Conditions: Lymphoma, Follicular
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 38
Healthy volunteers: no

Brief summary:
This study will evaluate the safety, efficacy, pharmacokinetics and immunogenicity of induction treatment consisting of atezolizumab in combination with obinutuzumab plus lenalidomide in patients with relapsed or refractory follicular lymphoma (FL), followed by maintenance treatment with atezolizumab plus obinutzumab plus lenalidomide in patients who achieve a complete response (CR), a partial response (PR), or stable disease at end of induction.

Detailed description:

Arms:
arm 1: Participants were administered obinutuzumab, Atezolizumab, and 15 mg of Lenalidomide. arm 2: Participants were administered obinutuzumab, Atezolizumab, and 20 mg of Lenalidomide.

Interventions: intervention 1: Atezolizumab (MPDL3280A) [TECENTRIQ] intervention 2: Lenalidomide intervention 3: Obinutuzumab
Intervention descriptions: intervention 1: Atezolizumab will be administered at a flat dose of 840 mg on Days 1 and 15 of Cycles 2 to 6, given in 28-day cycles as induction treatment and 840 mg on Days 1 and 2 of each month, given as maintenance treatment. intervention 2: Lenalidomide will be administered orally once daily on Days 1 to 21 of Cycles 1 to 6 (28-day cycles) during induction treatment and on Days 1 to 21 of each month during maintenance treatment. Lenalidomide will be administered at a dose of 15 or 20 mg (dose may be de-escalated to 10 mg) during induction treatment and at 10 mg during maintenance treatment. During the expansion phase, lenalidomide will be administered at the RP2D during induction treatment and at 10 mg during maintenance treatment. intervention 3: Obinutuzumab will be administered by intravenous infusion at an absolute (flat) dose of 1000 mg on Days 1, 8, and 15 of the first cycle and on Day 1 of each subsequent cycle during induction treatment, and on Day 1 of every other month (i.e., every 2 months) during maintenance treatment.

Protocol document:
Prot_SAP_001.pdf: 
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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 and Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol BO29562, Version 8
PROTOCOL
TITLE:
A PHASE Ib/II STUDY EVALUATING THE SAFETY 
AND EFFICACY OF ATEZOLIZUMAB IN 
COMBINATION WITH OBINUTUZUMAB PLUS 
LENALIDOMIDE IN PATIENTS WITH RELAPSED 
OR REFRACTORY FOLLICULAR LYMPHOMA
PROTOCOL NUMBER:
BO29562
VERSION NUMBER:
8
EUDRACT NUMBER:
2015-002467-42
IND NUMBER:
122,847
NCT NUMBER:
NCT02631577
TEST PRODUCTS:
Obinutuzumab (RO5072759)
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  29 July 2015
DATES AMENDED:
Version 2:  23 October 2015
Version 3:  8 June 2016
Version 4:  20 September 2016
Version 5:  5 May 2017
Version 6:  4 December 2017
Version 7:  7 November 2018
Version 8:  See electronic date stamp below.
 
26-Oct-2019 02:11:40
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol BO29562, Version 8
PROTOCOL AMENDMENT, VERSION 8:
RATIONALE
Protocol BO29562 has been amended to include new safety information.  Changes to 
the protocol, along with a rationale for each change, are summarized below:

Background information on atezolizumab has been updated to account for additional
approved indications (Section 1.3).

The list of atezolizumab risks has been updated to include myositis for consistency
with the list of identified risks in the Atezolizumab Investigator's Brochure
(Sections 1.3.2.1, 5.1.5.1 [Table 11], and 5.1.2).

To align with the Atezolizumab Investigator's Brochure, Version 15,
"immune-related" has been changed to "immune-mediated" when describing events
associated with atezolizumab (Sections 1.3.2.1, 3.3.4.1, 4.6.2, 5.1.2, and 5.1.5.1
[Table 11]).

Added language to clarify use of samples after withdrawal of patient consent
(Section 4.5.7).

Language has been added to clarify that, after withdrawal of consent for
participation in the Roche Clinical Repository (RCR), remaining RCR samples will
be destroyed or will no longer be linked to the patient.  Instructions about patient
withdrawal from the RCR after site closure have been modified to indicate that the
investigator must inform the Sponsor of patient withdrawal by emailing the study
number and patient number to global_rcr-withdrawal@roche.com (Section 4.5.9.6).

To address a request by the 
, language regarding atezolizumab risks has been revised to
remove the description and management guidelines for systemic immune activation
and to add descriptions and management guidelines for hemophagocytic
lymphohistiocytosis and macrophage activation syndrome.  In addition, systemic
immune activation has been removed from the list of adverse events of special
interest (Sections 5.1.2, 5.1.5.1 [Table 11], and 5.2.3).  As a result, Section 5.1.5.1
has been deleted and subsequent sections have been renumbered.

Language has been revised to account for the fact that some sites may not allow
follow-up on partner pregnancies (Section 5.4.3.2).

Language has been updated to indicate that therapeutic or elective abortions are
not considered adverse events unless performed because of an underlying maternal
or embryofetal toxicity.  In such cases, the underlying toxicity should be reported as
a serious adverse event.  Language has also been added to clarify that all abortions
are to be reported on the paper Clinical Trial Pregnancy Reporting Form
(Section 5.4.3.4).

Language has been added for consistency with Roche's current data retention
policy and to accommodate more stringent local requirements (if applicable)
(Section 7.5).

Language has been added to indicate that the study will comply with applicable local,
regional, and national laws (Section 8.1).


Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
3/Protocol BO29562, Version 

Language has been revised to clarify that redacted Clinical Study Reports and other 
summary reports will be made available upon request (Section 9.5).

The Appendix 7 (Anaphylaxis Precautions) has been modified to remove the 
requirement for use of a tourniquet.  The application of a tourniquet is no longer
recommended due to the limited therapeutic benefit and risk of losing time for more 
important measures (Ring J, Beyer K, Biedermann T, et al. Allergo J Int
2014;23:96112).

Guidelines for managing patients who experience atezolizumab-associated adverse 
events have been provided in Appendix 10 so there is no longer a need to consult 
the Atezolizumab Investigator's Brochure for management guidelines.
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
4/Protocol BO29562, Version 8
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13
PROTOCOL SYNOPSIS .................................................................................... 14
1.
BACKGROUND .......................................................................................... 26
1.1
Background on Follicular Lymphoma .................................... 26
1.2
Background on Obinutuzumab .............................................. 26
1.2.1
Nonclinical Studies with Obinutuzumab................................. 27
1.2.2
Clinical Studies with Obinutuzumab ...................................... 27
1.2.2.1
Summary of Clinical Efficacy of Obinutuzumab in 
Patients with NHL .................................................................. 27
1.2.2.2
Summary of Clinical Safety of Obinutuzumab ....................... 28
1.2.2.3
Clinical Pharmacokinetics of Obinutuzumab.......................... 29
1.3
Background on Atezolizumab................................................ 29
1.3.1
Nonclinical Studies with Atezolizumab .................................. 29
1.3.2
Clinical Studies with Atezolizumab ........................................ 30
1.3.2.1
Summary of Clinical Safety of Atezolizumab ......................... 30
1.3.2.2
Clinical Pharmacokinetics of Atezolizumab ........................... 32
1.3.2.3
Summary of Clinical Activity of Atezolizumab........................ 32
1.4
Study Rationale and Benefit–Risk Assessment..................... 33
1.4.1
PD-L1/PD-1 Pathway in Lymphoma ...................................... 33
1.4.2
Clinical Experience with PD-L1/PD-1 Pathway 
Inhibitors in Lymphoma.......................................................... 34
1.4.3
Rationale for Treatment Combination.................................... 35
1.4.3.1
Nonclinical Data..................................................................... 35
1.4.3.2
Available Clinical Data........................................................... 36
2.
OBJECTIVES AND ENDPOINTS ............................................................... 38
2.1
Safety Objectives................................................................... 38
2.2
Efficacy Objectives ................................................................ 38
2.2.1
Primary Efficacy Objective..................................................... 38
2.2.2
Secondary Efficacy Objectives .............................................. 38
2.2.3
Exploratory Efficacy Objectives ............................................. 39
2.3
Pharmacokinetic Objective .................................................... 39


