease progression per investigator assessment  
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  
Patients will return to the clinic for a safety follow-up visit at 3 months (90 days (± 10 
days)) after the final dose of study drug (see Appendix 1 for additional details). 


 
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4.6.2 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
• 
Patient withdrawal of consent at any time 
• 
Completed the safety follow-up after discontinuing obinutuzumab for patients in the 
maintenance or induction phase  
• 
Adverse event 
• 
Loss to follow-up 
• 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
Every effort should be made to obtain a reason for patient discontinuation from the 
study. The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF. However, patients will not be followed for any reason after 
consent has been withdrawn. 
If a patient withdraws consent, this request must be documented in the source 
documents and signed by the investigator. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
• 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time. Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Council for Harmonisation (ICH) guidelines 
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• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
The safety plan for patients in this study is based on clinical experience with 
obinutuzumab in completed and ongoing studies. The anticipated important safety risks 
for obinutuzumab are outlined below. Please refer to the obinutuzumab Investigator's 
Brochure for a complete summary of safety information.  
Several measures will be taken to ensure the safety of patients participating in this 
study. Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities. Patients will undergo safety monitoring during the study, including assessment 
of the nature, frequency, and severity of adverse events. In addition, guidelines for 
managing adverse events, including criteria for treatment interruption or discontinuation, 
are provided below. 
5.1.1 
Risks Associated With Obinutuzumab 
The following adverse events are considered to be important risks associated or 
potentially associated with obinutuzumab: IRRs, TLS, thrombocytopenia (including acute 
thrombocytopenia), neutropenia (including late onset and prolonged neutropenia), 
prolonged B-cell depletion, infections (including PML and HBV reactivation), worsening 
of pre-existing cardiac conditions, GI perforation, and secondary malignancies. These 
events are described below.  
5.1.1.1 
Infusion-Related Reactions and Hypersensitivity Reactions 
IRRs have been reported predominantly during the first infusion of obinutuzumab. The 
incidence and severity of IRRs decreased substantially with the second and subsequent 
infusions. In the majority of patients, irrespective of indication, IRRs were mild to 
moderate and could be managed by the slowing or temporary halting of the first infusion, 
but severe and life-threatening IRRs requiring symptomatic treatment have also been 
reported. The commonly experienced IRRs have been characterized by hypotension, 
fever, chills, dyspnea, flushing, nausea, vomiting, hypertension, fatigue, headache, 
tachycardia, dizziness, diarrhea, and other symptoms.  
IRRs may be clinically indistinguishable from IgE-mediated allergic reactions (e.g. 
anaphylaxis).  
Patients who have pre-existing cardiac or pulmonary conditions should be monitored 
carefully throughout the infusion and the post-infusion period. Hypotension may occur 
during obinutuzumab intravenous infusions. Therefore, withholding of antihypertensive 
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obinutuzumab infusion and for the first hour after administration. Patients at acute risk of 
hypertensive crisis should be evaluated for the benefits and risks of withholding their 
anti-hypertensive medication.  
Premedication to reduce the risk of IRRs is described in Section 4.3.3.1. Guidelines for 
medical management of IRRs and anaphylaxis are provided in Section 5.1.5 and 
Appendix 6 and Appendix 7.  
Hypersensitivity reactions with immediate (e.g., anaphylaxis) and delayed onset (e.g., 
serum sickness) have been reported in patients treated with obinutuzumab. 
Hypersensitivity reactions typically occur after previous exposure and very rarely with the 
first infusion. In the case a hypersensitivity reaction is suspected during or after an 
infusion, the infusion should be stopped and treatment permanently discontinued. 
5.1.1.2 
Tumor Lysis Syndrome 
TLS, including fatal events, has been reported with obinutuzumab administration. TLS is 
a potentially serious condition that can lead to acute electrolyte imbalance (e.g., 
hyperkalemia and hypocalcemia), arrhythmia, acute renal failure, and sudden death.  
Patients at risk for TLS (e.g. patients with a high tumor burden or a high circulating 
lymphocyte count [>25 x 109/L] and/or renal impairment [CrCl <70 mL/min]) should 
receive prophylaxis as indicated in Section 4.3.3.2. Guidelines for the management of 
patients who experience TLS in this study are provided in Section 5.1.5. 
For reporting purposes, TLS can be classified as laboratory or clinical. Laboratory TLS 
requires that two or more of the following metabolic abnormalities occur within 3 days 
before or up to 7 days after the initiation of therapy: hyperuricemia, hyperkalemia, 
hyperphosphatemia, and hypocalcemia. Clinical TLS is present when laboratory TLS is 
accompanied by an increased creatinine level, seizures, cardiac dysrhythmia, or death 
(Howard et al. 2011). TLS of any grade, irrespective of causality, are considered an 
Adverse Event of Special Interest and must be reported to the Sponsor immediately (see 
Section 5.2.3). Whilst reporting the event, if diagnosis is available, diagnosis should be 
reported as an event rather than individual signs and symptoms i.e. in this case, TLS 
should be reported. Further guidance is provided in Section 5.3.5.2. 
5.1.1.3 
Neutropenia 
Grade 3 or 4 neutropenia, including febrile neutropenia, has been reported with 
obinutuzumab administration. Neutropenia resolved spontaneously or with use of 
hematopoietic growth factors. Patients who experience Grade 3 or 4 neutropenia should 
be closely monitored until neutrophil values return to at least Grade 2. Cases of late-
onset neutropenia (ANC <1000 cells/µL occurring ≥28 days after obinutuzumab 
treatment has been completed or stopped) or prolonged neutropenia (ANC <1000 
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been reported. The use of G-CSF is allowed for treatment of neutropenia in this study. 
Prophylactic treatment with antibiotics should be administered as per standard practice.  
5.1.1.4 
Prolonged B-cell depletion 
Prolonged B-cell depletion is defined as the absence of B-cell recovery 12 months after 
the end of treatment. Prolonged B-cell depletion is considered an important identified 
risk, due to the potential of severe infections. Prolonged B-cell depletion may be related 
to the risks of PML and HBV, which are described separately. No severity scale has 
been established for this condition. No preventative action is envisaged. Patients with 
prolonged B-cell depletion should be closely monitored for infections. 
 
5.1.1.5 
Thrombocytopenia 
Severe and life-threatening thrombocytopenia, including acute thrombocytopenia 
(occurring within 24 hours after the infusion), has been observed during treatment with 
obinutuzumab. In CLL patients exposed to obinutuzumab, fatal hemorrhagic events have 
also been reported in Cycle 1. A clear relationship between thrombocytopenia and 
hemorrhagic events has not been established. Patients receiving concomitant 
medication that could possibly worsen thrombocytopenia related events (e.g., platelet 
inhibitors and anticoagulants) may be at greater risk of bleeding. When possible, replace 
prior vitamin K antagonist therapy with LMWH prior to Day 1 of Cycle 1. Patients should 
be closely monitored for thrombocytopenia, especially during the first cycle. For patients 
who experience thrombocytopenia, regular laboratory tests should be performed until the 
event resolves, and dose delays should be considered in case of severe or life-
threatening thrombocytopenia. Transfusion of blood products (i.e., platelet transfusion) 
may be performed at the discretion of the treating physician, according to institutional 
practice. 
5.1.1.6 
Infections 
On the basis of its mechanism of action, resulting in profound B-cell depletion, 
obinutuzumab may be associated with an increased risk of infections. Obinutuzumab 
should not be administered to patients with active infection, and caution should be 
exercised when including patients with a history of recurrent or chronic infections. 
Serious bacterial, fungal, and new or reactivated viral infections can occur during and 
following the completion of obinutuzumab therapy. Fatal infections have been reported.  
In the FL studies, a high incidence of infections was observed in all phases of the 
studies, including follow-up, with the highest incidence seen during maintenance. Details 
are provided in the Obinutuzumab Investigator’s Brochure.  
Reactivation of hepatitis B in patients with chronic hepatitis (HBsAg positive) with 
evidence of prior hepatitis B exposure, or in patients who are carriers (HBsAg negative 
and HBcAb positive) has been reported with other anti-CD20 antibodies. The risk is 


 
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increased particularly when anti-CD20 antibodies are administered with 
immunosuppressive therapies, such as steroids or chemotherapy. In obinutuzumab 
studies, patients with active HBV infection are excluded. However, patients with prior 
HBV infection or carriers are eligible to participate if HBV DNA is undetectable at 
screening and provided they agree to DNA testing at least every 3 months (during the 
study and for at least 1 year after completion of lymphoma treatment). These patients 
with positive HBcAb should consult liver disease experts before start of treatment and 
should be monitored and managed following local medical standards to prevent hepatitis 
reactivation. HBV reactivation in these patients with positive HBcAb at screening is 
defined as confirmed presence of HBV DNA >100 IU/mL in the serum or positive after 
baseline. 
John Cunningham (JC) viral infection resulting in PML has been reported in patients 
treated with obinutuzumab. The diagnosis of PML should be considered in any patient 
presenting with new-onset neurologic manifestations. The symptoms of PML are 
unspecific and can vary depending on the affected region of the brain. Motor symptoms 
with corticospinal tract findings (e.g., muscular weakness, paralysis, and sensory 
disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are 
common. Some signs or symptoms regarded as “cortical” (e.g., aphasia or visual-spatial 
disorientation) may occur. Evaluation of PML includes, but is not limited to, consultation 
with a neurologist, brain MRI, and lumbar puncture (cerebrospinal fluid testing for JC 
viral DNA). Therapy with obinutuzumab should be withheld during the investigation of 
potential PML and permanently discontinued in case of confirmed PML. Discontinuation 
or reduction of any concomitant chemotherapy should also be considered. 
5.1.1.7 
Immunizations 
The safety of immunization with live virus vaccines following obinutuzumab therapy has 
not been studied. Vaccination with live virus vaccines is not recommended during 
treatment and until B-cell recovery. 
Given the mechanism of action of obinutuzumab, it is expected that the efficacy of 
COVID-19 vaccines may be diminished in patients receiving obinutuzumab. Patients 
should be informed that vaccine efficacy may be diminished. The discussion should be 
documented in the patient records. 
Patients who are vaccinated should be instructed to continue to adhere to personal 
hygiene measures, social distancing and other measures to prevent infection. 
Currently there are no data that support precise recommendations for the timing of 
COVID-19 vaccine administration in patients receiving obinutuzumab. The 
investigator should use clinical judgement to decide on the most suitable timing of 
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Suppression of response to vaccination may persist for more than 12–18 months after 
treatment with obinutuzumab. Hence, there is no strong rationale for withholding or 
delaying therapy to allow immune recovery prior to vaccination. 
COVID-19 vaccines must be given in accordance with the approved vaccine label. 
5.1.1.8 
Worsening of Preexisting Cardiac Condition 
In patients with underlying cardiac disease and treated with obinutuzumab, adverse 
events such as angina pectoris, acute coronary syndrome, myocardial infarction, heart 
failure, and arrhythmias, including atrial fibrillation and tachyarrhythmia, have been 
observed. These events may occur as part of an IRR and can be fatal. Therefore, 
patients with a history of cardiac disease should be monitored closely. In addition, these 
patients should be hydrated with caution to prevent a potential fluid overload.  
5.1.1.9 
Gastrointestinal Perforation 
GI perforation has been reported in patients treated with obinutuzumab, mainly in NHL, 
including fatal events. Patients with GI involvement should be monitored for signs of GI 
perforation. 
5.1.1.10 
Secondary Malignancies 
Epidemiology data suggest that patients with CLL and NHL are at a higher risk of 
experiencing a secondary malignancy compared with the general population and this 
appears to be independent of exposure to treatment. The increased incidence of 
secondary malignancies in patients with CLL and NHL may be attributable to multiple 
factors, including immune dysfunction associated with the underlying disease (especially 
in patients with CLL,) carcinogenic and immunosuppressive effects of the various 
chemotherapeutic agents and radiotherapy, and the increased and close medical 
surveillance that patients with CLL and NHL receive from trained oncologists leading to 
earlier diagnosis of malignancies (Faguet 1979, Hisada et al. 2001). To date, in patients 
treated with obinutuzumab, the risk is considered an important potential risk. 
 
5.1.2 
Risks Associated With Bendamustine 
Refer to prescribing information for bendamustine for risks related to bendamustine. 
5.1.3 
Risks Associated With CHOP 
Refer to prescribing information for doxorubicin, cyclophosphamide, vincristine, and 
prednisone/prednisolone/methylprednisolone for risks related to CHOP chemotherapy. 
5.1.4 
Risks Associated With CVP 
Refer to prescribing information for cyclophosphamide, vincristine, and 
prednisone/prednisolone/methylprednisolone for risks related to CVP chemotherapy. 


 
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5.1.5 
Management of Patients Who Experience Adverse Events 
5.1.5.1 
Management Guidelines 
There will be no dose reductions of obinutuzumab. Study treatments may be delayed for 
toxicity for a maximum amount of time, as specified in the table below. Treatment delays 
apply to all toxicities described below; dose modifications apply only to toxicities that are 
considered to be related to any of the study treatment components. Toxicities that occur 
during the cycle and subside prior to the next cycle should not trigger the suggested 
dose modifications. Guidelines for management of specific adverse events are outlined 
in Table 3 and Table 4. Additional guidelines are provided in the subsections below. 
The guidelines for management of patients who experience adverse events for “Other 
non-hematologic toxicities” during induction treatment (Table 3) do not apply to toxicity 
related to vincristine in patients receiving CHOP/CVP. Such toxicity can be managed 
according to the clinical judgement of the investigator. A decrease in vincristine dose is 
permitted and study treatment may be withheld for up to a maximum of 21 days, 
however obinutuzumab dose must resume at full dose (no dose reductions are 
permitted). 
Table 3 
Guidelines for Management of Patients who Experience Adverse 
Events During Induction Treatment 
Event 
Action to Be Taken 
General guidance for 
treatment delays and 
discontinuation 
• If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, 
requiring delay of obinutuzumab treatment, these doses should 
be given after resolution of toxicity. In such instances, all 
subsequent visits and the start of Cycle 2 will be shifted to 
accommodate for the delay in Cycle 1. 
• If study treatment is withheld for > 21 days permanently 
discontinue study treatment 
• When a treatment cycle is delayed because of toxicity resulting 
from any component of the regimen, all study treatment should 
generally be held and resumed together to remain synchronized. 
Hematologic toxicity: 
Grade 1 or 2 
• No action required. 


 
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Event 
Action to Be Taken 
Hematologic toxicity: 
Grade 3 & 4 
• Withhold all study treatment for a maximum of 21 days.a 
• If improvement to Grade ≤2 or baseline does not occur within 21 
days discontinue all study treatment. 
• Give supportive treatment. 
• Administer RBCs or platelets as required. 
• If patient has not already initiated G-CSF, initiate prophylactic G-
CSF for current and subsequent cycles. 
• For patients who develop platelet countc of <20,000/µL while 
receiving LMWH, reduce the dose of LMWH. For patients who 
develop platelet count of <20,000/µL while receiving platelet 
inhibitors, consider temporarily withholding platelet inhibitors. 
• If improvement to Grade ≤2 or baseline within 13 days after the 
scheduled date for the next cycle, resume obinutuzumab at full 
dose and resume chemotherapy components at current dose. 
• If improvement to Grade ≤2 or baseline 14−21 days after the 
scheduled date for the next cycle, resume obinutuzumab at full 
dose and resume chemotherapy components at a reduced 
dosea,b  for current and subsequent cycles as outlined below: 
• First episode: If improvement to Grade ≤2 or baseline, decrease 
cyclophosphamide dose to 500 mg/m2, doxorubicin dose to 
35 mg/m2 and bendamustine dose to 70 mg/m2 for subsequent 
cycles. 
• Second episode: If improvement to Grade ≤2 or baseline, 
decrease cyclophosphamide dose to 375 mg/m2, doxorubicin 
dose to 25 mg/m2 and bendamustine dose to 50 mg/m2 for 
subsequent cycles. 
• No more than two dose reductions of chemotherapy are allowed. 
For patients who have had two prior chemotherapy dose reductions: 
• Permanently discontinue study treatment. 
IRRs and anaphylaxis 
• See Appendix 6 for guidance on managing IRRs. 
• In case of anaphylaxis, study treatment should be permanently 
discontinued. Anaphylaxis precautions are provided in Appendix 
7. 
TLS 
• Withhold study treatment. 
• Perform chemistry panel on a regular basis during the first week 
• Correct electrolyte abnormalities, monitor renal function, cardiac 
function and fluid balance, and administer supportive care, 
including dialysis as indicated.  
• If symptoms have resolved completely, resume obinutuzumab at 
full dose and resume chemotherapy components at current 
dose. 