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2.4
Immunogenicity Objectives.................................................... 40
2.5
Biomarker Objective .............................................................. 40
3.
STUDY DESIGN......................................................................................... 40
3.1
Description of Study .............................................................. 40
3.1.1
Overview of Study ................................................................. 40
3.1.2
Dose-Escalation Phase ......................................................... 41
3.1.2.1
Definition of Dose-Limiting Toxicity........................................ 42
3.1.2.2
Treatment Regimens and Dose-Escalation Rules................. 42
3.1.3
Expansion Phase................................................................... 44
3.1.4
Internal Monitoring Committee............................................... 47
3.1.5
Independent Review Committee............................................ 47
3.1.6
Post-Treatment Follow-Up and Survival Follow-
Up.......................................................................................... 47
3.2
End of Study and Length of Study......................................... 48
3.3
Rationale for Study Design.................................................... 48
3.3.1
Rationale for Patient Population ............................................ 48
3.3.2
Rationale for Dose and Schedule.......................................... 48
3.3.2.1
Rationale for Atezolizumab Dose and Schedule.................... 48
3.3.2.2
Rationale for Obinutuzumab and Lenalidomide 
Dose and Schedule ............................................................... 50
3.3.2.3
Rationale for Treatment Duration .......................................... 50
3.3.3
Rationale for PET-CT–Based Complete 
Response as the Primary Efficacy Endpoint.......................... 51
3.3.4
Rationale for Biomarker Assessments................................... 52
3.3.4.1
Rationale for Assessment of Immune-Mediated 
Biomarkers ............................................................................ 52
3.3.4.2
Rationale for Assessment of Minimal Residual 
Disease.................................................................................. 53
4.
MATERIALS AND METHODS .................................................................... 53
4.1
Patients.................................................................................. 53
4.1.1
Inclusion Criteria.................................................................... 53
4.1.2
Exclusion Criteria................................................................... 55
4.2
Method of Treatment Assignment.......................................... 58
4.3
Study Treatment.................................................................... 58


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4.3.1
Formulation, Packaging, and Handling.................................. 58
4.3.1.1
Obinutuzumab ....................................................................... 58
4.3.1.2
Atezolizumab......................................................................... 59
4.3.1.3
Lenalidomide ......................................................................... 59
4.3.2
Dosage, Administration, and Compliance.............................. 59
4.3.2.1
Obinutuzumab ....................................................................... 59
4.3.2.2
Atezolizumab......................................................................... 63
4.3.2.3
Lenalidomide ......................................................................... 63
4.3.2.4
Induction Treatment with Atezolizumab, 
Obinutuzumab, and Lenalidomide 
(Atezo G Len) .................................................................. 64
4.3.2.5
Maintenance Treatment with Atezolizumab, 
Obinutuzumab, and Lenalidomide 
(Atezo G Len) .................................................................. 65
4.3.2.6
Premedication and Other Prophylaxis Treatment.................. 65
4.3.3
Investigational Medicinal Product Accountability ................... 68
4.3.4
Post-Trial Access to Atezolizumab and 
Obinutuzumab ....................................................................... 68
4.4
Concomitant Therapy ............................................................ 68
4.4.1
Permitted Therapy................................................................. 68
4.4.2
Prohibited Therapy ................................................................ 69
4.5
Study Assessments............................................................... 69
4.5.1
Informed Consent Forms and Screening Log........................ 70
4.5.2
Medical History and Demographic Data ................................ 70
4.5.3
Physical Examinations........................................................... 71
4.5.4
Vital Signs.............................................................................. 71
4.5.5
Tumor and Response Evaluations......................................... 71
4.5.6
Radiographic Assessments ................................................... 71
4.5.6.1
Bone Marrow Assessments................................................... 72
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 72
4.5.8
Electrocardiograms................................................................ 76
4.5.9
Samples for Roche Clinical Repository.................................. 76
4.5.9.1
Overview of the Roche Clinical Repository............................ 76


Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
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4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 76
4.5.9.3
Sample Collection.................................................................. 77
4.5.9.4
Confidentiality........................................................................ 77
4.5.9.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 78
4.5.9.6
Withdrawal from the Roche Clinical Repository..................... 78
4.5.9.7
Monitoring and Oversight....................................................... 79
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 79
4.6.1
Patient Discontinuation.......................................................... 79
4.6.2
Study Treatment Discontinuation........................................... 79
4.6.3
Study and Site Discontinuation.............................................. 80
5.
ASSESSMENT OF SAFETY....................................................................... 81
5.1
Safety Plan ............................................................................ 81
5.1.1
Risks Associated with Obinutuzumab.................................... 81
5.1.1.1
Infusion-Related Reactions and Hypersensitivity 
Reactions............................................................................... 81
5.1.1.2
Tumor Lysis Syndrome.......................................................... 82
5.1.1.3
Neutropenia........................................................................... 82
5.1.1.4
Thrombocytopenia................................................................. 83
5.1.1.5
Infections ............................................................................... 83
5.1.1.6
Immunizations ....................................................................... 84
5.1.1.7
Worsening of Preexisting Cardiac Condition ......................... 84
5.1.1.8
Gastrointestinal Perforation ................................................... 84
5.1.2
Risks Associated with Atezolizumab ..................................... 84
5.1.3
Risks Associated with Lenalidomide...................................... 84
5.1.3.1
Embryo-Fetal Toxicity............................................................ 84
5.1.3.2
Hematologic Toxicity ............................................................. 85
5.1.3.3
Venous and Arterial Thromboembolism................................. 85
5.1.3.4
Tumor Flare Reaction............................................................ 85
5.1.3.5
Severe Skin Reactions .......................................................... 86
5.1.3.6
Tumor Lysis Syndrome.......................................................... 86
5.1.3.7
Hepatotoxicity........................................................................ 86


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5.1.3.8
Renal Impairment .................................................................. 86
5.1.3.9
Thyroid Disorders .................................................................. 86
5.1.3.10
Peripheral Neuropathy........................................................... 86
5.1.3.11
Second Primary Malignancies ............................................... 86
5.1.3.12
Drug-Drug Interactions .......................................................... 87
5.1.4
Risk of Overlapping Toxicities and Drug-Drug 
Interactions............................................................................ 87
5.1.5
Management of Specific Adverse Events .............................. 88
5.1.5.1
Toxicities during Induction Treatment.................................... 89
5.1.5.2
Toxicities during Maintenance Treatment............................ 104
5.2
Safety Parameters and Definitions ...................................... 104
5.2.1
Adverse Events ................................................................... 105
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 105
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 106
5.2.4
Selected Adverse Events..................................................... 107
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 107
5.3.1
Adverse Event Reporting Period ......................................... 108
5.3.2
Dose-Limiting Toxicities (Immediately Reportable 
to the Sponsor).................................................................... 108
5.3.3
Eliciting Adverse Event Information..................................... 108
5.3.4
Assessment of Severity of Adverse Events ......................... 108
5.3.5
Assessment of Causality of Adverse Events ....................... 109
5.3.6
Procedures for Recording Adverse Events.......................... 110
5.3.6.1
Infusion-Related Reactions.................................................. 110
5.3.6.2
Diagnosis versus Signs and Symptoms............................... 110
5.3.6.3
Adverse Events That are Secondary to Other 
Events.................................................................................. 110
5.3.6.4
Persistent or Recurrent Adverse Events.............................. 111
5.3.6.5
Abnormal Laboratory Values ............................................... 111
5.3.6.6
Abnormal Vital Sign Values ................................................. 112
5.3.6.7
Abnormal Liver Function Tests............................................ 113
5.3.6.8
Deaths ................................................................................. 113