 
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Event 
Action to Be Taken 
New-onset neurologic 
manifestations suggestive 
of PML 
• Withhold study treatment. 
• Consult with a neurologist if PML is suspected (refer to Section 
5.1.1.6 for guidance on investigations). 
• If PML is ruled out, resume obinutuzumab at full dose and 
resume chemotherapy components at current dose. 
• If PML is confirmed, permanently discontinue study treatment. 
Other non-hematologic 
toxicities: Grade 1 
• No action required.  
Other non-hematologic 
toxicities (excluding 
alopecia): Grade 2 
• 
Withhold all study treatment for a maximum of 21 days. 
• 
If improvement to baseline or Grade 1 or better does not occur 
within 21 days, discontinue all study treatment. 
• 
If improvement to baseline or Grade 1 or better, resume 
chemotherapy components at current dose and resume 
obinutuzumab at full dose. 
Other non-hematologic 
toxicities: Grade 3 or 4 
• 
Withhold all study treatment for a maximum of 21 days.a 
• 
If improvement to baseline or Grade 1 or better does not occur 
within 21 days, discontinue all study treatment. 
• 
First episode: If improvement to baseline or Grade 1 or better, 
decrease cyclophosphamide dose to 500 mg/m2, doxorubicin 
dose to 35 mg/m2 and bendamustine dose to 70 mg/m2 for 
subsequent cycles. 
• 
Second episode: If improvement to baseline or Grade 1 or 
better, decrease cyclophosphamide dose to 375 mg/m2, 
doxorubicin dose to 25 mg/m2 and bendamustine dose to 50 
mg/m2 for subsequent cycles. 
• 
No more than two dose reductions of chemotherapy are 
allowed. 
For patients who have had two prior chemotherapy dose reductions: 
• 
Permanently discontinue study treatment. 


 
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Event 
Action to Be Taken 
Infections 
• 
Advice should be given to patients to minimize the risks of 
acquiring infections from endogenous sources e.g., oral 
hygiene, avoidance of constipation etc. Dental assessment may 
be warranted prior to starting treatment in some cases. 
• 
Signs or symptoms of infection should result in prompt 
evaluation and collection of appropriate samples for 
bacteriological investigation prior to starting antibiotic or other 
treatment by the treating physician. 
• 
Empiric therapy with broad-spectrum antibiotics should be 
initiated promptly in all patients with suspected infections 
(including those receiving antimicrobial prophylaxis) to reduce 
the risk of serious morbidity and mortality. 
• 
Antibiotic prophylaxis may be considered in high risk patients as 
it is associated with significantly reduced occurrence of fever, 
fewer clinically documented and microbiologically documented 
infections, fewer infections due to both gram-positive and gram-
negative bacteria, fewer cases of bacteremia, and a lower risk of 
infection related death.  
Hepatitis B reactivation 
1. Patients with positive hepatitis B serology should consult liver 
disease experts before start of treatment and should be 
monitored and managed following local medical standards to 
prevent hepatitis reactivation. 
2. HBV DNA level of > 100 IU/mL: 
• 
Hold study treatment. 
• 
Begin anti-viral medication immediately as per local medical 
standards and immediately refer the patient to a 
gastroenterologist or hepatologist for additional management. 
• 
Patients may resume study treatment once HBV DNA levels 
decrease to undetectable levels. 
• 
If the HBV DNA level exceeds 100 IU/mL while a patient is 
receiving anti-viral medication, permanently discontinue study 
treatment. 
CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone/ 
methylprednisolone; G-CSF = granulocyte colony-stimulating factor; LMWH = low-molecular-
weight heparin. 
Note: A hematologic toxicity is defined as neutropenia, anemia, or thrombocytopenia. 
a Treatment delays apply to all toxicities; dose modifications apply only to toxicities that are 
considered to be related to any of the study treatment components. Toxicities that occur during 
the cycle and subside prior to the next cycle should not trigger the suggested dose modifications. 
b If cytopenia is thought to be caused mainly by iNHL infiltration of the bone marrow, the 
investigator may decide not to reduce the chemotherapy doses. 
c Severe thrombocytopenia is defined as a platelet count <10,000/µL for patients who are not 
receiving concomitant anticoagulants or platelet inhibitors and <20,000/µL for patients who are 
receiving concomitant anticoagulants or platelet inhibitors. 
 


 
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Table 4 
Guidelines for Management of Patients Who Experience Adverse 
Events during Maintenance Treatment 
Event 
Action to Be Taken 
Hematologic toxicity: 
Grade 3 or 4 b 
• Withhold obinutuzumaba 
• Administer G-CSF for neutropenia per institutional guidelines. 
• Administer RBCs or platelets as required. 
• If improvement to Grade ≤2, resume obinutuzumab at full dose. 
• If obinutuzumab is withheld for > 42 days, permanently 
discontinue study treatment. 
Non-hematologic toxicity: 
Grade ≥2 b 
• Withhold obinutuzumaba 
• If improvement to Grade ≤1 or baseline, resume obinutuzumab 
at full dose. 
• If obinutuzumab is withheld for > 42 days, permanently 
discontinue study treatment. 
a Treatment delays apply to all events; dose modifications apply only to events that are 
considered to be related to obinutuzumab. Dose reduction for obinutuzumab is not allowed 
during the study. Toxicities that occur during the cycle and subside prior to the next cycle should 
not trigger the suggested dose modifications. 
b For additional guidance on AE management refer to Table 3. 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution. An adverse event can therefore 
be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 
and 5.3.5.10 for more information) 


 
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• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 


 
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5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions). Adverse events of special interest for this study 
are as follows: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product. This term applies only 
when a contamination of the study drug is suspected. 
• 
TLS of any grade, irrespective of causality 
• 
Secondary malignancies 
 
5.2.4 
Selected Adverse Events 
Adverse events of special interest are listed in Section 5.2.3. Selected adverse events in 
this study are defined as adverse events for which additional data collection or analyses 
will be performed. Selected adverse events do not require immediate reporting if they 
are not serious. 
The following adverse events are considered selected adverse events: 
• 
Thrombocytopenia, including acute thrombocytopenia (events occurring during and 
within 24 hours following obinutuzumab infusion) 
• 
Hepatitis B reactivation 
• 
Cardiac events 
• 
IRRs 
• 
All infections, including PML 
• 
Neutropenia, including prolonged neutropenia (neutropenia <1000 cells/µL that does 
not resolve after 28 days without obinutuzumab treatment) and late-onset 
neutropenia (neutropenia <1000 cells/µL occurring ≥28 days after obinutuzumab 
treatment has been completed or stopped) 
• 
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Events for which additional data collection will be required are PML, and hepatitis B 
reactivation. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4−5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact. All adverse 
events, whether reported by the patient or noted by study personnel, will be recorded in 
the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 3 months (90 days 
(± 10 days)) after the last dose of study treatment. After this period, the investigator 
should report any serious adverse events that are believed to be related to prior study 
treatment (see Section 5.6). 
An exception is made for Grade 3–4 infections (related and unrelated to study 
treatment), which should be reported until resolution or until up to 2 years after the last 
dose of obinutuzumab. 
All study drug–related SAEs and secondary malignancies are to be reported and data 
collected indefinitely from the last study drug administration (even if the study has been 
closed) (see Section 5.6). Secondary malignancies are an AESI and must therefore be 
reported within 24 hours to the sponsor regardless of the seriousness. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints. Examples of non-directive 
questions include the following: 


 
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"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
Physicians should elicit AE information at every patient study visit. 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 5 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Based on the most recent version of NCI CTCAE (v5.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly. The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 


 
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• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to infusion of any study treatment component should be 
captured as a diagnosis (e.g. "infusion-related reaction") on the Adverse Event eCRF. If 
possible, avoid ambiguous terms such as "systemic reaction." Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF. If a 
patient experiences both a local and systemic reaction to the same dose of study 
treatment, each reaction should be recorded separately on the Adverse Event eCRF, 
with signs and symptoms also recorded separately on the dedicated Infusion-Related 
Reaction eCRF. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 


 
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5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events. A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF. For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints. Such events should only be recorded once on the Adverse 
Event eCRF. The initial severity (intensity or grade) of the event will be recorded at the 
time the event is first reported. If a persistent adverse event becomes more severe, the 
most extreme severity should also be recorded on the Adverse Event eCRF. If the event 
becomes serious, it should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning that the event became serious; see Section 5.4.2 for reporting 
instructions). The Adverse Event eCRF should be updated by changing the event from 
"non-serious" to "serious," providing the date that the event became serious, and 
completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs. Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 


 
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• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment  
Note: For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator's responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium"). If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event. For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result must be 
reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 


 
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If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law). Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
Deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1) that are attributed by the investigator solely to progression of FL should 
be recorded on the Study Completion/Early Discontinuation and Death Attributed to 
Progressive Disease eCRF. All other deaths that occur during the adverse event 
reporting period, regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). The 
IMC will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be 
reported. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF. If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 


 
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Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Follicular Lymphoma 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events. The determination of 
clinical progression will be based on the investigator assessment in routine clinical 
practice. In most cases, the expected pattern of progression will be based on the Lugano 
2014 criteria (Cheson et al 2014) and the Cheson et al 2007 criteria. In rare cases, the 
determination of clinical progression will be based on symptomatic deterioration. 
However, every effort should be made to document progression through use of objective 
criteria. If there is any uncertainty as to whether an event is due to disease progression, 
it should be reported as an adverse event. The disease progression will be captured on 
the early discontinuation CRF. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration)  


 
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• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
• 
Hospitalization due solely to progression of the underlying cancer 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Cases of Accidental Overdose and Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
• 
Accidental overdose: accidental administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Medication error: accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of the 
drug. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events. Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF. If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2). For 
obinutuzumab, adverse events associated with special situations should be recorded as 
described below for each situation: 
• 
Accidental overdose: Enter the adverse event term. Check the "Accidental 
overdose" and "Medication error" boxes. 
• 
Medication error that does not qualify as an overdose: Enter the adverse event term. 
Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose: Enter the adverse event term. Check 
the "Accidental overdose" and "Medication error" boxes. 
 


 
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In addition, all special situations associated with obinutuzumab, regardless of whether 
they result in an adverse event, should be recorded on the Adverse Event eCRF as 
described below: 
• 
Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes. 
• 
Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose: Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication 
error" boxes. Enter a description of the error in the additional case details. 
• 
Intercepted medication error: Enter the drug name and "intercepted medication 
error" as the event term. Check the "Medication error" box. Enter a description of the 
error in the additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache. The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages. 
5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data. Sites are not expected to review the 
PRO data for adverse events. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event. The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
• 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
• 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 


 
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For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information for these events to the Sponsor immediately 
(i.e., no more than 24 hours after becoming aware of the information). New significant 
information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event's outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls. The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week. Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported. 
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 3 months (90 days (± 10 days)) after the final dose of study 
drug.  After this period, the investigator should report any serious adverse events that 
are believed to be related to prior study treatment (see Section 5.6).  


 
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Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system. A report will be generated and sent to 
Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators. Once the EDC 
system is available, all information will need to be entered and submitted via the EDC 
system.  
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 18 months after the last 
dose of study treatment.  
A paper Clinical Trial Pregnancy Reporting Form should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators. Pregnancy should not be recorded on the 
Adverse Event eCRF. The investigator should discontinue study treatment immediately 
counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy. Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF. In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.  
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 3 
months after the last dose of study treatment.  
A paper Clinical Trial Pregnancy Reporting Form should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 


 
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pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators. Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug. When permitted by the site, the pregnant partner would 
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to 
allow for follow-up on her pregnancy. If the authorization has been signed, the 
investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available. An 
investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent. Every effort should be made to follow all 


 
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serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
3 months (90 days (± 10 days)) after the last dose of study treatment), if the event is 
believed to be related to prior study drug treatment. These events should be reported 
through use of the Adverse Event eCRF. 
An exception is made for Grade 3–4 infections (related and unrelated), which should be 
reported until up to 2 years after the last dose of study treatment. 
The Sponsor should also be notified of events of secondary malignancies indefinitely 
(related and unrelated) for patients who received obinutuzumab. 
If the EDC system is not available, the investigator should report these events directly to 
the Sponsor or its designee, either by faxing or by scanning and emailing the paper 
Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 


 
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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
• 
Obinutuzumab Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The purpose of this study is to evaluate the safety of administering obinutuzumab as a 
short duration infusion (SDI; target 90-minute infusion) during cycle 2 and from cycle 2 
onwards in combination with chemotherapy in patients with previously untreated 
advanced FL. 
The primary analysis will be analyzed and reported based on all patients’ data up to the 
time when all patients have completed 2 cycles of obinutuzumab treatment. The End of 
Induction (EOI) analysis will be analyzed and reported once all patients have completed 
the induction period. The final analysis will be performed at the end of the study and 
include PFS and OS rates. 
The analysis populations are defined as follows: 
• 
The SDI population includes all patients who received obinutuzumab as an SDI at 
cycle 2 and who did not experience a Grade 3 or 4 IRR during the infusion of 
obinutuzumab given at the standard rate during cycle 1. This population will be used 
for the analysis of the primary endpoint and one of the secondary endpoints (time to 
IRR during cycle 2).  
• 
The safety population includes all patients who received at least one dose of 
obinutuzumab. This population will be used for all remaining analyses. 
No formal statistical hypothesis tests will be performed, and all analyses are considered 
descriptive. 
6.1 
DETERMINATION OF SAMPLE SIZE 
A sample size of approximately 112 patients is planned for this study. 
The incidence of Grade ≥3 IRRs during cycle 2 was chosen as the safety endpoint of 
primary interest and used to justify the sample size. Based on experience from previous 
studies (BO21223/GALLIUM, GAO4915g/GATHER), it is assumed to have an incidence 
rate of only 1% or 2%, and hence to observe only few events.  


 
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The upper bounds of two-sided 95% Clopper-Pearson confidence intervals (CIs) 
according to the sample size and the number of observed Grade ≥3 IRRs during cycle 2 
are shown in Table 6. 
Table 6 
Relationship Between the Sample Size, the Number of Observed 
≥G3 IRRs and the Upper Bound of the Corresponding Two-sided 
95% Clopper-Pearson Confidence Interval 
 
  
Number of observed ≥G3 IRRs 
Sample size 
0 
1 
2 
3 
4 
90 
4.0% 
6.0% 
7.8% 
9.4% 
11.0% 
100 
3.6% 
5.4% 
7.0% 
8.5% 
9.9% 
 
For instance, observing two Grade ≥3 IRRs during cycle 2 would yield an upper bound of 
7.0% in an SDI population of 100 patients and of 7.8% in an SDI population of 90 
patients. Not observing any Grade ≥3 IRRs during cycle 2 would yield upper bounds of 
3.6% and 4.0%, respectively.  
There will be no formal hypothesis test for the primary endpoint.  
Taking into account an estimated drop-out rate of 10%, a total of approximately 112 
patients will be enrolled in this study to have 100 patients in the SDI population. If the 
drop-out rate would be lower, accrual would be stopped after 100 patients in the SDI 
population. If the drop-out rate would be higher, with 112 patients enrolled into the study 
a drop-out rate of 19.7% would still leave 90 patients in the SDI population which would 
result in a reasonable precision for the CI. If there would be less than 90 patients in the 
SDI population at the end of the planned enrolment phase, the IMC would decide 
whether to continue enrolment or not. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue, or complete the study will be 
summarized. Reasons for premature study discontinuation will be listed and 
summarized. Major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, etc.) will be summarized 
using means, standard deviations, medians, and ranges for continuous variables and 
frequencies and percentages for categorical variables, as appropriate. 


 
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6.4 
SAFETY ANALYSES 
The primary objective of this study is to evaluate the safety of obinutuzumab 
administered as an SDI from cycle 2 in patients with previously untreated advanced FL 
on the basis of the following endpoints: 
Primary endpoint:  
• 
The incidence of Grade ≥3 IRRs* during cycle 2 in patients who had previously 
received obinutuzumab at the standard infusion rate during cycle 1 without 
experiencing a Grade 3 or 4 IRR, with severity determined according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 5.0. 
* IRRs are defined as all adverse events (AEs) that occur during or within 24 hours from the end 
of study treatment infusion and are judged as related to infusion of study treatment 
components (obinutuzumab and chemotherapy during induction and obinutuzumab alone 
during maintenance) by the investigator. 
Secondary safety endpoints: 
• 
Incidence, nature, and severity of all AEs from during cycle 1 and from cycle 1 
onwards (including maintenance) 
• 
Incidence of IRRs regardless of grade by cycle (separately) 
• 
Time to IRR (in hours) from infusion to onset of the IRR during cycle 2 
• 
Duration (in minutes) of obinutuzumab administration by cycle (all cycles including 
maintenance) 
• 
Type and duration of Grade ≥3 IRRs, during all cycles, where obinutuzumab was 
administered as an SDI. 
 
The SDI population will be used for the analysis of the primary endpoint and of the time 
to IRR during cycle 2. The analysis of the primary endpoint will occur once all patients 
have completed cycle 2.  
The safety population which includes all patients who received at least one dose of 
obinutuzumab will be the analysis set used for all remaining analyses.  
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0. 
Descriptive summaries of discrete data will present the number of patients and incidence 
as a frequency and as a percentage. For the primary endpoint a two-sided 95% Clopper-
Pearson confidence interval will be presented. Moreover, the incidence of IRRs for cycle 
1 will be described by day of the cycle (day 1, day 8, or day 15). 


 
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The duration of obinutuzumab administration and infusion-related AEs will be 
summarized descriptively (mean, median, standard deviation, minimum, and maximum 
duration) by cycle. 
6.5 
SECONDARY EFFICACY ANALYSES 
The secondary efficacy objective for this study is to evaluate the efficacy of 
obinutuzumab administered as an SDI from cycle 2 in patients with previously untreated 
advanced FL on the basis of the following endpoints: 
• 
Objective response rate at the end of induction therapy as determined by the 
investigator and according to the guidelines used at the site (Lugano [Cheson et al 
2014], Cheson et al 2007, or Cheson et al 1999). 
• 
Progression-free survival rate at the end of the study 
• 
Overall survival at the end of the study 
• 
Complete response (CR) rate at 30 months (CR30), as assessed by the investigator 
and according to the guidelines used at the site. 
 
There were no power calculations for the efficacy endpoints. No formal statistical 
hypothesis tests will be performed, and all analyses are considered descriptive.  
The ORR will be presented along with a 95% Clopper-Pearson confidence interval; 
overall and by type of response assessment. ORR will be reported at the primary 
analysis, for patients that have already reached end of induction. In addition, ORR will 
be reported at the EOI analysis and at the final analysis for all patients. 
PFS in patients with follicular lymphoma is defined as the time from start of treatment to 
the first occurrence of progression or relapse as assessed by the investigator according 
to the used at the site (Lugano [Cheson et al 2014], Cheson et al 2007, or Cheson et al 
1999), or death from any cause. It will be presented as the Kaplan-Meier estimate at the 
end of the study along with its 95% confidence interval. Note that with different criteria 
and tumour assessment schedules between sites the value of these data will be limited. 
OS is defined as the time from start of treatment to death from any cause. It will be 
presented as the Kaplan-Meier estimate at the end of the study along with its 95% 
confidence interval. 
PFS and OS will be analysed only once, as part of the final analysis at the end of the 
study. 
Note that the follow-up time is not driven by PFS and OS. With a study duration of only 
approximately 4 years very few events are expected to have occurred in this patient 
population. This study will not make a substantial contribution to the data on these 


 
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endpoints. But, as the progression dates are used for treatment management and OS 
data are easy to obtain these data will be collected and reported. 
 
6.6 
EXPLORATORY ANALYSES 
6.6.1 
Exploratory Safety Analyses 
The exploratory safety objectives for this study are to further evaluate the safety of 
obinutuzumab administered in patients with previously untreated advanced FL on the 
basis of the following endpoints to evaluate the impact of time to IRR: 
• 
The incidence of Grade ≥3 IRRs* (with severity determined according to NCI 
CTCAE Version 5.0) during the first SDI cycle:  
– 
cycle 2 in patients who received obinutuzumab at the standard infusion rate 
without experiencing a Grade 3 IRR in cycle 1  
– 
cycle 3 in patients who experienced a Grade 3 IRR when administered 
obinutuzumab at the standard infusion rate in cycle 1 and subsequently 
received obinutuzumab at the standard infusion rate in cycle 2 without 
experiencing a Grade 3 IRR  
• 
Time to IRR (in hours) from infusion to onset of the IRR in cycle 1 or cycle 3 
* IRRs are defined as all adverse events (AEs) that occur during or within 24 hours from the end 
of study treatment infusion and are judged as related to infusion of study treatment 
components (obinutuzumab and chemotherapy during induction and obinutuzumab alone 
during maintenance) by the investigator. 
Descriptive summaries of discrete data will present the number of patients and incidence 
as a frequency and as a percentage. The time from obinutuzumab administration to AEs 
will be summarized descriptively (mean, median, standard deviation, minimum, and 
maximum duration) over all and by cycle. 
6.6.2 
Exploratory Efficacy Analyses 
The exploratory efficacy objectives for this study are to evaluate patients with a partial 
response (PR) at the end of induction treatment who convert to complete response (CR) 
during maintenance treatment and to evaluate and compare the objective response and 
CR rate after the end of induction treatment with and without 18F-fluorodeoxyglucose 
positron emission tomography (FDG-PET): 
• 
Proportion of patients with a PR at the end of induction treatment who convert to CR 
during maintenance treatment, as assessed by the investigator and according to the 
guidelines used at the site (see above) 
• 
Objective response rate and CR rate after the end of induction treatment, as 
assessed by the investigator and according to the guidelines used at the site (see 


 
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above), with and without 18F-fluorodeoxyglucose positron emission tomography 
(FDG-PET). 
Again, descriptive summaries of these discrete data will present the number of patients 
and incidence as a frequency and as a percentage. 
 
6.6.3 
Exploratory Provider and Patient-reported Analyses 
The exploratory patient-reported objective for this study is to evaluate the severity and 
interference of disease- and treatment-related symptoms in patients with previously 
untreated advanced FL treated with obinutuzumab administered as an SDI during cycle 
2 and from cycle 2 onwards, on the basis of the following endpoint: 
• 
Severity of disease symptoms experienced by patients and the interference with 
daily living caused by these symptoms, as assessed through use of the MD 
Anderson Symptom Inventory (MDASI; Appendix 2). 
The exploratory provider-reported objective is to evaluate the site experience with the 
SDI, specifically: 
• 
Physician / nurse experience on time savings with obinutuzumab SDI compared 
with obinutuzumab at the regular infusion rate 
• 
Physician / nurse experience on the convenience of and preference for 
obinutuzumab SDI compared with obinutuzumab at the regular infusion rate. 
 
For all patients that completed the questionnaire, the MDASI items and subscales will be 
summarized by the mean and median change from baseline. The MDASI subscales will 
be plotted over time.  
For the provider-reported questions, the frequency of individuals reporting the responses 
to each question will be obtained and reported. 
6.7 
INTERIM ANALYSIS 
No formal Interim analysis is planned for this study. There will be three reporting events: 
the primary analysis, the end of induction analysis, and the final analysis.  
In addition, the data will be monitored by an Internal Monitoring Committee (IMC). The 
first IMC data review will take place after the first 10 patients have completed the first 
SDI infusion (i.e. cycle 2). The second IMC data review will happen after 50 patients 
have completed the first SDI infusion (i.e. cycle 2) or at 6 months after the first IMC, 
whichever occurs first. Furthermore, the IMC will review results obtained for the primary 
analysis, end of induction analysis, and final analysis. Further meetings will be 
scheduled as deemed necessary. See the IMC charter for details. 


 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for the data management of 
this study, including quality checking of the data. Data entered manually will be collected 
via EDC through use of eCRFs. Sites will be responsible for data entry into the EDC 
system. In the event of discrepant data, the CRO will request data clarification from the 
sites, which the sites will resolve electronically in the EDC system.  
The Sponsor will perform oversight of the data management of this study. The CRO will 
produce eCRF Specifications for the study based on Sponsor’s templates including 
quality checking to be performed on the data.  
eCRFs and correction documentation will be maintained in the EDC system's audit trail. 
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
Patient- and provider-reported data will be collected on paper questionnaires. The data 
from the questionnaires will be entered into the EDC system by site staff. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system. Sites will 
receive training and have access to a manual for appropriate eCRF completion. eCRFs 
will be submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the CRO. 
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records. Acknowledgement of receipt of 
the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 


 
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and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan. This includes any protocol data to be entered 
directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review. The study site must also 
allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research. An 
acceptable computerized data collection system allows preservation of the original entry 
of data. If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO data, Informed Consent Forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator 
for 15 years after completion or discontinuation of the study or for the length of time 
required by relevant national or local health authorities, whichever is longer. After that 
period of time, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 


 
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Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site. If applicable, it will be provided in a certified translation of 
the local language. The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission. The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures. The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure. 
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason. A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures. Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 


 
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to participate. The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative. All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996. If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated. 
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. Investigators are also 
responsible for promptly informing the IRB/EC of any protocol amendments (see Section 
9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC. Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor. Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  


 
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8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
The aggregate results of any conducted research will be available in accordance with 
the effective Sponsor policy on study data publication (see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study. These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease. In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.5). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 


 
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governmental approval. In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of ICH Good Clinical Practice guidelines and 
require reporting to health authorities. As per the Sponsor's standard operating 
procedures, prospective requests to deviate from the protocol, including requests to 
waive protocol eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs. The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd. The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 40 sites globally will participate to enroll approximately 112 patients. 
Enrollment will occur through an IxRS.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
An IMC will be employed to monitor and evaluate patient safety throughout the study. 
Tumor response and progression will be evaluated locally. 
9.5 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results. Study data may be shared 
with others who are not participating in this study (see Section 8.4 for more details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 


 
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met. For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following website: 
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
The results of this study may be published or presented at scientific congresses. For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report. In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation. This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Any formal publication of 
the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
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Appendix 1  
Schedule of Activities 
Day 
Screening a 
Treatment 
Follow-up 
(3 months)aa 
Induction (6–8 cycles) b 
EOI 
Maintenance e 
(every 8 weeks 
± 10 days) 
EOM  
Cycle 1  
Cycle 2  
Cycles 3–6/8 
D–28  
to D–1  
D–7 
to D–1 
D1 
D8 
D15 
D1 
D1 
Informed consent 
x f 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
Medical history and baseline 
conditions 
x 
 
 
 
 
 
 
 
 
 
 
Ann Arbor, FLIPI, and FLIPI2 
x 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
x 
 
 
 
 
 
 
 
 
 
 
Vital signs g 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight 
x 
 
 
 
 
 
 
 
 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
LVEF (echocardiography or MUGA 
scan) z 
x 
 
 
 
 
 
 
 
 
 
 
Complete physical examination h,i 
x 
 
 
 
 
 
 
 
 
 
x 
Targeted physical examination j,k 
 
 
 
 
 
 
 
x 
 
x 
 
B symptoms l 
x 
 
 
 
 
 
 
 
 
 
 
Hematology m 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Chemistry n 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
Pregnancy test o 
 
x 
 
 
 
 
 
 
 
 
 
Coagulation INR, aPTT or PTT and 
PT 
 
x 
 
 
 
 
 
 
 
 
 
Urinalysis p 
 
x 
 
 
 
 
 
x 
 
x 
 
HIV, HTLV-1, Hep B / C testing q 
x 
 
 
 
 
 
 
 
 
 
 
Study drug 
administration 
obinutuzumab r 
 
 
x c 
x c 
x c 
x d 
x d 
 
x d 
 
 
chemotherapy s 
 
 
x 
 
 
x 
x 
 
 
 
 
Tumor assessment t 
x 
 
 
 
 
 
 
x 
 
x 
 
Concomitant medications u,v 
x u 
x u 
x u 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events w 
x w 
x w 
x w 
x 
x 
x 
x 
x 
x 
x 
x 
Provider-reported measures 
 
 
 
 
 
 
x x 
 
 
 
 
Patient-reported measures y 
 
 
x 
 
 
x 
x 
x 
x 
x 
x 
(a)PTT=(activated) partial thromboplastin time; D=day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOI=end of 
induction; EOM=end of maintenance; FLIPI=Follicular Lymphoma International Prognostic Index; HIV, human immunodeficiency virus; HTLV-1, 
human T-lymphotropic virus 1; INR=International Normalized Ratio; LVEF=left ventricular ejection fraction; MUGA= multigated acquisition (scan); 
PT=prothrombin time.  


Appendix 1: Schedule of Activities 
  
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Notes:  Dosing (i.e., Day 1 of each cycle), in induction phase should be done within ± 2 days of the scheduled visit date, with the exception of C1D1 
which should take place within 28 days of the patient entering screening. All assessments should be performed within 2 days of the scheduled visit, 
unless otherwise specified.  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. Results from 
hematology and biochemistry must be reviewed, and the review documented, prior to study drug administration. 
a 
Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within the defined window may be used; 
such tests do not need to be repeated for screening.   
b 
The total number of cycles of G-chemo indication therapy and the cycles length depends on the chemotherapy chosen for each patient (see 
Section 4.3.2.2 Combination chemotherapy).  
c 
Obinutuzumab administered according to the regular infusion rate (see Table 1, Section 3.1). 
d 
Obinutuzumab administered according a 90-minute short duration infusion (see Table 1, Section 3.1) for patients who do not experience any 
Grade ≥3 IRRs during the first or previous cycle. If a patient experiences any Grade 3 IRRs during any SDI administrations of obinutuzumab 
(i.e. after Cycle 1, Day 1), the next dose of obinutuzumab will be administered at the regular infusion rate.  If the patient experiences a second 
occurrence of a Grade 3 IRR, the obinutuzumab infusion must be stopped and the therapy must be permanently discontinued. 
e 
Patients who achieve at least a partial response (PR) following the completion of induction therapy will receive obinutuzumab maintenance 
therapy (1000 mg as single agent every 8 weeks (± 10 days) for 2 years or until disease progression). The first administration of obinutuzumab 
maintenance therapy is expected to start 8 weeks ± 10 days from Day 1 of the last induction cycle. Patients with stable disease or progressive 
disease will go to safety follow-up. For the timing of the safety follow-up assessment, please see footnote aa. 
f 
Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days 
before initiation of study treatment. 
g 
Includes blood pressure, pulse rate and temperature. Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
h 
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
i 
As part of tumor assessment, the physical examination should include evaluation for the presence of enlarged nodes, palpable hepatomegaly, 
and splenomegaly. This information will be recorded on the appropriate tumor assessment eCRF. 
j 
Includes systems of primary relevance (e.g., cardiovascular and respiratory systems), systems associated with symptoms (newly emergent or 
monitored from baseline), and areas associated with tumor assessment (lymph nodes, liver, spleen, and any other areas identified at baseline). 
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
k 
Perform at the same time as tumor assessments after the end of induction treatment. 
l 
Unexplained fever >38ºC, night sweats, unexplained weight loss >10% of body weight over 6 months. 
m 
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). 