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5.3.6.9
Preexisting Medical Conditions............................................ 113
5.3.6.10
Lack of Efficacy or Worsening of Lymphoma....................... 114
5.3.6.11
Hospitalization or Prolonged Hospitalization........................ 114
5.3.6.12
Adverse Events Associated with an Overdose or 
Error in Treatment Administration........................................ 115
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 115
5.4.1
Emergency Medical Contacts.............................................. 116
5.4.2
Reporting Requirements for Serious Adverse 
Events, Adverse Events of Special Interest, and 
Dose-Limiting Toxicities....................................................... 116
5.4.2.1
Events That Occur prior to Study Treatment 
Initiation ............................................................................... 116
5.4.2.2
Events That Occur after Study Treatment 
Initiation ............................................................................... 116
5.4.3
Reporting Requirements for Pregnancies............................ 117
5.4.3.1
Pregnancies in Female Patients.......................................... 117
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 117
5.4.3.3
Exposure of Pregnant Female to Lenalidomide................... 117
5.4.3.4
Abortions ............................................................................. 118
5.4.3.5
Congenital Anomalies/Birth Defects .................................... 118
5.5
Follow-Up of Patients after Adverse Events ........................ 118
5.5.1
Investigator Follow-Up......................................................... 118
5.5.2
Sponsor Follow-Up .............................................................. 119
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 119
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 119
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 120
6.1
Determination of Sample Size ............................................. 120
6.2
Definition of Analysis Populations........................................ 121
6.3
Summaries of Conduct of Study.......................................... 121
6.4
Summaries of Demographic and Baseline 
Characteristics..................................................................... 122
6.5
Safety Analyses................................................................... 122


Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
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6.6
Efficacy Analyses ................................................................ 122
6.6.1
Primary Efficacy Endpoint.................................................... 122
6.6.2
Secondary Efficacy Endpoints............................................. 123
6.6.3
Exploratory Efficacy Endpoints............................................ 123
6.7
Pharmacokinetic Analyses................................................... 124
6.8
Immunogenicity Analyses.................................................... 124
6.9
Biomarker Analyses............................................................. 124
6.10
Interim Analyses.................................................................. 124
6.11
Stopping Rules for Safety.................................................... 125
7.
DATA COLLECTION AND MANAGEMENT ............................................. 126
7.1
Data Quality Assurance....................................................... 126
7.2
Electronic Case Report Forms............................................. 126
7.3
Source Data Documentation................................................ 126
7.4
Use of Computerized Systems ............................................ 127
7.5
Retention of Records........................................................... 127
8.
ETHICAL CONSIDERATIONS.................................................................. 128
8.1
Compliance with Laws and Regulations .............................. 128
8.2
Informed Consent................................................................ 128
8.3
Institutional Review Board or Ethics Committee.................. 129
8.4
Confidentiality...................................................................... 130
8.5
Financial Disclosure ............................................................ 130
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 130
9.1
Study Documentation .......................................................... 130
9.2
Protocol Deviations.............................................................. 130
9.3
Site Inspections ................................................................... 131
9.4
Administrative Structure....................................................... 131
9.5
Publication of Data and Protection of 
Trade Secrets...................................................................... 131
9.6
Protocol Amendments ......................................................... 132
10. REFERENCES ......................................................................................... 133


Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
11/Protocol BO29562, Version 8
LIST OF TABLES
Table 1
Induction Treatment for Dose-Escalation Phase......................... 43
Table 2
Induction Treatment for Expansion Phase .................................. 45
Table 3
Maintenance Treatment .............................................................. 45
Table 4
Induction Treatment.................................................................... 65
Table 5
Maintenance Treatment .............................................................. 65
Table 6
Premedication............................................................................. 67
Table 7
Proposed Non-Inherited Biomarkers........................................... 74
Table 8
Summary of Potentially Overlapping Adverse Events................. 88
Table 9
Lenalidomide Dose Reduction .................................................... 89
Table 10
Guidelines for Management of Hematologic Toxicities that 
Occur during Induction Treatment............................................... 90
Table 11
Guidelines for Management of Non-Hematologic Toxicities........ 92
Table 12
Guidelines for Management of Toxicities That Occur during 
Maintenance Treatment ............................................................ 104
Table 13
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 109
Table 14
Potential 90% CI for the True Probability of Achieving a  
PET-CT–Defined Complete Response at EOI .......................... 121
Table 15
Early Stopping Rules Based on Number of Fatal Adverse 
Events....................................................................................... 125
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 46
Figure 2
Guidelines for Obinutuzumab Infusions:  First Infusion............... 61
Figure 3
Guidelines for Obinutuzumab Infusions:  Second and 
Subsequent Infusions ................................................................. 62


Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
12/Protocol BO29562, Version 8
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 139
Appendix 2
Pharmacokinetic and Immunogenicity Sampling Schedule for 
Obinutuzumab, Atezolizumab, and Lenalidomide..................... 146
Appendix 3
Lugano Response Criteria for Malignant Lymphoma................ 149
Appendix 4
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 154
Appendix 5
Ann Arbor Staging..................................................................... 155
Appendix 6
Follicular Lymphoma International Prognostic Index................. 156
Appendix 7
Anaphylaxis Precautions........................................................... 158
Appendix 8
Preexisting Autoimmune Diseases ........................................... 159
Appendix 9
Calculation of Creatinine Clearance Using  the Cockcroft-
Gault Formula ........................................................................... 160
Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab.......................................................................... 161


Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
13/Protocol BO29562, Version 8
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE Ib/II STUDY EVALUATING THE SAFETY 
AND EFFICACY OF ATEZOLIZUMAB IN 
COMBINATION WITH OBINUTUZUMAB PLUS 
LENALIDOMIDE IN PATIENTS WITH RELAPSED 
OR REFRACTORY FOLLICULAR LYMPHOMA
PROTOCOL NUMBER:
BO29562
VERSION NUMBER:
8
EUDRACT NUMBER:
2015-002467-42
IND NUMBER:
122,847
NCT NUMBER:
NCT02631577
TEST PRODUCTS:
Obinutuzumab (RO5072759)
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, Ph.D.
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 as 
instructed by your local study monitor at 
.


Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
14/Protocol BO29562, Version 8
PROTOCOL SYNOPSIS
TITLE:
A PHASE Ib/II STUDY EVALUATING THE SAFETY AND 
EFFICACY OF ATEZOLIZUMAB IN COMBINATION WITH 
OBINUTUZUMAB PLUS LENALIDOMIDE IN PATIENTS WITH 
RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA
PROTOCOL NUMBER:
BO29562
VERSION NUMBER:
8
EUDRACT NUMBER:
2015-002467-42
IND NUMBER:
122,847
NCT NUMBER:
NCT02631577
TEST PRODUCTS:
Obinutuzumab (RO5072759)
Atezolizumab (RO5541267)
PHASE:
Phase Ib/II
INDICATION:
Follicular or diffuse large B-cell lymphoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Outcome Measures
This study will evaluate the safety, efficacy, pharmacokinetics, and immunogenicity of induction 
treatment consisting of atezolizumab in combination with obinutuzumab plus lenalidomide 
(Atezo G Len) in patients with relapsed or refractory follicular lymphoma (FL), followed by 
maintenance treatment with Atezo G Len in patients who achieve a complete response (CR), 
a partial response (PR), or stable disease at end of induction (EOI).  Specific objectives and 
corresponding endpoints for the study are outlined below.  
In this study, “study treatment” refers to the combination of all study treatment components.
Safety Objectives
The safety objectives for this study are as follows:

To determine the recommended Phase II dose (RP2D) for lenalidomide when given in 
combination with fixed doses of obinutuzumab and atezolizumab on the basis of the 
following endpoint:
Incidence of dose-limiting toxicities during Cycle 2 of study treatment

To evaluate the safety and tolerability of Atezo G Len on the basis of the following 
endpoints:
Nature, frequency, severity, and timing of adverse events 
Changes in vital signs, ECGs, and clinical laboratory results during and following study 
treatment administration
Efficacy Objectives
Response will be determined through use of the positron emission tomography-computed 
tomography (PET-CT) scans or CT scans alone, using Revised Lugano Response Criteria for 
Malignant Lymphoma, hereinafter referred to as Lugano 2014 criteria.  Response will be 
determined by an Independent Review Committee (IRC) and by the investigator.


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Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of induction treatment 
with AtezoGLen on the basis of the following endpoint:

CR at EOI as determined by the IRC on the basis of PET-CT scans
Secondary Efficacy Objectives
The secondary efficacy objective for this study is to evaluate the efficacy of induction and 
maintenance treatments with AtezoGLen on the basis of the following endpoints:

CR at EOI as determined by the investigator on the basis of PET-CT scans

CR at EOI as determined by the IRC and by the investigator on the basis of CT scans alone

Objective response (defined as a CR or PR) at EOI as determined by the IRC and by the 
investigator on the basis of PET-CT scans

Objective response (defined as a CR or PR) at EOI as determined by the IRC and by the 
investigator on the basis of CT scans alone

Best response of CR or PR during the study as determined by the investigator on the basis 
of CT scans alone
Exploratory Efficacy Objectives
The exploratory efficacy objective for this study is to evaluate the long-term efficacy of 
AtezoGLen on the basis of the following endpoints:

For patients who have positive PET scans at EOI:  CR at 12 months as determined by the 
IRC and by the investigator on the basis of PET-CT scans

Progression-free survival (PFS), defined as the time from initiation of study treatment to first 
occurrence of disease progression or relapse, as determined by the investigator on the
basis of CT scans alone or death from any cause

Event-free survival (EFS), defined as the time from initiation of study treatment to any 
treatment failure, including disease progression or relapse, as determined by the 
investigator on the basis of CT scans alone; initiation of new anti-lymphoma therapy; or 
death from any cause, whichever occurs first

Disease-free survival (DFS), defined as the time from the first occurrence of a documented 
CR to relapse among patients achieving a CR, as determined by the investigator on the 
basis of CT scans alone or death from any cause, whichever occurs first

Duration of objective response (DOR), defined as the time from the first occurrence of a 
documented objective response to the time of disease progression or relapse, as 
determined by the investigator on the basis of CT scans alone or death from any cause, 
whichever occurs first.

Overall survival (OS), defined as the time from initiation of study treatment to death from 
any cause
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the pharmacokinetics of 
atezolizumab, obinutuzumab, and lenalidomide, when given in combination, on the basis of the 
following endpoints:

Observed serum obinutuzumab concentration at specified timepoints

Observed serum atezolizumab concentration at specified timepoints

Observed plasma lenalidomide concentration at specified timepoints


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Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to 
obinutuzumab and to atezolizumab on the basis of the following endpoints:

Incidence of human anti-human antibodies (HAHAs) to obinutuzumab during the study 
relative to the prevalence of HAHAs at baseline

Incidence of anti-therapeutic antibodies to atezolizumab during the study relative to the 
prevalence of anti-therapeutic antibodies at baseline
The exploratory immunogenicity objective for this study is to evaluate potential effects of HAHAs 
or anti-therapeutic antibodies on the basis of the following endpoint:

Correlation between HAHA or anti-therapeutic antibody status and efficacy, safety, or 
PK endpoints
Biomarker Objective
The exploratory biomarker objective for this study is to identify non-inherited biomarkers that are 
predictive of response to study treatment (i.e., predictive biomarkers), are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
acquired resistance to study treatment, are associated with susceptibility to developing adverse 
events, can provide evidence of study treatment activity, can increase the knowledge and 
understanding of lymphoma biology or study treatment mechanism of action, or can contribute 
to improvement of diagnostic assays, on the basis of the following endpoint:

Association between non-inherited biomarkers and efficacy, safety, PK, or 
immunogenicity endpoints
Study Design
Description of Study
This Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study will evaluate 
the safety, efficacy, pharmacokinetics, and immunogenicity of Atezo G Len in patients with 
relapsed or refractory FL.  The study will include an initial dose-escalation phase designed to 
determine the RP2D for lenalidomide in this treatment combination followed by an expansion 
phase in which lenalidomide will be given at the RP2D.  All patients will receive induction 
treatment with Atezo G Len for six cycles.  Patients achieving a CR, a PR, or stable disease 
at EOI will be eligible to receive extended dosing of Atezo G Len as maintenance treatment 
(refer to protocol for details on treatment regimens).  A study schema is provided in the protocol.
Overall, it is planned to have approximately 46 patients enrolled in this study at approximately 
15 investigative sites around the world, mainly in Europe and North America.
All patients will be closely monitored for adverse events throughout the study and for at least 
35 days after the last dose of study treatment.  Adverse events will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0.  
An Internal Monitoring Committee (IMC) will be established to monitor patient safety throughout 
the study.
To characterize the PK properties of obinutuzumab, atezolizumab, and lenalidomide as well as 
the immunogenicity of obinutuzumab and atezolizumab when given in combination, blood 
samples will be taken at various timepoints before and during dosing.
Response will be determined by the IRC and the investigator using the Lugano 2014 criteria.  
The primary efficacy endpoint will be based on IRC assessment of response.  Refer to protocol
for details on tumor assessments.


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During induction treatment, all patients will have a CT scan performed at the end of Cycle 2 to 
confirm absence of early disease progression.  Because of the potential for tumor flares with 
immunotherapies, which result in early apparent radiographic progression 
(pseudoprogression/tumor immune infiltration), including the appearance of new lesions 
followed by delayed response, patients whose CT scans meet criteria for disease progression 
may continue to receive study treatment at the discretion of the investigator and following 
discussion with the Medical Monitor if a moderate increase is seen in one lesion only or if at 
least two of the following criteria are met:

Absence of symptoms and signs, including worsening of laboratory values (e.g., increased 
LDH) that indicate unequivocal disease progression

No decline in Eastern Cooperative Oncology Group (ECOG) Performance Status

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions
Patients with radiographic evidence of progression at the end of Cycle 2 who continue to 
receive study treatment per the above criteria should have a CT scan repeated 48 weeks later.
Number of Patients
Overall, it is planned to have approximately 46 patients enrolled in this study at approximately 
15 investigative sites around the world, mainly in Europe and North America.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years

ECOG Performance Status of 0, 1, or 2

Relapsed or refractory FL after treatment with at least one prior chemoimmunotherapy 
regimen that included an anti-CD20 monoclonal antibody and for which no other more 
appropriate treatment option exists as determined by the investigator

Histologically documented CD20-positive lymphoma as determined by the local laboratory

Fluorodeoxyglucose-avid lymphoma (i.e., PET-positive lymphoma)

At least one bi-dimensionally measurable lesion (1.5 cm in its largest dimension by CT 
scan or magnetic resonance imaging)

Availability of a representative tumor specimen and the corresponding pathology report for 
retrospective central confirmation of the diagnosis of FL
If archival tissue is unavailable or unacceptable, a pretreatment core-needle, excisional 
or incisional tumor biopsy is required.  Cytological or fine-needle aspiration samples are 
not acceptable.
If the available biopsy was performed more than 12 months prior to Day 1 of Cycle 1 for 
patients with FL, or the patient received anti-lymphoma treatment between the time of 
the most recent available biopsy and Day 1 of Cycle 1, a core-needle biopsy is strongly 
recommended.