Appendix 1: Schedule of Activities 
  
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n 
Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, ALP, ALT, AST, 
urate, beta-2 microglobulin (at screening and EOI only) and LDH. 
o 
All women of childbearing potential will have a serum pregnancy test at screening.  
p 
Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination if routinely performed (sediment, RBCs, 
WBCs, casts, crystals, epithelial cells, bacteria). 
q 
To include assessment of HBV/HCV DNA PCR in patients with resolved HBV/HCV infection at baseline. HBV DNA PCR testing at least every 3 
months should also be conducted (during the study and for at least 1 year after completion of lymphoma treatment) for patients with prior HBV 
infection or who are carriers of HBV. HTLV-1 testing will be performed at baseline in patients from endemic countries only. HIV testing will be 
performed at baseline if required by local regulations.  
r 
Obinutuzumab administered on Days, 1, 8 and 15 of cycle 1 and Day 1 of subsequent cycles. 
s 
Chemotherapy comprises either bendamustine (Days 1 and 2, Cycles 1–6; 28-day cycles), CHOP (Days 1–5, Cycles 1–6; 21-day cycles; 
followed by 2 cycles of obinutuzumab alone), or CVP (Days 1–5, Cycles 1–8; 21-day cycles). See Section 4.3.2.2 Combination chemotherapy. 
t 
By the investigator according to local practice and according to the guidelines used at the site (Lugano [Cheson et al 2014], Cheson et al 2007, 
or Cheson et al 1999). Including bone marrow where applicable. If bone marrow data are available in the patient’s medical record that were 
obtained within 3 months prior to study inclusion, these data can be used instead, and the patient does not need to undergo a new bone 
marrow biopsy with or without aspirate at screening. 
u 
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to study entry until 3 months after the final dose of study drug. 
v 
Concomitant medications and adverse events will be collected throughout the study. 
w 
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported. After initiation of study drug, all adverse events will be reported until 3 months (90 days (± 10 days)) after the 
final dose of study drug. After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is 
believed to be related to prior study treatment (see Section 5.6). An exception is made for Grade 3–4 infections (related and unrelated), which 
should be reported until resolution or until up to 2 years after the last dose of obinutuzumab and secondary malignancies should be reported 
indefinitely. The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as 
stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent. 
x 
After administration of SDI at Cycle 4 Day 1, providers will complete the evaluation of site experience questionnaire. 
y 
Before administration of treatment at Day 1 of Cycles 1–6, at the end of induction, during maintenance, at end of maintenance, and at end of 
study, patients will complete the MDASI. The MDASI will be self-administered before the patient receives any information on disease status, 
prior to the performance of non-PRO assessments, and prior to the administration of study treatment. 
z 
LVEF required for patients who receive CHOP only.  
aa Safety follow-up assessment at 3 months (90 days (+/- 10 days)) after the final dose of obinutuzumab. If a patient discontinues obinutuzumab 
early and requires another anticancer therapy, then a safety follow up visit must be performed prior to the initiation of the new anticancer 
therapy. 
 






Appendix 2 
Provider and Patient-reported Measures (cont.) 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
105/Protocol MO40597, Version 5 
Provider-Reported Outcomes: Evaluation of Site Experience 
Investigator physicians and nurses involved in this study will be asked to answer 
questions based on their site experience with the SDI and standard infusions of 
obinutuzumab, across all patients enrolled in the study. After each patient enrolled, 
physicians and nurses will be asked to complete the four questions below at one time 
points after Cycle 4 SDI administration or after the last cycle of SDI treatment if 
treatment is discontinued earlier. 
Physician / Nurse Experience on Time Savings 
If used in routine practice, on average, how much staff time could be saved with each 
administration of obinutuzumab SDI as compared to obinutuzumab at the standard 
infusion rate? 
 
□ Less than 1 hour 
 
□ At least 1 hour but less than 2 hours 
 
□ At least 2 hours but less than 3 hours 
 
□ At least 3 hours but less than 4 hours 
 
□ 4 or more hours 
 
□ No time savings 
 
□ Not applicable 
 
Physician / Nurse Experience on Convenience 
Which administration of obinutuzumab (SDI or standard) do you think is more 
convenient? 
 
□ Obinutuzumab SDI is much more convenient 
 
□ Obinutuzumab SDI is a little more convenient 
 
□ Both administrations are equally convenient 
 
□ Obinutuzumab at the standard infusion rate is a little more convenient 
 
□ Obinutuzumab at the standard infusion rate is much more convenient 


Appendix 2 
Provider and Patient-reported Measures (cont.) 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
106/Protocol MO40597, Version 5 
Physician / Nurse Experience on Preference 
Which formulation of obinutuzumab (SDI or standard) do you prefer? 
 
□ Obinutuzumab SDI 
 
□ Obinutuzumab at the standard infusion rate 
 
□ Have no preference 
 
If you have a preference for one of the formulations, what are the main reasons for your 
preference? 
 
□ Clinic/staff time savings 
 
□ Patient time savings 
 
□ Patient comfort 
 
□ Other 
If ‘other’ please specify: 
……………………..……………………………………………..…………………………………
…………..……………………………………………..……………………………………………
..……………………………………………..……………………………………………..……….
……………………………………..……………………………………………..………………… 
 


 
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107/Protocol MO40597, Version 5 
Appendix 3  
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active; able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework or office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about >50% of waking hours. 
3 
Capable of only limited self-care; confined to a bed or chair >50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair. 
5 
Dead. 
 


 
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108/Protocol MO40597, Version 5 
Appendix 4  
Ann Arbor Staging 
Grade 
Description 
Stage I 
Involvement of a single lymph node region (I) or of a single 
extralymphatic organ or site (IE) a 
Stage II 
Involvement of two or more lymph node regions or lymphatic structures 
on the same side of the diaphragm alone (II) or with involvement of 
limited, contiguous extralymphatic organ or tissue (IIE) 
Stage III 
Involvement of lymph node regions on both sides of the diaphragm (III), 
which may include the spleen (IIIS) or limited, contiguous extralymphatic 
organ or site (IIIE), or both (IIIES) 
Stage IV b 
Diffuse or disseminated foci of involvement of one or more 
extralymphatic organs or tissues, with or without associated lymphatic 
involvement 
Note: All cases are subclassified to indicate the absence (A) or presence (B) of the systemic B 
symptoms of significant unexplained fever (>38ºC), night sweats, or unexplained weight loss 
exceeding 10% of body weight during the 6 months prior to diagnosis. 
a The designation “E” generally refers to extranodal contiguous extension (i.e., proximal or 
contiguous extranodal disease) that can be encompassed within an irradiation field appropriate 
for nodal disease of the same anatomic extent. A single extralymphatic site as the only site of 
disease should be classified as IE, rather than Stage IV. 
b Involvement of bone marrow at screening will always qualify for Ann Arbor Stage IV and should 
be recorded as extranodal involvement.  
 
Adapted from: 
Carbone PP, Kaplan HS, Musshoff K, et al. Report of the committee on Hodgkin’s 
disease staging classification. Cancer Res 1971;31:1860–1. 
Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the 
evaluation and staging of patients with Hodgkin’s disease: Cotswolds Meeting. J Clin 
Oncol 1989;7:1630–6. 
 


 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
109/Protocol MO40597, Version 5 
Appendix 5  
Follicular Lymphoma International Prognostic Index 
 
Table 1 Follicular Lymphoma International Prognostic Index 
FLIPI risk factors 
• 
Ann Arbor Stage III or IV 
• 
Age > 60 years 
• 
Serum LDH > 1 x ULN 
• 
Anemia (hemoglobin < 120 g/L) 
• 
Involved nodal areas > 4 
  
FLIPI risk group 
Number of FLIPI risk factors 
Low 
0 or 1 
Intermediate 
2 
High 
3 to 5 
FDG=fluorodeoxyglucose; FLIPI=Follicular Lymphoma International Prognostic Index; 
PET=positron emission tomography; ULN=upper limit of normal. 
Note: The results of FDG-PET should not be taken into account for calculation of FLIPI 
since this prognostic score was established without FDG-PET. 
Adapted from: Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma 
international prognostic index. Blood 2004;104:1258–64. 
 
 


 
Appendix 5  
Follicular Lymphoma International Prognostic Index (cont) 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
110/Protocol MO40597, Version 5 
 
Table 1 Follicular Lymphoma International Prognostic Index 2 
FLIPI2 risk factors 
• 
Bone marrow involvement 
• 
Age > 60 years 
• 
β2 microglobulin > 1 x ULN 
• 
Anemia (hemoglobin < 120 g/L) 
• 
Longest diameter of largest involved node > 6 cm 
  
FLIPI2 risk group 
Number of FLIPI2 risk factors 
Low 
0 
Intermediate 
1 or 2 
High 
3 to 5 
FDG=fluorodeoxyglucose; FLIPI=Follicular Lymphoma International Prognostic Index; 
PET=positron emission tomography; ULN=upper limit of normal. 
Note: The results of FDG-PET should not be taken into account for calculation of FLIPI2 
since this prognostic score was established without FDG-PET. 
Adapted from: Federico M, Bellei M, Marcheselli L, et al. Follicular Lymphoma 
International Prognostic Index 2: a new prognostic index for follicular lymphoma 
developed by the International Follicular Lymphoma Prognostic Factor Project. J Clin 
Oncol 2009;27:4555–62. 
 
 


 
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111/Protocol MO40597, Version 5 
Appendix 6  
Management of Infusion-Related Reactions 
 
Management of IRRs may require temporary interruption and/or reduction in the rate of 
infusion, or treatment discontinuations of obinutuzumab, and is dependent on the 
infusion rate being used at the time the IRR occurred. Please refer to the flow charts on 
the following pages. 
In case of anaphylaxis, study treatment should be permanently discontinued. 
Anaphylaxis precautions are provided in Appendix 7.


Appendix 6 (a)  
Management of Infusion-Related Reactions During Cycle 1, Day 1 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
112/Protocol MO40597, Version 5 
 


Appendix 6 (b)  
Management of Infusion-Related Reactions During Cycle 1, Day 8 and Day 15 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
113/Protocol MO40597, Version 5 
 


Appendix 6 (c)  
Management of Infusion-Related Reactions During Short Duration Infusions 
Obinutuzumab—F. Hoffmann-La Roche Ltd 
114/Protocol MO40597, Version 5 
 


 
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115/Protocol MO40597, Version 5 
Appendix 7  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion: 
• 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
• 
Oxygen 
• 
Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines 
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed: 
1. 
Stop the study treatment infusion. 
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 

SAP_001.pdf: 
 
Official Title: 
 
A Multicentric, Open-Label, Single Arm Study Of Obinutuzumab 
Short Duration Infusion (Sdi) in Patients With Previously Untreated 
Advanced Follicular Lymphoma  
NCT Number: 
NCT03817853 
Document Date: 
SAP Version 1: 12-July-2020 
 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Obinutuzumab — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MO40597
STATISTICAL ANALYSIS PLAN
TITLE:
A MULTICENTER, OPEN-LABEL, SINGLE ARM STUDY OF 
GAZYVA SHORT DURATION INFUSION (SDI) IN PATIENTS 
WITH PREVIOUSLY UNTREATED ADVANCED 
FOLLICULAR LYMPHOMA
PROTOCOL NUMBER:
MO40597
STUDY DRUG:
Obinutuzumab (GA101, RO5072759)
VERSION NUMBER:
1.0
IND NUMBER:
104405
EUDRACT NUMBER:
2018-003255-38
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
, Cytel Inc.; 
, F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below.
Date and Time(UTC)        Reason for Signing                              Name
28-Jul-2020 07:32:56
Company Signatory


Obinutuzumab — F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan MO40597 (version 1.0)
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 6
2.1
Protocol Synopsis.................................................................... 9
2.2
Outcome Measures ................................................................. 9
2.2.1
Primary Safety Endpoint.......................................................... 9
2.2.2
Secondary Safety Endpoints ................................................... 9
2.2.3
Secondary Efficacy Endpoints................................................. 9
2.2.4
Exploratory Safety Endpoints ................................................ 10
2.2.5
Exploratory Efficacy Endpoints.............................................. 10
2.3
Determination of Sample Size ............................................... 11
2.4
Analysis Timing ..................................................................... 11
3.
STUDY CONDUCT..................................................................................... 12
3.1
Randomization....................................................................... 12
3.2
Independent Review Facility.................................................. 12
3.3
Data Monitoring ..................................................................... 12
4.
STATISTICAL METHODS .......................................................................... 13
4.1
Analysis Populations ............................................................. 13
4.1.1
All Patients Population........................................................... 13
4.1.2
Short Duration Infusion Population........................................ 13
4.1.3
Safety Population .................................................................. 13
4.2
Analysis of Study Conduct..................................................... 13
4.3
Analysis of Demographic and Baseline 
Characteristics....................................................................... 14
4.4
Efficacy Analysis.................................................................... 14
4.4.1
Secondary Efficacy Endpoints............................................... 14
4.4.1.1
Objective Response Rate at the EOI..................................... 14
4.4.1.2
Progression-Free Survival ..................................................... 15
4.4.1.3
Overall Survival ..................................................................... 15
4.4.1.4
Complete Response (CR) Rate at 30 months 
(CR30)................................................................................... 15


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4.4.2
Exploratory Efficacy Endpoints.............................................. 16
4.4.2.1
Proportion of Patients with a PR at EOI Who 
Convert to CR During Maintenance....................................... 16
4.4.2.2
ORR and CR Rate After the EOI by FDG-PET 
Status .................................................................................... 16
4.4.2.3
MD Anderson Symptom Inventory (MDASI) .......................... 16
4.4.2.4
Site Experience ..................................................................... 16
4.4.3
Subgroup Analysis................................................................. 17
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 17
4.6
Safety Analyses..................................................................... 17
4.6.1
Exposure of Study Medication............................................... 17
4.6.2
Infusion Related Reactions.................................................... 18
4.6.2.1
Primary Safety Endpoint........................................................ 19
4.6.2.2
Secondary Safety Endpoints ................................................. 19
4.6.2.3
Exploratory Safety Endpoints ................................................ 20
4.6.2.4
Sensitivity Analysis ................................................................ 20
4.6.3
Adverse Events ..................................................................... 20
4.6.4
Laboratory Data..................................................................... 22
4.6.5
Vital Signs.............................................................................. 22
4.7
Missing Data.......................................................................... 22
4.8
Interim Analyses .................................................................... 22
5.
REFERENCES ........................................................................................... 23
LIST OF TABLES
Table 1
Obinutuzumab infusion rates at induction and maintenance......... 7
Table 2
Relationship Between the Sample Size, the Number of 
Observed Grade 3 IRRs and the Upper Bound of the 
Corresponding Two-sided 95% Clopper-Pearson Confidence 
Interval ........................................................................................ 11
Table 3
Analysis Timings......................................................................... 12


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4/Statistical Analysis Plan MO40597 (version 1.0)
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 8
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 24
Appendix 2
Schedule of Assessments........................................................... 34
Appendix 3
MDASI: Details on Scoring.......................................................... 38
Appendix 4
Infusion Related Reactions: List of Predefined Preferred 
Terms.......................................................................................... 39


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List of abbreviations
Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
CHOP
cyclophosphamide, doxorubicin, vincristine, 
prednisone/prednisolone/methylprednisolone
CI
confidence interval
CR
complete response
CR30
complete response rate at 30 months
CSR
clinical study report
CVP
cyclophosphamide, vincristine, and 
prednisone/prednisolone/methylprednisolone
EOI
end of induction
EOS
end of study
FDG-PET
18F-fluorodeoxyglucose positron emission tomography
FL
follicular lymphoma
G-chemo
obinutuzumab-based chemotherapy
GI
gastrointestinal
IMC
internal monitoring committee
IRR
infusion-related reaction
MDASI
MD Anderson Symptom Inventory 
MedDRA
Medical Dictionary for Regulatory Activities
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
ORR
objective response rate
OS
overall survival
PFS
progression-free survival
PR
partial response
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
SDI
short duration infusion
SOC
system organ class
TEAE
treatment-emergent adverse event


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6/Statistical Analysis Plan MO40597 (version 1.0)
1.
BACKGROUND
This Statistical Analysis Plan (SAP) describes the analyses that are planned to be 
performed for the Internal Monitoring committee (IMC) and the Clinical Study Reports
(CSRs) of Study MO40597.
2.
STUDY DESIGN
This is an open-label, international, multicenter, single arm Phase IV study to investigate 
the safety and efficacy of the short duration infusion (SDI; target 90-minute infusion) 
obinutuzumab in patients with previously untreated advanced follicular lymphoma (FL).
The study has two phases: in the first phase patients will receive the first cycle of 
obinutuzumab-based chemotherapy (G-chemo) induction therapy as usual with the first 
three infusions of obinutuzumab (1000 mg) administered at the regular infusion rate 
(Table 1) on Day 1, 8, and 15 of cycle 1. The investigator is free to choose the 
chemotherapy for each patient (bendamustine, CHOP [cyclophosphamide, doxorubicin, 
vincristine, prednisone/prednisolone/methylprednisolone], or CVP [cyclophosphamide, 
vincristine, and prednisone/prednisolone/methylprednisolone]). The total number of 
cycles of G-chemo induction therapy and the cycle’s length depends on the 
chemotherapy chosen for each patient.
Study treatment refers to obinutuzumab plus chemotherapy during the induction phase 
and obinutuzumab monotherapy during the maintenance phase.
For the purpose of this study infusion-related reactions (IRRs) are defined as all AEs that 
occur during or within 24 hours from the end of study treatment infusion and are judged 
by the investigator as related to infusion of study treatment components (obinutuzumab 
or chemotherapy during induction and obinutuzumab alone during maintenance). In 
addition, IRRs are also defined as AEs within a pre-defined list of terms that occur during 
or within 24 hours from the end of study treatment infusion. Refer to Section 4.6.2 for a 
detailed definition of IRRs.
Patients who do not experience any Grade 3 IRRs during the first cycle will enter into 
the second, faster infusion, phase from Cycle 2 onwards. These patients will receive 
obinutuzumab at the SDI rate, starting on Cycle 2, Day 1.
Patients who experience a Grade 3 IRR during the first cycle will remain on the study but 
cycle 2 of obinutuzumab must be administered at the regular infusion rate. If these 
patients do not experience a Grade 3 IRRs during cycle 2 at the regular infusion rate, 
then they will be eligible to receive SDI dosing from cycle 3 onwards, according to 
investigator’s judgement.
Patients who experience a first occurrence of a Grade 3 IRR during any SDI 
administration of obinutuzumab may continue to receive SDI dosing during the current 




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Figure 1 presents an overview of the study design.
Figure 1
Study Schema
All patients will be assessed for disease response by the investigator at the end of 
induction therapy and end of maintenance therapy according to local practice and 
according to the guidelines used at the site (Lugano [Cheson et al 2014], Cheson et al 
2007, or Cheson et al 1999). No central confirmation of disease response will be 
conducted.
Patients who achieve at least a partial response (PR) following the completion of 
induction therapy will receive obinutuzumab maintenance therapy (1000 mg as single 
agent administered as an SDI every 8 weeks (10 days) for a maximum of 2 years or 
until disease progression). 
The first administration of obinutuzumab maintenance therapy is expected to start 
8 weeks 10 days from Day 1 of the last induction cycle.
Patients with stable disease or progressive disease as best response after induction 
therapy will discontinue study treatment and undergo a safety follow-up visit at 3 months
(90 days [10 days]). 
All patients will be followed up at 3 months (90 days [10 days]) from the time of the last 
dose of study treatment.


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9/Statistical Analysis Plan MO40597 (version 1.0)
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1. For additional details, see the Schedule of 
Assessments in Appendix 2.
2.2
OUTCOME MEASURES
See the Protocol Synopsis in Appendix 1 for a description of the outcome measures.
2.2.1
Primary Safety Endpoint

The incidence of Grade 3 IRRs* during cycle 2, in patients who had previously 
received obinutuzumab at the standard infusion rate only during cycle 1 without 
experiencing any Grade 3 or 4 IRR during Cycle 1, with severity determined 
according to National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) Version 5.0. 
* IRRs are defined as all adverse events (AEs) that occur during or within 24 hours from 
the end of study treatment infusion and are judged as related to infusion of study 
treatment components (obinutuzumab or chemotherapy during induction and 
obinutuzumab alone during maintenance) by the investigator.
2.2.2
Secondary Safety Endpoints

Incidence, nature, and severity of all AEs during cycle 1 and from cycle 1 onwards 
(including maintenance) 

Incidence of IRRs regardless of grade by cycle (separately) 

Time to IRR (in hours) from start of infusion to onset of the IRR during cycle 2 

Duration (in minutes) of obinutuzumab administration by cycle (all cycles including 
maintenance) 

Type and duration of Grade 3 IRRs, during all cycles, where obinutuzumab was 
administered as an SDI
2.2.3
Secondary Efficacy Endpoints
The secondary efficacy objective for this study is to evaluate the efficacy of 
obinutuzumab administered as an SDI from cycle 2 in patients with previously untreated 
advanced FL on the basis of the following endpoints: 

Objective response rate (ORR) at the end of induction (EOI) therapy as determined 
by the investigator and according to the guidelines used at the site (Cheson et al. 
2014, Cheson et al. 2007, or Cheson et al. 1999).

Progression-free survival (PFS) rate 

Overall survival (OS) 

Complete response (CR) rate at 30 months (CR30), as assessed by the investigator 
and according to the guidelines used at the site. 


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2.2.4
Exploratory Safety Endpoints
The exploratory safety objectives for this study are to further evaluate the safety of 
obinutuzumab administered in patients with previously untreated advanced FL on the 
basis of the following endpoints to evaluate the impact of time to IRR: 

The incidence of Grade 3 IRRs (with severity determined according to NCI CTCAE
Version 5.0) during the first SDI cycle:
–
- cycle 2 in patients who received obinutuzumab at the standard infusion rate 
without experiencing a Grade 3 IRR in cycle 1 
–
- cycle 3 in patients who experienced a Grade 3 IRR when administered 
obinutuzumab at the standard infusion rate in cycle 1 and subsequently 
received obinutuzumab at the standard infusion rate in cycle 2 without 
experiencing a Grade 3 IRR . 

Time to IRR (in hours) from infusion to onset of the IRR in cycle 1 or cycle 3 
2.2.5
Exploratory Efficacy Endpoints
The exploratory efficacy objectives for this study are to evaluate patients with a PR at 
the end of induction treatment who convert to CR during maintenance treatment and to 
evaluate and compare the objective response and CR rate after the end of induction
treatment with and without 18F-fluorodeoxyglucose positron emission tomography 
(FDG-PET): 

Proportion of patients with a PR at the end of induction treatment who convert to CR 
during maintenance treatment, as assessed by the investigator and according to the 
guidelines used at the site 

Objective response rate and CR rate after the end of induction treatment, as 
assessed by the investigator and according to the guidelines used at the site, for 
those with and those without FDG-PET separately.
The exploratory patient-reported objective for this study is to evaluate the severity and 
interference of disease- and treatment-related symptoms in patients with previously 
untreated advanced FL treated with obinutuzumab administered as an SDI from cycle 2:

Severity of disease symptoms experienced by patients and the interference with 
daily living caused by these symptoms, as assessed through use of the 
MD Anderson Symptom Inventory (MDASI). 
The exploratory provider-reported objective is to evaluate the site experience with the 
SDI:

Physician/ nurse experience on time savings with obinutuzumab SDI compared with 
obinutuzumab at the regular infusion rate 

Physician/ nurse experience on the convenience of and preference for 
obinutuzumab SDI compared with obinutuzumab at the regular infusion rate.


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2.3
DETERMINATION OF SAMPLE SIZE
A sample size of approximately 112 patients is planned for this study.
The incidence of Grade 3 IRRs during cycle 2 was chosen as the safety endpoint of 
primary interest and used to justify the sample size. Based on experience from previous 
studies (BO21223/GALLIUM, GAO4915g/GATHER), it is assumed to have an incidence 
rate of only 1% or 2%, and hence to observe only few events. 
The upper bounds of two-sided 95% Clopper-Pearson confidence intervals (CIs) 
according to the sample size and the number of observed Grade 3 IRRs during cycle 2 
are shown in Table 2.
Table 2
Relationship Between the Sample Size, the Number of Observed 
Grade 3 IRRs and the Upper Bound of the Corresponding Two-
sided 95% Clopper-Pearson Confidence Interval 
Sample size
Number of observed Grade 3 IRRs
0
1
2
3
4
90
4.0%
6.0%
7.8%
9.4%
11.0%
100
3.6%
5.4%
7.0%
8.5%
9.9%
Observing two Grade 3 IRRs during cycle 2 would yield an upper bound (of the 
Corresponding Two-sided 95% Clopper-Pearson CI) of 7.0% in an SDI population of 
100 patients and of 7.8% in an SDI population of 90 patients. Not observing any 
Grade 3 IRRs during cycle 2 would yield upper bounds of 3.6% and 4.0%, respectively. 
There will be no formal hypothesis test for the primary endpoint. 
Taking into account an estimated drop-out rate of 10%, a total of approximately 
112 patients will be enrolled in this study to have 100 patients in the SDI population. If 
the drop-out rate would be lower, accrual would be stopped after 100 patients in the SDI 
population. If the drop-out rate would be higher, with 112 patients enrolled into the study 
a drop-out rate of 19.7% would still leave 90 patients in the SDI population which would 
result in a reasonable precision for the CI. If there would be less than 90 patients in the 
SDI population after enrolment, the IMC would decide whether to continue enrolment or 
not.
2.4
ANALYSIS TIMING
The primary study data will be analyzed and reported based on all patients’ data up to 
the clinical cut-off date, corresponding to the time when all patients have completed 
2 cycles of obinutuzumab treatment. The EOI analysis will be performed and reported 


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based on all patients’ data up to the clinical cut-off date, corresponding to the time when 
all patients have completed the induction treatment period. The final analysis will be 
performed at the end of the study and include PFS, OS and CR30 rates (Table 3). PFS,
OS and CR30 will be analyzed only once, as part of the final analysis at the end of the 
study (except for the Japanese subgroup on which PFS and OS will be analyzed in the 
EOI analysis). The exploratory patient-reported endpoint and provider-reported 
endpoints, as well as the ORR at EOI, will not be part of the primary analysis, and will be 
included in the EOI and final analyses only. The total length of the study, from screening 
of the first patient to the end of the study, is expected to be approximately 4 years. The 
total length of the study for an individual patient is up to approximately 2.75 years.
No formal Interim analysis is planned for this study. An IMC will conduct full formal 
interim reviews (see Section 3.3).
Table 3
Analysis Timings
Analysis
Timing of Analysis
Primary 
all patients have completed 2 cycles of obinutuzumab treatment
EOI
end of induction treatment period (i.e. all patients have completed the 
induction treatment period)
Final 
end of the study
EOIend of induction
3.
STUDY CONDUCT
3.1
RANDOMIZATION 
Not applicable 
3.2
INDEPENDENT REVIEW FACILITY
Not applicable 
3.3
DATA MONITORING
The first scheduled IMC data review will take place after the first 10 patients have 
completed the first SDI infusion (i.e. cycle 2). The second IMC data review will happen 
after 50 patients have completed the first SDI infusion (i.e. cycle 2) or at 6 months after 
the first IMC, whichever occurs first. Furthermore, the IMC will review results obtained 
for the primary analysis, EOI analysis and final analysis. Further meetings will be 
scheduled as deemed necessary. Further details will be specified in the IMC charter.
If there would be less than 90 patients in the SDI population at the end of the planned 
enrolment phase, the IMC would decide whether to continue enrolment or not.


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4.
STATISTICAL METHODS
The analysis specifications described in this SAP supersede the specifications available 
in the protocol.
No formal statistical hypothesis tests will be performed and all analyses are considered 
descriptive.
Categorical data will be summarized using frequencies and percentages. Continuous 
data will be summarized using descriptive statistics (N, mean, standard deviation, 
median, minimum and maximum). Other analysis methods will be specified (below) 
where applicable.
4.1
ANALYSIS POPULATIONS
4.1.1
All Patients Population
The all patients population includes all enrolled patients.
4.1.2
Short Duration Infusion Population
The SDI population includes all enrolled patients who did not experience a Grade 3 or 4 
IRR during cycle 1 (i.e. at any of the three Cycle 1 infusions), received obinutuzumab 
given at the standard rate only during Cycle 1, and received obinutuzumab as an SDI at 
cycle 2 (refer to Section 4.6.1 for definition of SDI infusion). The SDI population will be 
used for the analysis of the primary endpoint and the secondary safety endpoint ‘Time to 
IRR (in hours) from infusion to onset of the IRR during cycle 2’.
4.1.3
Safety Population
The safety population includes all patients who received at least one dose of 
obinutuzumab.
4.2
ANALYSIS OF STUDY CONDUCT
Patient disposition and reason for study termination will be presented on All patients 
population, as well as on the SDI population and Safety population. Chemotherapy 
assignment and reasons for discontinuation from the study treatment will also be 
summarized, for the Safety population.
Major protocol deviations, including violations of inclusion/exclusion criteria and 
deviations during study conduct will be summarized for All patients population.
Major protocol deviations related to COVID-19 will be summarized and listed on the 
Safety population. 


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4.3
ANALYSIS OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic characteristics, such as age, sex, race/ethnicity, and other relevant 
baseline characteristics will be presented for the SDI population and for the Safety 
population, using appropriate descriptive statistics.
The other analyses described here below will be based on the safety population only. 
The relevant advanced FL characteristics will be presented using appropriate descriptive 
statistics.
The summaries of baseline and demographic characteristics and of FL characteristics 
will be repeated on the subset of patients with at least one Grade 3 IRR at any cycle.
The baseline value will be defined as the last available value recorded on or prior to the 
first administration of any study medication. 
Prior cancer therapy, radiotherapy and surgery, for any cancer other than FL, as well as 
follow-up anti-lymphoma therapy, will be summarized.
Previous and concurrent medical history, as well as medications, will also be 
summarized. Medications will be mapped to the WHODrug Global B3 Format dictionary.
4.4
EFFICACY ANALYSIS
Unless otherwise stated, all efficacy analyses are based on the safety population.
4.4.1
Secondary Efficacy Endpoints
4.4.1.1
Objective Response Rate at the EOI
ORR at the end of induction therapy is defined as the proportion of patients with either a 
CR, CR unconfirmed or PR at the EOI visit, as determined by the investigator and 
according to the guidelines used at the site (Lugano [Cheson et al. 2014], Cheson et al. 
2007, or Cheson et al. 1999). 
Patients without response assessment at the EOI visit will be considered as 
non-responders.
The ORR will be presented along with a 95% Clopper-Pearson CI; overall and by type of 
response assessment (i.e. guidelines used). In addition, the ORR will also be presented 
separately for patients with FDG-PET used for the response assessment and for patient 
without FDG-PET.
At each planned visit, the results of the response assessment will be summarized 
descriptively.