Agreement to comply with all local requirements of the lenalidomide risk minimization plan
In every country where lenalidomide has been approved, a risk minimization plan, 
which includes a pregnancy prevention program, is in place.  The risk minimization 
plan should be followed by patients using lenalidomide.  In addition, because 
lenalidomide will be administered in combination with atezolizumab and obinutuzumab, 
patients must comply with contraceptive measures designed to ensure safe 
administration of all three study treatments, as outlined below.  


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
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate methods of contraception, including at least 
one method with a failure rate of 1% per year, for at least 28 days prior to Day 1 of Cycle 1, 
during the treatment period (including periods of treatment interruption), and for at 
least 18 months after the last dose of study treatment
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of non-hormonal contraceptive methods with a failure rate of 1% per year 
include bilateral tubal ligation, male sterilization, established and proper use of 
progestogen-only hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices, and copper intrauterine devices.  Combined oral contraceptives 
are not recommended because of the increased risk of venous and arterial 
thromboembolism (TE) in patients taking lenalidomide.
The reliability of sexual abstinence should 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.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or 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 to avoid exposing the embryo.  Men 
must refrain from donating sperm during this same period.
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:

Grade 3b follicular lymphoma

History of transformation of indolent disease to DLBCL

Known CD20-negative status at relapse or progression

CNS lymphoma or leptomeningeal infiltration

Prior allogeneic stem-cell transplant (SCT)

Completion of autologous SCT within 100 days prior to Day 1 of Cycle 1 

History of resistance to lenalidomide or response duration of 1 year (for patients who had 
a response to a prior lenalidomide-containing regimen) 

Prior standard or investigational anti-cancer therapy as specified below:
Lenalidomide, fludarabine, or alemtuzumab within 12 months prior to Day 1 of Cycle 1
Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1
Monoclonal antibody or antibodydrug conjugate within 4 weeks prior to Day 1 of 
Cycle 1
Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule therapy 
within 2 weeks prior to Day 1 of Cycle 1
AntiPD-1, antiPD-L1, anti-CTLA4, antiCD137/41-BB agonist, or anti-CD40 agonist 
antibodies


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
Clinically significant toxicity (other than alopecia) from prior treatment that has not resolved 
to Grade 2 (per NCI CTCAE v4.0) prior to Day 1 of Cycle 1

Treatment with systemic immunosuppressive medications, including, but not limited to, 
prednisone, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor agents 
within 2 weeks prior to Day 1 of Cycle 1
Treatment with inhaled corticosteroids and mineralocorticoids is permitted.
If corticosteroid treatment is urgently required for lymphoma symptom control prior to
the start of study treatment, 100 mg of prednisone or equivalent can be given for a 
maximum of 5 days, but all tumor assessments must be completed prior to initiation of 
corticosteroid treatment.

History of solid organ transplantation

History of severe allergic or anaphylactic reaction to humanized, chimeric or murine
monoclonal antibodies

Known sensitivity or allergy to murine products

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or 
any component of the atezolizumab, obinutuzumab, or lenalidomide formulation, including 
mannitol

History of erythema multiforme, Grade 3 rash, or blistering following prior treatment with 
immunomodulatory derivatives such as thalidomide and lenalidomide

Known history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis or evidence of active pneumonitis on screening chest 
CT scan.
History of radiation pneumonitis in the radiation field (fibrosis) is allowed.

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
Caution should be exercised when considering the use of obinutuzumab in patients with 
a history of recurring or chronic infections.

Positive for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (HBcAb), or 
hepatitis C virus (HCV) antibody at screening

Known history of HIV positive status
For patients with unknown HIV status, HIV testing will be performed at screening if 
required by local regulations.

History of progressive multifocal leukoencephalopathy

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

History of other malignancy that could affect compliance with the protocol or interpretation of 
results, with the exception of the following:
Any of the following malignancies previously 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, low-grade, early-stage localized prostate cancer, or any other
previously treated malignancy that has been in remission without treatment for
5 years prior to enrollment

History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis 
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid-replacement hormone may be eligible for this study.


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Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be 
eligible for this study.

Contraindication to treatment for TE prophylaxis

Grade 2 neuropathy

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)

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

Inadequate hematologic function (unless due to underlying lymphoma), defined as follows:
Hemoglobin 9 g/dL
ANC 1.5109/L
Platelet count 75109/L

Any of the following abnormal laboratory values (unless due to underlying lymphoma):
Calculated creatinine clearance 60 mL/min 
AST or ALT 2.5 times the upper limit of normal (ULN)
Serum total bilirubin 1.5 ULN (or 3ULN for patients with Gilbert syndrome)
INR or PT 1.5ULN in the absence of therapeutic anticoagulation
PTT or aPTT 1.5ULN in the absence of a lupus anticoagulant

Pregnant or lactating or intending to become pregnant during the study
Women of childbearing potential must have two negative serum pregnancy test results 
(minimum sensitivity, 25 mIU/mL) prior to initiating therapy:  at 1014 days prior to 
Day 1 of Cycle 1 and within 24 hours prior to Day 1 of Cycle 1.

Life expectancy 3 months

Unable to comply with the study protocol, in the investigator’s judgment
End of Study
The end of this study is defined as the time when all enrolled patients have completed or 
discontinued study treatment (including induction treatment and maintenance treatment as 
applicable).
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
Obinutuzumab will be administered by intravenous infusion at an absolute (flat) dose of 
1000 mg on Days 1, 8, and 15 of the first cycle and on Day 1 of each subsequent cycle during 
induction treatment, and on Day 1 of every other month (i.e., every 2 months) during 
maintenance treatment. No dose modification for obinutuzumab is allowed.
Atezolizumab will be administered at a flat dose consisting of one of the following:  
1) 840 mg every 2 weeks (840 mg on Days 1 and 15 of Cycles 26, given in 28-day cycles as 
induction treatment) and 2) 1680 mg every 4 weeks (840 mg on Days 1 and 2 of each month, 
given as maintenance treatment).  No dose modification for atezolizumab is allowed.
Lenalidomide will be administered orally once daily on Days 121 of Cycles 16 (28-day cycles) 
during induction treatment and on Days 121 of each month during maintenance treatment.  
During the dose-escalation phase, lenalidomide will be administered at a dose of 15 or 20 mg
(dose may be de-escalated to 10 mg) during induction treatment and at 10 mg during 
maintenance treatment.  During the expansion phase, lenalidomide will be administered at the 
RP2D during induction treatment and at 10 mg during maintenance treatment.


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Statistical Methods
Primary Analysis
Safety
The safety analysis will be performed on the primary population; additional safety analysis will 
be performed on the intent-to-treat (ITT) population.
The safety analyses will be performed separately for each study phase (i.e., dose escalation 
and expansion).
Safety will be assessed through summaries of adverse events, changes from baseline in 
laboratory test results, laboratory data with values outside of the normal ranges, ECGs, and vital 
signs.
All adverse events occurring on or after the first study treatment will be summarized by mapped 
term, appropriate thesaurus levels, and NCI CTCAE v4.0 grade.  All serious adverse events, 
adverse events of special interest, and selected events will be summarized and listed.  
Deaths reported during the treatment period and during post-treatment follow-up will be listed.
Relevant laboratory and vital sign data will be displayed by time, with Grade 3 and 4 values 
identified as appropriate.
Efficacy
The efficacy analysis will be performed on the primary population.  Additional efficacy analysis 
will be performed on the ITT population.  
Patients who received lenalidomide at the RP2D during the dose-escalation phase will be 
pooled with patients treated in the expansion phase.
The primary efficacy analysis will be estimation of the proportion of patients achieving a CR at 
EOI, as determined by the IRC through use of the PET-CT-based Lugano 2014 criteria.  Point 
estimates will be presented, along with the corresponding two-sided 90% Clopper-Pearson 
exact CIs.  Patients without an EOI tumor assessment will be considered non-responders.
Determination of Sample Size
Limited dose finding will be conducted during the dose-escalation phase of this study.  
The estimated sample size follows from the dose-escalation rules for a 3 3 algorithm, as 
outlined in the protocol.  It is anticipated that enrollment of two dosing groups of 36 patients 
each, for a total of 612 patients with relapsed or refractory FL, will be required to establish the 
RP2D during the dose-escalation phase.
Approximately 40 patients will be enrolled during the expansion phase.
The primary efficacy analysis will be the estimation of the true proportion of patients expected to 
obtain a PET-CTdefined CR at EOI. 
Data from completed and ongoing studies in similar disease settings will be used as historical 
controls for comparison.  Currently available data from the GALEN study (Morschhauser et al. 
2017) indicate that the historical CR rate based on PET-CT scans is approximately 40% in 
relapsed or refractory setting, as assessed by Cheson 2007 criteria.  
A sample size of 40 patients is deemed sufficient to provide adequate precision for the point 
estimate and for the lower bound of the two-sided 90% CI to rule out a clinically uninteresting 
probability of response of 46%, assuming an observed PET-CTdefined CR rate of 60%.  
Updated estimates of the proportion of patients expected to achieve a PET-CTdefined CR are 
expected to be available from ongoing studies by the time of the first interim analysis and will be 
used as reference data.
Interim Analyses
It is anticipated that at least one interim analysis will be conducted during the expansion phase 
of the study, when at least 15 patients treated at the RP2D of lenalidomide have been evaluated 
for PET-CTdefined CR at the EOI.  Additional analyses will be conducted approximately every 
4 months to guide early stopping of enrollment for safety on the basis of observed toxicities.  
Stopping rules for excess toxicity, including fatal adverse events, have been included.


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During the expansion phase, a modified version of the predictive probability design may be 
used to guide early stopping for futility by comparing the observed proportion of patients who 
achieve a PET-CTdefined CR at EOI with that in historical controls.  The earliest interim 
analysis would occur after at least 15 patients have been evaluated for PET-CTdefined CR 
at EOI.  
If, at any time, an interim analysis suggests that the proportion of patients achieving a 
PET-CTdefined CR is lower or higher than expected, the IMC will review the data and decide 
whether to recommend an early decision to stop enrollment.  Interim analysis decision rules will 
be based on the modified version of the predictive probability that the trial will have a positive 
outcome if carried out to completion and will use the historical control data available at the time 
of analysis.
Additional review of safety and/or efficacy data by the IMC may be requested by and carried out 
at the discretion of the Medical Monitor.  Further details regarding the rules and guidelines of 
data review will be provided in an IMC charter.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ALP
alkaline phosphatase
ATA
anti-therapeutic antibody
Atezo
atezolizumab
AUC
area under the concentrationtime curve
CHOP
cyclophosphamide, doxorubicin, vincristine, and 
prednisone
CLL
chronic lymphocytic leukemia
CR
complete response
CT
computed tomography
Ctrough
trough concentration
CYP
cytochrome P450
DDI
drugdrug interaction
DFS
disease-free survival
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DOR
duration of objective response
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EFS
event-free survival
EOI
end of induction
EOM
end of maintenance
EORTC
European Organization for Research and Treatment of 
Cancer
FDA
U.S. Food and Drug Administration
FDG
fluorodeoxyglucose
FL
follicular lymphoma
FLIPI, FLIPI2
Follicular Lymphoma International Prognostic Index
Follicular Lymphoma International Prognostic Index 2
G
obinutuzumab (GA101)
GB
obinutuzumab plus bendamustine
GCP
Good Clinical Practice
G-CHOP
obinutuzumab plus CHOP
G-CSF
granulocyte colony-stimulating factor
GEP
gene expression profile


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Abbreviation
Definition
GI
gastrointestinal
HAHA
human anti-human antibody
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
IC
immune cell
ICH
International Conference on Harmonisation
IFN-
interferon gamma
IL
interleukin
IL-2
interleukin-2
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug
iNHL
indolent non-Hodgkin’s lymphoma
IPI
International Prognostic Index
IRB
Institutional Review Board
IRC
Independent Review Committee
IRR
infusion-related reaction
ITT
intent to treat
IV
intravenous
IxRS
interactive voice or web-based response system
JC
John Cunningham
Len
lenalidomide
LFT
liver function test
LMWH
low-molecular-weight heparin
Lugano 2014 criteria
Lugano Response Criteria for Malignant Lymphoma 
MRD
minimal residual disease
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NHL
non-Hodgkin’s lymphoma
NK
natural killer
NSCLC
nonsmall cell lung cancer


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Abbreviation
Definition
ORR
overall response rate
OS
overall survival
PD-1
programmed death1
PD-L1
programmed deathligand 1
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
R-CHOP
rituximab plus CHOP
RANKL
receptor activator of nuclear factor kappa-B ligand
RCC
renal cell carcinoma
RCR
Roche Clinical Repository
RP2D
recommended Phase II dose
SCT
stem-cell transplantation
SPM
second primary malignancy
T4
thyroxine
TE
thromboembolism
Teff
T cell
TFH
follicular helper T cell
TFR
tumor flare reaction
TIL
tumor-infiltrating lymphocyte
TLS
tumor lysis syndrome
TSH
thyroid-stimulating hormone
UC
urothelial carcinoma
ULN
upper limit of normal
UBC
urothelial bladder cancer