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4.4.1.2
Progression-Free Survival 
PFS is defined as the time from start of treatment (date of first intake of any study 
treatment component) to the first occurrence of disease progression as assessed by the 
investigator according to the guidelines used at the site (Lugano [Cheson et al. 2014], 
Cheson et al. 2007, or Cheson et al. 1999), or death from any cause.
Data for patients who have not experienced disease progression or death at the time of 
analysis data cut-off will be censored at the last tumor assessment date.
The PFS rate at 12, 24 and 30 months will be presented as the Kaplan-Meier estimate 
along with its 95% CI, overall and by type of response assessment (i.e. guidelines used).
In addition, the Kaplan-Meier curve will be provided for the PFS overall. 
4.4.1.3
Overall Survival 
OS is defined as the time from start of treatment (date of first intake of any study 
treatment component) to death from any cause. For patients who are alive at the time of 
analysis data cut-off, OS time will be censored at the date the patient was last known to 
be alive.
The OS rate at 12, 24 and 30 months will be presented as the Kaplan-Meier estimate 
along with its 95% CI and the Kaplan-Meier curve will be provided. 
4.4.1.4
Complete Response (CR) Rate at 30 months (CR30)
The CR30 rate is defined as the proportion of patients with a CR at 30 months from 
study treatment initiation (date of first intake of any study treatment component), as 
determined by the investigator according to the guidelines used at the site (Lugano 
[Cheson et al. 2014], Cheson et al. 2007, or Cheson et al. 1999). 
Month 30 occurs at Study Day 913. Allowing 3 months either side of the exact Month 30 
study day, assessments that occur between Month 27 (Study Day 811) and Month 33 
(Study Day 991) inclusive will be considered as a Month 30 assessment.
Patients with a CR at 30 months from study treatment initiation are patients: 

With a CR assessed within the window of Month 27 (Study Day 811) – Month 33 
(Study Day 991) inclusive.

Or With two consecutive assessments of CR, before and after the 30-month 
timepoint (Study Day 913) 
CR30 rate will be presented together with a 95% Clopper-Pearson CI, overall and by 
type of response assessment (i.e. guidelines used). 


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4.4.2
Exploratory Efficacy Endpoints
4.4.2.1
Proportion of Patients with a PR at EOI Who Convert to CR 
During Maintenance
The proportion of patients with a PR at the EOI visit and with a CR during the 
maintenance period, as assessed by the investigator according to the guidelines used at 
the site (Lugano [Cheson et al. 2014], Cheson et al. 2007, or Cheson et al. 1999) will be 
provided, overall and by type of response assessment (i.e. guidelines used). The 
number of patients with a PR at the EOI visit will be used for the denominator.
4.4.2.2
ORR and CR Rate After the EOI by FDG-PET Status
The ORR and the CR rates are defined as the proportion of patients with best response 
either a CR or PR and with a CR, respectively, as determined by the investigator 
according to the guidelines used at the site (Lugano [Cheson et al. 2014], Cheson et al. 
2007, or Cheson et al. 1999), at any time after the EOI visit.
The ORR and the CR rate will be summarized separately for patients with FDG-PET 
used for the response assessment and for patient without FDG-PET. This summary will 
be provided overall and type of response assessment (i.e. guidelines used).
4.4.2.3
MD Anderson Symptom Inventory (MDASI)
Patient-reported data on the severity of disease and treatment-related symptoms, and 
the interference from those symptoms, is assessed by MDASI. The MDASI includes 
13 items for the severity of symptoms (pain, fatigue, nausea, disturbed sleep, distressed, 
shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sad, 
vomiting, and numbness or tingling) and an additional 6 items for the interference of the 
symptoms with 6 areas of function (general activity, walking, work, mood, relations with 
other people, and enjoyment of life).
The MDASI severity and interference subscales (see Appendix 3 [Cleeland 2009]), as 
well as each of the 19 items, will be summarized at each visit, together with the change 
from baseline at each visit. The severity and interference subscales will also be plotted 
over time.
The number and percentage of patients who complete the MDASI will be summarized at 
each scheduled time point. The compliance rate will be provided. The compliance rate is 
based on the total number of patients expected to complete the questionnaire at a 
particular time point – i.e., those patients who had the opportunity to complete the scale. 
4.4.2.4
Site Experience
Provider-reported data will be summarized in a frequency table:

Time Savings

Convenience

Preference


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
Main reason for preference.
4.4.3
Subgroup Analysis
A subgroup analysis will be performed and the subgroups to be considered include (but 
may not be limited to):

sex (female, male)
The analyses of the following endpoints will be repeated by subgroup:

Secondary efficacy endpoints
–
ORR at EOI (see Section 4.4.1.1)
–
PFS (see Section 4.4.1.2)
–
OS (see Section 4.4.1.3)
–
CR30 (see Section 4.4.1.4)

Safety endpoints
–
Grade 3 IRRs during cycle 2, in patients who had previously received 
obinutuzumab at the standard infusion rate during cycle 1 without experiencing 
a Grade 3 or 4 IRR (see Section 4.6.2.1)
–
All IRRs of any grade (see Section 4.6.2.2)
–
All AEs (see Section 4.6.3)
–
All SAEs (see Section 4.6.3)
In addition, some of the safety and efficacy analyses will be repeated on the subgroup of 
Japanese patients (EOI analysis only).
4.5
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Not applicable.
4.6
SAFETY ANALYSES
Unless otherwise stated, safety analyses are based on the safety population.
4.6.1
Exposure of Study Medication
Secondary Safety Endpoint:
The duration of obinutuzumab administration (in minutes) by cycle (all cycles including 
maintenance) is defined as the difference between the end time and the start time of 
obinutuzumab administration and will be summarized descriptively. 
The following summaries on obinutuzumab exposure will also be provided:

Proportion of patients with SDI infusion, defined as an infusion with a duration 110 
minutes (i.e. target of 90 minutes with a tolerance of plus 20 minutes), by cycle


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
Overall duration of obinutuzumab treatment (in weeks)

Number of initiated cycles of obinutuzumab

Dose of obinutuzumab (in mg) administered, by cycle

Cumulative dose of obinutuzumab (in mg) overall, during induction period and 
during maintenance period

Proportion of patients with low dose intensity of obinutuzumab, by cycle up to Cycle 
2, in the rest of induction period and in the maintenance period
For summaries by cycle, the cycle 1 will be described by day of the cycle (day 1, day 8, 
or day 15). 
The infusion modifications and infusions delayed will also be summarized for 
obinituzumab.
For chemotherapy exposure, the number of initiated cycles of bendamustine, CHOP, 
and CVP will be provided.
The number of patients receiving premedication and the type of premedication will be 
summarized by visit.
4.6.2
Infusion Related Reactions
IRRs are defined as:
Definition A: IRRs
IRRs are defined as all AEs that:

occur during or within 24 hours from the end of infusion of any study treatment 
component,

are judged as related to any study treatment component (i.e. the corresponding AE) 
by the investigator. 
Definition B: IRRs related to Obinutuzumab
Some of the analyses will be restricted to IRRs related to obinituzumab only, defined as
all AE’s that:

occur during or within 24 hours from the end of infusion of obinutuzumab,

are judged as related to obinutuzumab by the investigator. 


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Definition C: IRRs based on pre-defined list of terms related to Obinutuzumab
IRRs are defined as all AEs with PT within a pre-defined list of terms (see Appendix 4) 
that: 

occur during or within 24 hours from the end of infusion of obinutuzumab,

are judged as related to obinutuzumab by the investigator. 
“Any study component” refers to obinutuzumab and chemotherapy during induction 
period and obinutuzumab alone during maintenance period.
By default, analysis of IRRs will be based on Definition A of IRRs.
IRRs will be linked to the cycle corresponding to the last infusion received on or prior to 
the onset of the IRR. 
In a general manner, in analyses performed by cycle, the cycle 1 will be summarized by 
day of the cycle: day 1, day 2 (if applicable), day 8 or day 15. Day 2 is applicable only to 
analyses of all IRRs and not to analyses of IRRs related to obinutuzumab.
4.6.2.1
Primary Safety Endpoint
The proportion and number of patients with Grade 3 IRRs during cycle 2, in patients 
who had previously received obinutuzumab at the standard infusion rate during cycle 1 
without experiencing any Grade 3 or 4 IRR during cycle 1, with severity determined 
according to NCI CTCAE Version 5.0 will be displayed. The proportion will be presented 
along with a 95% Clopper-Pearson CI. The analysis of the primary safety endpoint is 
based on the SDI population.
All IRRs during cycle 2 will also be summarized on the SDI population at the EOI 
analysis.
4.6.2.2
Secondary Safety Endpoints
The proportion and number of patients with IRRs of any grade will be provided by cycle
and by highest NCI CTCAE grade. This analysis will be repeated on the subset of 
patients who received obinutuzumab as SDI in the given cycle.
Time to IRR (in hours) during cycle 2 is defined as the time from the start of infusion (i.e. 
start date/ time of infusion of the first component of study treatment) in Cycle 2 to the 
onset of the IRR during cycle 2 and will be summarized descriptively. The analysis of 
time to IRR during cycle 2 will be based on the SDI population.
For each cycle from the cycle 2, the type and duration (in minutes) of symptoms of 
Grade 3 IRRs, in patients who received obinutuzumab as SDI in the given cycle, will be 
summarized overall and by cycle. This summary will be repeated for all symptoms of 
IRRs of any grade from the cycle 2, as well as for all symptoms of IRRs of any grade in 


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cycle 1. In addition, the symptoms of Grade 3 IRRs will be listed together with the 
details on the planned and actual infusion rate of obinutuzumab at the corresponding 
cycle.
4.6.2.3
Exploratory Safety Endpoints
The proportion and number of patients with Grade 3 IRRs during:

Cycle 2, in patients who had received obinutuzumab at the standard infusion rate 
without experiencing a Grade 3 or 4 IRR in cycle 1,
Or

Cycle 3, in patients who had received obinutuzumab at the standard infusion rate 
and experienced a Grade 3 or 4 IRR in cycle 1 and subsequently had received 
obinutuzumab at the standard infusion rate without experiencing a Grade 3 or 4 IRR 
in cycle 2, with severity determined according to NCI CTCAE Version 5.0, will be 
provided.
Time to IRR (in hours) from start of infusion (i.e. start date/time of infusion of the first 
component of study treatment) to onset of the IRR in cycle 1 or cycle 3 will be 
summarized descriptively overall and by cycle. The time to IRR will be summarized 
separately for patients with SDI and with regular infusion. 
The proportion and number of patients with IRRs of any grade and by highest NCI 
CTCAE grade will be provided for the first cycle received as SDI, by the highest NCI 
CTCAE grade of IRR in any previous cycle.
4.6.2.4
Sensitivity Analysis
The analysis of the incidence of Grade 3 IRRs during cycle 2, in patients who had 
previously received obinutuzumab at the standard infusion rate during cycle 1 without 
experiencing a Grade 3 or 4 IRR, as described in Section 4.6.2.1, will be repeated based 
on IRRs related to obinutuzumab only (Definition B) for the SDI population.
The summary with the proportion and number of patients with IRRs of any grade by 
cycle and by highest NCI CTCAE grade will be repeated based on:

IRRs related to obinutuzumab only (Definition B);

IRRs based on pre-defined list of terms related to Obinutuzumab (Definition C).
4.6.3
Adverse Events
Verbatim description of AEs will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus levels and graded according to the NCI CTCAE Version 
5.0. 


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AEs will be summarized by MedDRA term, appropriate MedDRA levels (system organ 
class [SOC] and PT), and when specified by NCI CTCAE grade. For each patient, 
multiple occurrences of the same event will be counted once at the maximum severity. 
AEs will be reported by study period (induction, maintenance, follow-up) as well as 
overall. The summary of all AEs by highest NCI CTCAE grade will display AEs during 
cycle 1 and from cycle 2 onwards separately.
Treatment-emergent AEs (TEAEs) are AEs that occur during or after the first dose of 
study treatment and on or before the last dose of study treatment 90 days. TEAEs will 
be included in the summary tables. All AEs will be listed.
The following AEs will be summarized:

All AEs

All AEs by highest NCI CTCAE grade

SAEs

SAEs by highest NCI CTCAE grade

NCI CTCAE Grade 3 AEs

NCI CTCAE  Grade 3 AEs by highest NCI CTCAE grade

Adverse events of special interest (AESIs)

Selected AEs:

AEs related to i) obinutuzumab, ii) any study treatment

NCI CTCAE Grade 3 AEs related to any study treatment (EOI analysis only)

AEs leading to interruption of i) obinutuzimab, ii) any study treatment

AEs leading to infusion rate reduction of obinutuzimab

AEs leading to dose modification of chemotherapy

AEs leading to discontinuation of i) obinutuzumab, ii) any study treatment, iii) each 
chemotherapy component separately

AEs leading to discontinuation from the study

Fatal AEs

AEs occurring during infusion or within 24 hours from end of infusion of any study 
treatment, during the induction period (EOI analysis only)

NCI CTCAE Grade 3 AEs occurring during infusion or within 24 hours from end of 
infusion of any study treatment, during the induction period (EOI analysis only)

AEs reported in 5% of patients by highest NCI CTCAE grade
All deaths and causes of death will be summarized.


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AEs associated with COVID-19 and AEs associated with COVID-19 leading to 
discontinuation from the study will be listed.
4.6.4
Laboratory Data
Laboratory data will be summarized over time including change from baseline. Values 
outside the normal ranges will be summarized. 
Additionally, laboratory data will be classified in accordance with NCI CTCAE v5.0.
Highest NCI CTCAE grade post-baseline will be reported, and shift tables from baseline 
to worst value during the study post-baseline will be presented.
4.6.5
Vital Signs
Changes in selected vital signs will be summarized by cohort and by change over time
including change from baseline.
4.7
MISSING DATA
Please refer to Section 4.4 for methods of handling missing data for the efficacy 
endpoints.
Any incomplete or missing death date will be handled separately for safety and efficacy 
analyses. In safety analyses, all deaths will be included, regardless of completeness of 
death date; patients who died with a partial or missing death date will be included as an 
event. In efficacy analyses, a death is considered an event only if a complete death date 
is available; patients who died with only a partial or missing death date will be censored.
4.8
INTERIM ANALYSES
No formal Interim analysis is planned for this study. 
The IMC will review safety data as described in the IMC charter. The IMC reviews will be 
performed after the first 10 patients had their second cycle (first SDI infusion), after 
50 patients had their second cycle or at 6 months from first patient enrolled, whichever 
occurs first. Furthermore, the IMC will review results obtained for the primary analysis 
and end of induction analysis. Further meetings will be scheduled as deemed necessary. 
IMC analyses will be based on all enrolled patients’ data up to fixed clinical cut-off 
defined based on each IMC milestone.
The outputs provided for IMC review will be a subset of the outputs planned for the CSR.