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1.
BACKGROUND
1.1
BACKGROUND ON FOLLICULAR LYMPHOMA
Indolent non-Hodgkin lymphoma (iNHL) refers to a heterogeneous group of malignant 
B-cell lymphomas and account for approximately one-third of all non-Hodgkin’s 
lymphomas (NHLs).  Follicular lymphoma (FL) 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  with the IgH locus and results in the overexpression of the 
anti-apoptotic protein, Bcl-2.
Despite currently available therapies, FL remains an incurable disease.  The addition of 
rituximab, an anti-CD20 monoclonal antibody, to commonly used induction 
chemotherapy (including cyclophosphamide, doxorubicin, vincristine, and prednisone
[CHOP]; cyclophosphamide, vincristine, and prednisone; fludarabine; or bendamustine 
[Dreyling et al. 2014; Zelenetz et al. 2014]) followed by rituximab maintenance therapy, 
leads to prolonged remission and improved patient outcomes.  Updated results from 
Study MO18264 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 (hazard ratio [HR]0.625; 
p0.0001; Salles et al. 2013).
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 by decreasing duration of response to 
subsequent lines of therapy.  Thus, new treatments are needed to improve the outcome 
for these patients.  Several Phase II studies documented the high potential of the 
rituximab plus lenalidomide combination, which was first tested in relapsed FL
(Tuscano et al. 2014; Leonard et al. 2012) and, more recently, as initial treatment for FL 
(Fowler et al. 2014; Martin et al. 2014).  The overall response rate (ORR) in previously 
untreated patients with FL was 98%, with 87% of the patients achieving complete and 
durable responses and 90% of patients becoming positron emission tomography 
(PET)-computed tomography (CT) negative and achieving a molecular remission 
(Fowler et al. 2014).  Based on these data, this regimen is currently being investigated in 
a randomized Phase III study in previously untreated patients with FL (RELEVANCE; 
ClinicalTrial.gov, number NCT01476787).
1.2
BACKGROUND ON OBINUTUZUMAB
Obinutuzumab (also known as GA101) is a novel glycoengineered type II anti-CD20 
antibody.  Compared with rituximab, obinutuzumab is characterized by more potent 
direct B-cell death induction and increased affinity for FcRIII receptors expressed on 
natural killer (NK) cells, macrophages, and monocytes, resulting in enhanced 
antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis 
(Beers et al. 2010; Mössner et al. 2010; Herter et al. 2014).  Together, these 


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characteristics confer obinutuzumab with enhanced immune effector functions and 
B-cell-depleting activity compared with rituximab.
Obinutuzumab is approved for use in combination with chlorambucil for the treatment of 
patients with previously untreated chronic lymphocytic leukemia (CLL).  Obinutuzumab 
is also approved for use in combination with bendamustine followed by obinutuzumab 
maintenance for the treatment of patients with FL who did not respond to or who 
progressed during or after treatment with rituximab or a rituximab-containing regimen.
1.2.1
Nonclinical Studies 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) and of malignant B cells from the blood of patients with CLL 
(Patz et al. 2011).  Nonclinical xenograft experiments performed with obinutuzumab as 
monotherapy and in combination with chemotherapy have consistently showed that 
obinutuzumab has promising anti-tumor activity (Mössner et al. 2010; Dalle et al. 2011) 
and have demonstrated the superiority of obinutuzumab over rituximab 
(Herting et al. 2014).
For more detailed nonclinical information on obinutuzumab, please refer to the current 
version of the Obinutuzumab Investigator’s Brochure.
1.2.2
Clinical Studies with Obinutuzumab
To date, clinical data from studies sponsored by F. Hoffmann-La Roche Ltd. 
(the Sponsor) on obinutuzumab are available from eight Phase I or II studies 
(Studies BO20999, BO21003, JO21900, BO21000, GAO4915g, GAO4779g, YP25623, 
and GAO4768g) and five Phase III studies (GAO4753g, BO21004/CLL11, MO28543, 
BO21223, and BO21005).  The available efficacy results from the NHL cohorts in these 
studies and available safety and pharmacokinetic (PK) results from all patients are 
summarized in Sections 1.2.2.1 and 1.2.2.3.
For more detailed clinical information on obinutuzumab, including results in the CLL 
cohorts of the clinical studies and exposure data, please refer to the Obinutuzumab 
Investigator’s Brochure.
1.2.2.1
Summary of Clinical Efficacy of Obinutuzumab in Patients 
with NHL
In studies of obinutuzumab monotherapy in patients with relapsed or refractory NHL 
(Studies BO20999, BO21003, YP25623, and JO21900), the proportion of patients who
had a response (complete response [CR] or partial response [PR]) at the end of 
treatment (as determined on the basis of CT scans alone) ranged from 28% to 58%.  
The CR rate ranged from 0% to 19%. 


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In early studies of obinutuzumab in combination with chemotherapy (e.g., CHOP and 
bendamustine) in patients with previously untreated or relapsed or refractory NHL 
(Studies BO21000, GAO4915g, and GAO4753g), the proportion of patients with a CR or 
PR at the end of induction (EOI) treatment ranged from 69% to 96%.  The CR rate was 
higher with combination therapy (35%39% in patients with previously untreated FL, 
39%50% in patients with relapsed or refractory FL, and 55% in patients with previously 
untreated diffuse large B-cell lymphoma [DLBCL]) than with monotherapy. 
A Phase III study, Study BO21223, investigated obinutuzumab (G)chemotherapy 
(obinutuzumab plus bendamustine and obinutuzumab plus CHOP [G-CHOP]) compared 
with rituximabchemotherapy in patients with previously untreated iNHL (FL cohort, 
n1202).  On the basis of positive results from a pre-planned interim analysis of this 
study, demonstrating significant improvement in PFS in the G-chemotherapy arm, the 
Independent Data Monitoring Committee recommended that the study be unblinded to 
the Sponsor.  
A Phase III study, Study BO21005, investigated G-CHOP compared with 
rituximabCHOP in patients with previously untreated DLBCL. The study did not meet 
its primary endpoint of PFS at final analysis.
1.2.2.2
Summary of Clinical Safety of Obinutuzumab
As of 30 April 2016, an estimated 4454 patients with NHL (including DLBCL, iNHL, and
CLL) have been treated with obinutuzumab given as monotherapy or in combination with 
CHOP, bendamustine, fludarabine plus cyclophosphamide, or chlorambucil, at doses 
ranging from 50 to 2000 mg.  Overall, the safety of obinutuzumab monotherapy and 
obinutuzumab combination therapy was manageable.
The most frequent causes of death 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 
ongoing trials.  In Study GAO4768g (obinutuzumab 1000 vs. 2000 mg), the incidence of 
deaths did not increase with increased obinutuzumab dose (7.5% vs. 2.6%, respectively).
Of particular interest, a high incidence of infusion-related reactions (IRRs) was observed 
consistently in all obinutuzumab trials.  The reported incidence of IRRs varied across 
studies. In the CLL population, the incidence ranged from 66% in patients with 
previously untreated CLL who received obinutuzumab plus chlorambucil 
(Study BO21004) to 100% in patients with relapsed or refractory CLL who received
obinutuzumab monotherapy (pooled data from the CLL cohorts in Studies BO21003 and 
BO20999).  Anaphylaxis has also been reported in patients treated with obinutuzumab.  
In the NHL population, the incidence of IRRs in studies of obinutuzumab monotherapy 
was 75.1% (pooled data from Study BO21003 and from high-dose NHL cohorts from 
Study BO20999).  In studies of obinutuzumab in combination with either CHOP 