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5.
REFERENCES
Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to 
standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored 
International Working Group. J Clin Oncol. 1999;17(4):1244. 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol 2007;25:579−86. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the 
Lugano classification. J Clin Oncol. 2014;32(27):3059–68.
Cleeland CS. The M. D. Anderson Symptom Inventory User Guide. Version 1, 2009. 
Available from: https://www.mdanderson.org/documents/Departments-and-
Divisions/Symptom-Research/MDASI_userguide.pdf. Last accessed: 27 December 
2018


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Appendix 1
Protocol Synopsis
PROTOCOL SYNOPSIS
TITLE:
A MULTICENTRIC, OPEN-LABEL, SINGLE ARM STUDY OF 
OBINUTUZUMAB SHORT DURATION INFUSION (SDI) IN 
PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED 
FOLLICULAR LYMPHOMA
PROTOCOL NUMBER:
MO40597
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-003255-38
IND NUMBER:
104405
TEST PRODUCT:
Obinutuzumab (GA101, RO5072759)
PHASE:
Phase IV
INDICATION:
Follicular lymphoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
The primary objective of this study is to evaluate the safety of administering obinutuzumab as a 
short duration infusion (SDI; target 90-minute infusion) during cycle 2 and from cycle 2 onwards 
in combination with chemotherapy in patients with previously untreated advanced follicular 
lymphoma (FL) on the basis of the following endpoints:
Primary endpoint: 

The incidence of Grade ≥3 infusion-related reactions (IRRs*) during cycle 2 in patients who 
had previously received obinutuzumab at the standard infusion rate during cycle 1 without 
experiencing a Grade 3 or 4 IRR, with severity determined according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.
* IRRs are defined as all adverse events (AEs) that occur during or within 24 hours from the 
end of study treatment infusion and are judged as related to infusion of study treatment 
components (obinutuzumab and chemotherapy during induction and obinutuzumab alone during 
maintenance) by the investigator.
Secondary safety endpoints:

Incidence, nature, and severity of all AEs during cycle 1 and from cycle 1 onwards 
(including maintenance)

Incidence of IRRs regardless of grade by cycle (separately)

Time to IRR (in hours) from infusion to onset of the IRR during cycle 2

Duration (in minutes) of obinutuzumab administration by cycle (all cycles including 
maintenance)

Type and duration of Grade ≥3 IRRs, during all cycles, where obinutuzumab was administered as 
an SDI.


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Secondary efficacy objective:
The secondary efficacy objective for this study is to evaluate the efficacy of obinutuzumab 
administered as an SDI from cycle 2 in patients with previously untreated advanced FL on the 
basis of the following endpoints:

Objective response rate at the end of induction (EOI) therapy as determined by the 
investigator and according to the guidelines used at the site (Lugano [Cheson et al 2014], 
Cheson et al 2007, or Cheson et al 1999)

Progression-free survival rate at the end of the study

Overall survival at the end of the study

Complete response (CR) rate at 30 months (CR30), as assessed by the investigator and 
according to the guidelines used at the site.
Exploratory objectives:
The exploratory safety objectives for this study are to further evaluate the safety of 
obinutuzumab administered in patients with previously untreated advanced FL on the basis of
the following endpoints to evaluate the impact of time to IRR:

The incidence of Grade ≥3 IRRs* (with severity determined according to NCI CTCAE Version 5.0) 
during the first SDI cycle: 
o
cycle 2 in patients who received obinutuzumab at the standard infusion rate without 
experiencing a Grade 3 IRR in cycle 1 
o
cycle 3 in patients who experienced a Grade 3 IRR when administered obinutuzumab at the 
standard infusion rate in cycle 1 and subsequently received obinutuzumab at the standard 
infusion rate in cycle 2 without experiencing a Grade 3 IRR

Time to IRR (in hours) from infusion to onset of the IRR in cycle 1 or cycle 3
* IRRs are defined as all adverse events (AEs) that occur during or within 24 hours from the 
end of study treatment infusion and are judged as related to infusion of study treatment 
components (obinutuzumab and chemotherapy during induction and obinutuzumab alone during 
maintenance) by the investigator.
The exploratory efficacy objectives for this study are to evaluate patients with a partial response 
(PR) at the end of induction treatment who convert to CR during maintenance treatment and to 
evaluate and compare the objective response and CR rate after the end of induction treatment 
with and without 18F-fluorodeoxyglucose positron emission tomography (FDG-PET):

Proportion of patients with a PR at the end of induction treatment who convert to CR during 
maintenance treatment, as assessed by the investigator and according to the guidelines 
used at the site (see above)

Objective response rate and CR rate after the end of induction treatment, as assessed by 
the investigator and according to the guidelines used at the site (see above), for those with 
and those without 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)
separately.
The exploratory patient-reported objective for this study is to evaluate the severity and 
interference of disease- and treatment-related symptoms in patients with previously untreated 
advanced FL treated with obinutuzumab administered as an SDI from cycle 2.

Severity of disease symptoms experienced by patients and the interference with daily living 
caused by these symptoms, as assessed through use of the MD Anderson Symptom 
Inventory (MDASI; Appendix 2).
The exploratory provider-reported objective is to evaluate the site experience with the SDI, 
specifically:

Physician / nurse experience on time savings with obinutuzumab SDI compared with 
obinutuzumab at the regular infusion rate

Physician / nurse experience on the convenience of and preference for obinutuzumab SDI 
compared with obinutuzumab at the regular infusion rate.


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Study Design
Description of Study
This is an open-label, international, multicenter, single arm Phase IV study to investigate the 
safety and efficacy of the short duration infusion (SDI; target 90-minute infusion) obinutuzumab 
in patients with previously untreated advanced FL.
The study has two phases: in the first phase patients will receive the first cycle of 
obinutuzumab-based chemotherapy (G-chemo) induction therapy as usual with the first three 
infusions of obinutuzumab (1000 mg) administered at the regular infusion rate (Table 1) on Day 
1, 8, and 15 of cycle 1. The investigator is free to choose the chemotherapy for each patient 
(bendamustine, CHOP [cyclophosphamide, doxorubicin, vincristine, 
prednisone/prednisolone/methylprednisolone], or CVP [cyclophosphamide, vincristine, and 
prednisone/prednisolone/methylprednisolone]). The total number of cycles of G-chemo 
induction therapy and the cycles length depends on the chemotherapy chosen for each patient
(see Section 4.3.1).
Study treatment in this protocol refers to obinutuzumab and chemotherapy during the induction phase 
and obinutuzumab monotherapy during the maintenance phase.
For the purpose of this study IRRs are defined as all AEs that occur during or within 24 hours 
from the end of study treatment infusion and are judged as related to infusion of study treatment 
components (obinutuzumab and chemotherapy during induction and obinutuzumab alone during 
maintenance) by the investigator. 
Patients who do not experience any Grade ≥3 IRRs during the first cycle will enter into the 
second, faster infusion, phase from Cycle 2 onwards. These patients will receive obinutuzumab 
at the SDI rate, starting on Cycle 2, Day 1 (Table 1). 
Patients who experience a Grade 3 IRR during the first cycle will remain on the study but cycle 2 of 
obinutuzumab must be administered at the regular infusion rate. If these patients do not experience a 
Grade ≥3 IRR during cycle 2 at the regular infusion rate, then they will be eligible to receive SDI dosing 
from cycle 3 onwards, according to investigator judgement.
Patients who experience a first occurrence of a Grade 3 IRR during any SDI administration of 
obinutuzumab may continue to receive SDI dosing during the current infusion, and in the next cycle, as 
long as the Grade 3 IRR resolves after the infusion is interrupted and symptoms are treated, and no 
further IRR symptoms reoccur after restarting the SDI. Guidance on IRR management during both 
regular and SDI infusions is given in Appendix 6. 
The obinutuzumab infusion must be stopped, and obinutuzumab must be permanently discontinued, in 
any patient who experiences a second occurrence of any Grade 3 IRR, regardless of the rate of infusion.
Patients who experience a Grade 4 IRR at any time during the study will permanently 
discontinue obinutuzumab treatment.




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of induction analysis, and final analysis. Further meetings will be scheduled as deemed necessary. 
Further details will be specified in the IMC charter.
Safety will be evaluated by monitoring dose delays and dose intensity, adverse events, serious 
adverse events, and deaths. These will be graded using the NCI CTCAE, Version 5.0. 
Laboratory safety assessments will include regular monitoring of hematology and blood 
chemistry.
Provider and patient-reported outcome data will be collected via questionnaires to document the 
severity of disease and treatment-related symptoms experienced by patients and the 
interference with daily living caused by these symptoms, as assessed through use of the MD 
Anderson Symptom Inventory (MDASI; Appendix 2); and to evaluate the site experience with 
the SDI and standard infusions of obinutuzumab.
Number of Patients
A total of 100 patients is needed in the SDI population. Allowing for drop-outs this means that 
approximately 112 patients will be enrolled in this study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:
1.
Signed Informed Consent Form
2.
Age 18 years at time of signing Informed Consent Form
3.
Able and willing to comply with all study related procedures including completion of 
patient-reported outcome (PRO) endpoints
4.
Ability to comply with the study protocol, in the investigator's judgment
5.
Patients with previously untreated Stage III or IV FL or Stage II bulky disease scheduled 
to receive obinutuzumab and chemotherapy due to at least one of the following criteria:
Bulky disease, defined as a nodal or extranodal (except spleen) mass ≥7 cm in the 
greatest diameter
Local symptoms or compromise of normal organ function due to progressive nodal 
disease or extranodal tumor mass
Presence of B symptoms (fever [> 38ºC], drenching night sweats, or unintentional 
weight loss of > 10% of normal body weight over a period of 6 months or less)
Presence of symptomatic extranodal disease (e.g., pleural effusions, peritoneal 
ascites)
Cytopenias due to underlying lymphoma (i.e., absolute neutrophil count < 1.0 × 109/L, 
hemoglobin < 10 g/dL, and/or platelet count < 100 × 109/L)
Involvement of ≥ 3 nodal sites, each with a diameter of ≥ 3 cm
Symptomatic splenic enlargement
6.
Histologically documented CD-20-positive FL, as determined by the local laboratory
7.
Eastern Cooperative Oncology Group (ECOG) performance status 0−2
8.
Adequate hematologic function (unless abnormalities are related to FL), defined as 
follows:
a.
Hemoglobin ≥ 9.0 g/dL
Absolute neutrophil count ≥ 1.5 × 109/L
Platelet count ≥ 75 × 109/L
9.
Life expectancy of ≥ 12 months


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10. For women who are not postmenopausal (≥12 consecutive months of non-therapy-
induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement 
to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods 
that result in a failure rate of < 1% per year during the treatment period and for at least 18
months after the last dose of obinutuzumab, for at least 3 months after the last dose of 
bendamustine or according to institutional guidelines for CHOP or CVP chemotherapy, 
whichever is longer
a.
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of progestogen-
only hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices (IUDs), and copper IUDs
The reliability of sexual abstinence needs to be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception
Barrier methods must always be supplemented with the use of a spermicide
11. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined 
below:
a.
With female partners of childbearing potential, men must remain abstinent or use 
a condom plus an additional contraceptive method that together result in a failure 
rate of < 1% per year during the treatment period and for at least 3 months after 
the last dose of study treatment. Men must refrain from donating sperm for the 
same period
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for at least 3 months after the last dose of study 
treatment
The reliability of sexual abstinence needs to be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
1.
Relapsed / refractory FL
2.
Prior treatment for FL with chemotherapy, radiotherapy, or immunotherapy
3.
Grade IIIb FL
4.
Histological evidence of transformation of FL into high-grade B-cell NHL
5.
Treatment with systemic immunosuppressive medications, including, but not limited to, 
prednisone/prednisolone/methylprednisolone (at a dose equivalent to >30 mg/day 
prednisone), azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor 
agents within 2 weeks prior to Day 1 of Cycle 1
a.
Treatment with inhaled corticosteroids and mineralocorticoids is permitted
Patients receiving corticosteroid treatment with ≤30 mg/day of prednisone or equivalent must 
be documented to be on a stable dose of at least 4 weeks' duration prior to enrolment
If glucocorticoid treatment is urgently required for medical reasons (e.g., complications 
imminent if not treated at least with glucocorticoids; strong discomfort/pain of the patient 


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due to lymphoma), prednisone 100 mg or equivalent can be given for a maximum of 5 
sequential days, but all tumor assessments must be completed prior to the start of 
glucocorticoid treatment. Glucocorticoid treatment must be stopped prior to enrolment
In cases when a glucocorticoid pre-treatment/pre-phase was done externally prior to 
considering the patient for study inclusion, glucocorticoids must be stopped for at least 7 
days before screening assessments can begin
6.
History of solid organ transplantation
7.
History of anti-CD20 antibody therapy
8.
History of severe allergic or anaphylactic reaction to humanized, chimeric, or murine 
monoclonal antibodies
9.
Known sensitivity or allergy to murine products
10. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells 
or any of the study drugs
11. Active bacterial, viral, fungal, or other infection or any major episode of infection requiring 
treatment with intravenous (IV) antibiotics within 4 weeks of Day 1 of Cycle 1
a.
Caution should be exercised when considering the use of obinutuzumab in 
patients with a history of recurring or chronic infections
12. Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive 
HBsAg serology)
a.
Patients with occult or prior HBV infection (defined as negative HBsAg and 
positive total HBcAb) may be included if HBV DNA is undetectable, provided that 
they are willing to undergo DNA testing at least every 3 months (during the study and 
for at least 1 year after completion of lymphoma treatment). Patients who have 
protective titers of hepatitis B surface antibody (HBsAb) after vaccination or prior 
but cured hepatitis B are eligible
13. Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing)
a.
Patients positive for HCV antibody are eligible only if the polymerase chain 
reaction (PCR) is negative for HCV RNA
14. Known history of human immunodeficiency virus (HIV) positive status
a.
For patients with unknown HIV status, HIV testing will be performed at screening if 
required by local regulations
15. History of progressive multifocal leukoencephalopathy (PML)
16. Vaccination with a live virus vaccine within 28 days prior to Day 1 of Cycle 1 or 
anticipation that such a live, attenuated vaccine will be required during the study
17. History of prior other malignancy with the exception of:
a.
Curatively treated carcinoma in situ of the cervix, good-prognosis ductal 
carcinoma in situ of the breast, basal- or squamous-cell skin cancer, Stage I 
melanoma, or low-grade, early-stage localized prostate cancer
Any previously treated malignancy that has been in remission without treatment for ≥
2 years prior to enrollment
18. Evidence of any significant, uncontrolled concomitant disease that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV cardiac 
disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or 


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unstable angina) or significant pulmonary disease (such as obstructive pulmonary 
disease or history of bronchospasm)
19. Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle 
1, Day 1, or anticipation of a major surgical procedure during the course of the study
20. For patients who will be receiving CHOP: left ventricular ejection fraction (LVEF) < 50% 
by multigated acquisition (MUGA) scan or echocardiogram
21. Any of the following abnormal laboratory values:
a.
Creatinine > 1.5 × the upper limit of normal (ULN) (unless creatinine clearance 
normal) or creatinine clearance < 40 mL/min
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN
Total bilirubin ≥ 1.5 × the ULN: Patients with documented Gilbert disease may be 
enrolled if total bilirubin is ≤ 3.0 × the ULN.
International normalized ratio (INR) > 1.5 in the absence of therapeutic anticoagulation
Partial thromboplastin time or activated partial thromboplastin time > 1.5 × ULN in the 
absence of a lupus anticoagulant
22. Pregnant or lactating, or intending to become pregnant during the study
a.
Women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test
result within 7 days prior to Day 1 of Cycle 1
23. Any investigational therapy within 28 days prior to the start of Cycle 1
24. Positive test results for human T-lymphotropic virus 1 (HTLV-1)
a.
HTLV testing is required in patients from endemic countries
Patients who meet the following criteria will be excluded from further study participation after 
Cycle 1:

Development of a Grade 4 IRR during Cycle 1.
End of Study
The end of the study is defined as the Last Patient, Last Visit (LPLV) which will occur when the 
last patient to discontinue participation in the study has completed the safety follow-up visit or at the 
time that one of the following is documented:

Patient has withdrawn consent
OR

Patient is lost to follow-up
OR

Patient death.
In addition, the Sponsor may decide to terminate the study at any time.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4 years.
Investigational Medicinal Products
Test Product (Investigational Drug)
Obinutuzumab will be administered intravenously at a flat dose of 1000 mg on Day 1, 8 and 15 
during Cycle 1, and on Day 1 of subsequent cycles, according to the infusion rates shown in 
Table 1. Splitting of the obinutuzumab dose (i.e. 100 mg + 900 mg) will not be permitted in this
study. The cycle length and number of cycles depends on the chemotherapy combination (see 
below).


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Following induction obinutuzumab and chemotherapy, maintenance obinutuzumab 
monotherapy will be administered at a dose of 1000 mg once every 8 weeks (± 10 days) for 
2 years or until disease progression (whichever occurs first).
Non-Investigational Medicinal Products
Combination chemotherapy
Obinutuzumab will be administered in combination with one of the following chemotherapy 
regimens:

Six 28-day cycles in combination with bendamustine

Six 21-day cycles in combination with CHOP, followed by two additional cycles of 
obinutuzumab alone

Eight 21-day cycles in combination with CVP.
Chemotherapy combinations will be administered according to the standard preparation and 
infusion procedures of each site. Body surface area (BSA) may be capped at 2 m2 per 
institutional standards.
Premedication
Premedication to reduce the risk of IRRs is mandatory for the first standard infusion of 
obinutuzumab (Cycle 1, Day 1) and the first infusion of obinutuzumab given as an SDI and will 
comprise IV corticosteroid, oral analgesic/anti-pyretic, and antihistamine (e.g. 50 mg 
diphenhydramine) administered according to local guidelines.
For subsequent cycles, premedication will depend on whether the patient experienced an IRR 
with the previous infusion.
Patients with a high tumor burden, a circulating lymphocyte count (>25 × 109/L), or renal 
impairment (CrCL <70 mL/min) will receive premedication for TLS comprising hydration and 
uricostatics or urate oxidase 12–24 hours before infusion of obinutuzumab according to 
standard practice.
Statistical Methods
The primary analysis will be analyzed and reported based on all patients’ data up to the time 
when all patients have completed 2 cycles of obinutuzumab treatment. The End of Induction 
analysis will be analyzed and reported once all patients have completed the induction period. The final 
analysis will be performed at the end of the study and include PFS and OS rates.
The analysis populations are defined as follows:

The SDI population includes all patients who received obinutuzumab as an SDI at cycle 2 
and who did not experience a Grade 3 or 4 IRR during the infusion of obinutuzumab given 
at the standard rate during cycle 1. This population will be used for the analysis of the 
primary endpoint and one of the secondary endpoints (time to IRR during cycle 2). 

The safety population includes all patients who received at least one dose of obinutuzumab. 
This population will be used for all remaining analyses.
No formal statistical hypothesis tests will be performed, and all analyses are considered 
descriptive.
Primary Analysis
The primary objective for this study is to evaluate the safety of obinutuzumab administered as 
an SDI in patients with previously untreated advanced FL on the basis of the following endpoint:

The incidence of Grade ≥3 IRRs* during cycle 2 in patients who had previously received 
obinutuzumab at the standard infusion rate without experiencing a Grade 3 or 4 IRR, with 
severity determined according to NCI CTCAE v 5.0
* IRRs are defined as all adverse events (AEs) that occur during or within 24 hours from the 
end of study treatment infusion and are judged as related to infusion of study treatment 
components (obinutuzumab and chemotherapy during induction and obinutuzumab alone during 
maintenance) by the investigator.
Determination of Sample Size
A sample size of approximately 112 patients is planned for this study.


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The incidence of Grade ≥3 IRRs during cycle 2 was chosen as the safety endpoint of primary 
interest and used to justify the sample size. Based on experience from previous studies 
(BO21223/GALLIUM, GAO4915g/GATHER), it is assumed to have an incidence rate of only 1% 
or 2%, and hence to observe only a few events.
Observing two Grade ≥3 IRRs during cycle 2 would yield an upper bound (of the Corresponding 
Two-sided 95% Clopper-Pearson Confidence Interval [CI]) of 7.0% in an SDI population of 100 
patients and of 7.8% in an SDI population of 90 patients. Not observing any Grade ≥3 IRRs 
during cycle 2 would yield upper bounds of 3.6% and 4.0%, respectively. 
There will be no formal hypothesis test for the primary endpoint.
Taking into account an estimated drop-out rate of 10%, a total of approximately 112 patients will 
be enrolled in this study to have 100 patients in the SDI population. If the drop-out rate would be 
lower, accrual would be stopped after 100 patients in the SDI population. If the drop-out rate 
would be higher, with 112 patients enrolled into the study a drop-out rate of 19.7% would still 
leave 90 patients in the SDI population which would result in a reasonable precision for the CI. If 
there would be less than 90 patients in the SDI population at the end of the planned enrolment 
phase, the IMC would decide whether to continue enrolment or not.
Interim Analyses 
No formal Interim analysis is planned for this study. There will be three reporting events: the primary 
analysis, the end of induction analysis, and the final analysis.
In addition, the data will be monitored by an Internal Monitoring Committee (IMC). The first IMC data 
review will take place after the first 10 patients have completed the first SDI infusion (i.e. cycle 2). The 
second IMC data review will happen after 50 patients have completed the first SDI infusion (i.e. cycle 2) 
or at 6 months after the first IMC, whichever occurs first. Furthermore, the IMC will review results 
obtained for the primary analysis, end of induction analysis, and final analysis. Further meetings will be 
scheduled as deemed necessary. See the IMC charter for details.


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Appendix 2
Schedule of Assessments
Day
Screening a
Treatment
Follow-up
(3 months)aa
Induction (6–8 cycles) b
EOI
Maintenance e
(every 8 weeks 
± 10 days)
EOM 
Cycle 1 
Cycle 2 
Cycles 3–6/8
D–28 
to D–1 
D–7
to D–1
D1
D8
D15
D1
D1
Informed consent
x f
Demographic data
x
Medical history and baseline 
conditions
x
Ann Arbor, FLIPI, and FLIPI2
x
ECOG performance status
x
Vital signs g
x
x
x
x
x
x
x
x
x
x
Weight
x
Height
x
ECG
x
LVEF (echocardiography or MUGA 
scan) z
x
Complete physical examination h,i
x
x
Targeted physical examination j,k
x
x
B symptoms l
x
Hematology m
x
x
x
x
x
x
x
x
x
Chemistry n
x
x
x
x
x
x
x
x
Pregnancy test o
x
Coagulation INR, aPTT or PTT and 
PT
x
Urinalysis p
x
x
x
HIV, HTLV-1, Hep B / C testing q
x
Study drug
administration
obinutuzumab r
x c
x c
x c
x d
x d
x d
chemotherapy s
x
x
x
Tumor assessment t
x
x
x
Concomitant medications u,v
x u
x u
x u
x
x
x
x
x
x
x
x
Adverse events w
x w
x w
x w
x
x
x
x
x
x
x
x
Provider-reported measures
x x
Patient-reported measures y
x
x
x
x
x
x
x


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(a)PTT=(activated) partial thromboplastin time; D=day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOI=end of 
induction; EOM=end of maintenance; FLIPI=Follicular Lymphoma International Prognostic Index; HIV, human immunodeficiency virus; HTLV-1, 
human T-lymphotropic virus 1; INR=International Normalized Ratio; LVEF=left ventricular ejection fraction; MUGA= multigated acquisition (scan);
PT=prothrombin time. 
Notes:  Dosing (i.e., Day 1 of each cycle), in induction phase should be done within ± 2 days of the scheduled visit date, with the exception of C1D1 which should 
take place within 28 days of the patient entering screening. All assessments should be performed within 2 days of the scheduled visit, unless otherwise 
specified.  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. Results from hematology and 
biochemistry must be reviewed, and the review documented, prior to study drug administration.
a
Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within the defined window may be used; 
such tests do not need to be repeated for screening.  
b
The total number of cycles of G-chemo indication therapy and the cycles length depends on the chemotherapy chosen for each patient 
c
Obinutuzumab administered according to the regular infusion rate.
d
Obinutuzumab administered according a 90-minute short duration infusion for patients who do not experience any Grade 3 IRRs during the 
first or previous cycle. If a patient experiences any Grade 3 IRRs during any SDI administrations of obinutuzumab (i.e. after Cycle 1, Day 1), the 
next dose of obinutuzumab will be administered at the regular infusion rate. If the patient experiences a second occurrence of a Grade 3 IRR, 
the obinutuzumab infusion must be stopped and the therapy must be permanently discontinued.
e
Patients who achieve at least a partial response (PR) following the completion of induction therapy will receive obinutuzumab maintenance 
therapy (1000 mg as single agent every 8 weeks (10 days) for 2 years or until disease progression). The first administration of obinutuzumab 
maintenance therapy is expected to start 8 weeks 10 days from Day 1 of the last induction cycle. Patients with stable disease or progressive disease 
will go to safety follow-up. For the timing of the safety follow-up assessment, please see footnote aa.
f
Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days 
before initiation of study treatment.
g
Includes blood pressure, pulse rate and temperature. Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
h
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.


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i
As part of tumor assessment, the physical examination should include evaluation for the presence of enlarged nodes, palpable hepatomegaly, 
and splenomegaly. This information will be recorded on the appropriate tumor assessment eCRF.
j
Includes systems of primary relevance (e.g., cardiovascular and respiratory systems), systems associated with symptoms (newly emergent or 
monitored from baseline), and areas associated with tumor assessment (lymph nodes, liver, spleen, and any other areas identified at baseline). 
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
k
Perform at the same time as tumor assessments after the end of induction treatment.
l
Unexplained fever 38ºC, night sweats, unexplained weight loss 10% of body weight over 6 months.
m
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
n
Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, ALP, ALT, AST, 
urate, beta-2 microglobulin (at screening and EOI only) and LDH.
o
All women of childbearing potential will have a serum pregnancy test at screening. 
p
Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination if routinely performed (sediment, RBCs, 
WBCs, casts, crystals, epithelial cells, bacteria).
q
To include assessment of HBV/HCV DNA PCR in patients with resolved HBV/HCV infection at baseline. HBV DNA PCR testing at least every 3 
months should also be conducted (during the study and for at least 1 year after completion of lymphoma treatment) for patients with prior HBV infection 
or who are carriers of HBV. HTLV-1 testing will be performed at baseline in patients from endemic countries only. HIV testing will be performed at 
baseline if required by local regulations. 
r
Obinutuzumab administered on Days, 1, 8 and 15 of cycle 1 and Day 1 of subsequent cycles.
s
Chemotherapy comprises either bendamustine (Days 1 and 2, Cycles 1–6; 28-day cycles), CHOP (Days 1–5, Cycles 1–6; 21-day cycles; 
followed by 2 cycles of obinutuzumab alone), or CVP (Days 1–5, Cycles 1–8; 21-day cycles).
t
By the investigator according to local practice and according to the guidelines used at the site (Lugano [Cheson et al 2014], Cheson et al 2007, 
or Cheson et al 1999). Including bone marrow where applicable. If bone marrow data are available in the patient’s medical record that were obtained 
within 3 months prior to study inclusion, these data can be used instead, and the patient does not need to undergo a new bone marrow biopsy with or without 
aspirate at screening.
u
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to study entry until 3 months after the final dose of study drug.
v
Concomitant medications and adverse events will be collected throughout the study.
w
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported. After initiation of study drug, all adverse events will be reported until 3 months (90 days (10 days)) after the final 
dose of study drug. After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is 
believed to be related to prior study treatment. An exception is made for Grade 3–4 infections (related and unrelated), which should be reported 
until resolution or until up to 2 years after the last dose of obinutuzumab and secondary malignancies should be reported indefinitely. The 


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investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the 
investigator, the patient is lost to follow-up, or the patient withdraws consent.
x
After administration of SDI at Cycle 4 Day 1, providers will complete the evaluation of site experience questionnaire.
y
Before administration of treatment at Day 1 of Cycles 1–6, at the end of induction, during maintenance, at end of maintenance, and at end of 
study, patients will complete the MDASI. The MDASI will be self-administered before the patient receives any information on disease status, 
prior to the performance of non-PRO assessments, and prior to the administration of study treatment.
z
LVEF required for patients who receive CHOP only.
aa
Safety follow-up assessment at 3 months (90 days (+/- 10 days)) after the final dose of obinutuzumab. If a patient discontinues obinutuzumab early and 
requires another anticancer therapy, then a safety follow up visit must be performed prior to the initiation of the new anticancer therapy.


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Appendix 3
MDASI: Details on Scoring
Scoring the MDASI as an Outcome Measure (Cleeland 2009):
The MDASI assesses the severity of symptoms at their worst in the last 24 hours on a 
010 numerical rating scale, with 0 being “not present” and 10 being “as bad as you can 
imagine.” 
In addition, the MDASI measures how much the symptoms have interfered with six daily 
activities: general activity, mood, work, relations with others, walking, and enjoyment of 
life. Interference is rated on a 010 numerical rating scale, 0 being “did not interfere” and 
10 being “interfered completely.”
The ratings in the MDASI can be averaged into several subscale scores, including mean 
core symptom severity (13 core symptom items) and mean interference (6 interference 
items only). Symptom items and interference items may be presented individually.
For each subscale, the score is defined as the arithmetic mean of items in the subscale.
When calculating any subscale score, more than 50% of the subscale’s items must have 
been responded to (i.e., 7 of the 13 core symptom severity items or 4 of the 6 
interference items), on a given administration. If the patient responded to fewer than half 
of the subscale’s items, consider the subscale “missing”.


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Appendix 4
Infusion Related Reactions: List of Predefined Preferred Terms

Infusion related reaction

All PTs containing “anaphylactoid,” “anaphylactic” or “anaphylaxis” (e.g., 
anaphylactic shock, anaphylactic reaction, anaphylactoid reaction)

All PTs containing “hypersensitivity”

All PTs containing “tachycardia”, “arrhythmia”, or “ventricular”, alone or in part (e.g., 
tachyarrhythmia) Gleich’s syndrome

All PTs containing the term “allergic,” or “urticaria”

All PTs containing “angioedema,” “edema,” or “dyspnea,”

All PTs containing “pruritus” or “pruritic”

Cytokine release syndrome

Circulatory collapse

Peripheral circulatory failure

Swelling face

Eye swelling

Circumoral swelling

Mouth swelling

Palatal swelling

Swollen tongue

Lip swelling

Oropharyngeal swelling

Pharyngeal swelling

Gingival swelling

Limbal swelling

Oculorespiratory syndrome

Oxygen saturation decreased

Hypoxia

Conjunctival hyperemia

Hypotension

Wheezing

Flushing

Throat tightness

Chest discomfort, chest pain, chest crushing, noncardiac chest pain, palpitations

All PTs containing “shock”, with the exception of septic shock

Pyrexia

Pulmonary congestion

Respiratory distress

Stridor

Reversible airways obstruction

Upper airway obstruction

Obstructive airway disorder

Upper airway cough syndrome


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
Chills

Kounis syndrome

Bronchospasm

Laryngospasm

Rhonchi

Back pain