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(Study GAO4915g) or bendamustine (Study BO21000), the incidence of IRRs, 
regardless the relationship with obinutuzumab, was 70%78%.
Other important risks associated or potentially associated with obinutuzumab are tumor 
lysis syndrome (TLS), thrombocytopenia (including acute thrombocytopenia),
neutropenia (including prolonged and late-onset neutropenia), prolonged B-cell depletion, 
infections (including progressive multifocal leukoencephalopathy and hepatitis B virus 
[HBV] reactivation), worsening of preexisting cardiac conditions, gastrointestinal (GI) 
perforation, impaired immunization response immunogenicity, and second malignancies.  
The important identified risks associated with obinutuzumab are presented in detail in 
Section 5.1.1 and in the Obinutuzumab Investigator’s Brochure. 
1.2.2.3
Clinical Pharmacokinetics of Obinutuzumab
On the basis of available PK data, a two-compartment PK model comprising both a 
linear clearance pathway and a non-linear time varying clearance pathway adequately 
described serum obinutuzumab concentration data.  The initial clearance of 
obinutuzumab was approximately 2.8 times higher than the steady-state clearance, 
consistent with a decrease in the time-varying clearance component, which was high at 
the start of treatment and declined with repeated cycles of obinutuzumab treatment.  
The time-varying clearance pathway is consistent with target-mediated drug disposition, 
such that at the start of treatment, when there is a large quantity of CD20-positive cells, 
this rapidly binds obinutuzumab.  Repeated dosing of obinutuzumab saturates the pool 
of CD20-positive cells, hence reducing this component in clearance.  The linear 
clearance pathway is consistent with catabolism of Ig G antibodies and is therefore 
independent of CD20-positive cells. Refer to the Obinutuzumab Investigator’s Brochure
for additional details.
1.3
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab is a humanized IgG1 monoclonal antibody that targets programmed
deathligand 1 (PD-L1) and inhibits its interaction with its receptors, programmed death 
1 (PD-1) and B7-1 (also known as CD80).  Both of these interactions are reported to 
provide inhibitory signals to T cells.  Therapeutic blockade of PD-L1 binding by 
atezolizumab is expected to enhance the magnitude and quality of the tumor-specific 
T-cell responses, resulting in improved anti-tumor activity.  Atezolizumab was 
engineered to impair its binding to Fc receptors, thus eliminating detectable Fc-effector 
function and associated antibody-mediated clearance of activated effector T cells (Teffs).
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer (NSCLC), small-cell lung cancer, and triple-negative breast cancer.
1.3.1
Nonclinical Studies with Atezolizumab
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in 
mice and cynomolgus monkeys to support intravenous (IV) administration and to aid in
projecting the appropriate starting dose in humans.  Given the similar binding of 


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atezolizumab for cynomolgus monkey and human PD-L1, the cynomolgus monkey was 
selected as the primary and relevant nonclinical model for understanding the safety, 
pharmacokinetics, and toxicokinetics of atezolizumab.  Overall, the nonclinical 
pharmacokinetics and toxicokinetics observed for atezolizumab supported entry into 
clinical studies, including providing adequate safety factors for the proposed Phase I 
starting doses.  The results of the toxicology program were consistent with the 
anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway.  
Improved immune responses and the potential to increase immune-associated 
inflammatory lesions were identified as possible safety risks in patients.
The combination of a surrogate anti-mouse PD-L1 antibody with an anti-mouse 
CD20-depleting antibody has been tested using a syngeneic A20 lymphoma model in 
immune-competent mice.  Results from this nonclinical study demonstrated superior 
tumor-growth inhibition and extended time to progression when compared with either 
agent alone.  Combination and single-agent treatments were well tolerated, with no 
significant loss of body weight in any group over the study’s duration.  Enhanced 
combination efficacy was also observed in a study using A20 cells transfected with 
human CD20 and green fluorescent protein (data available on request).  
Refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical studies.
1.3.2
Clinical Studies with Atezolizumab
Atezolizumab is currently being tested in multiple Phase I, II, and III studies, both as 
monotherapy and in combination with several anti-cancer therapies.  The majority of the 
safety and efficacy data summarized below are from Phase Ia study PCD4989g, a 
multicenter, first-in-human, open-label, dose-escalation trial evaluating the safety, 
tolerability, immunogenicity, pharmacokinetics, exploratory pharmacodynamics, and 
preliminary evidence of biologic activity of atezolizumab administered as a single agent 
by IV infusion every 3 weeks (Q3W) to patients with locally advanced or metastatic solid 
or hematologic malignancy.
1.3.2.1
Summary of Clinical Safety of Atezolizumab
The safety data for atezolizumab have been derived from Study PCD4989g, in which 
atezolizumab is being used as single-agent therapy in patients with locally advanced or 
metastatic solid tumors or hematologic malignancies.  As of the data cutoff date of 
15 December 2015, the clinical database contained preliminary safety data from 
629 patients who received atezolizumab at doses ranging from 0.01 to 20 mg/kg across 
multiple tumor types.  No dose-limiting toxicities (DLTs) have been observed at any dose 
level, and no maximum tolerated dose (MTD) has been established.  In Study GP28328, 
a Phase Ib multi-arm study, patients with solid tumors were treated with atezolizumab
1200 mg q3w or 840 mg every 2 weeks (Q2W) in combination with commonly used 
chemotherapies (i.e., FOLFOX [oxaliplatin, leucovorin, and 5-fluorouracil], carboplatin, 
paclitaxel, pemetrexed, nanoparticle albumin-bound paclitaxel) and/or bevacizumab 
(biologic agent) at standard doses. Preliminary data available for 144 patients show a 


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manageable safety profile without exacerbation of chemotherapy- or 
bevacizumab-associated adverse events.
Summary of Adverse Events
Adverse events were reported in 619 of the 629 (98.4%) safety-evaluable patients.  
Adverse events occurring in 10% of treated patients included fatigue, decreased 
appetite, nausea, pyrexia, constipation, cough, dyspnea, diarrhea, anemia, vomiting, 
asthenia, back pain, headache, arthralgia, pruritus, rash, abdominal pain, insomnia, 
peripheral edema, urinary tract infection, dizziness, and chills.  Grade 3 adverse 
events were reported in approximately 50.2% of patients.
Treatment-related adverse events (per investigator’s assessment of causality) were 
reported in 444 of 629 (70.6%) patients.  Related Grade 34 events were reported in 
13.7% of patients, with fatigue and asthenia (1.3% each), AST increased and dyspnea 
(1.1% each), and hyponatremia (0.8%) as the most frequently occurring (0.8% or 
5 patients). 
Serious adverse events have been reported in 261 of 629 (41.5%) patients in 
Study PCD4989g.  Reported serious adverse events were consistent with the underlying 
disease.  Treatment-related serious adverse events were reported in 9.1% patients.
Atezolizumab-related serious adverse events occurring in 2 patients (0.3%) were 
pyrexia (2.1%), dyspnea (0.8%), pneumonitis (0.6%), fatigue, malaise, hypoxia, and 
colitis (0.5%), and bone pain (0.3%).
Ten patients (1.6%) had Grade 5 events.  The 3 events assessed by the investigator as 
related to atezolizumab were death (not otherwise specified), hepatic failure, and 
pulmonary hypertension.  Additional details for each case are provided in the 
Atezolizumab Investigator’s Brochure.
Immune-Mediated Adverse Events
Given the mechanism of action of atezolizumab, events associated with inflammation or 
immune-mediated adverse events have been closely monitored during the atezolizumab 
clinical program.  To date immune-mediated adverse events associated with 
atezolizumab include hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré syndrome, 
myasthenic syndrome/myasthenia gravis, meningoencephalitis, myocarditis, 
hypophysitis, nephritis, and myositis.
Guidelines for the management of potential immune-mediated adverse events are
described in Section 5.1.5.
Refer to the Atezolizumab Investigator’s Brochure for details on adverse events 
observed in patients treated with atezolizumab. 


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Clinical Pharmacokinetics of Atezolizumab
On the basis of available preliminary PK data (0.0320 mg/kg), atezolizumab showed
linear pharmacokinetics at doses 1 mg/kg. Serum atezolizumab concentrations 
exhibited a biphasic disposition with an initial rapid distribution phase followed by a slow 
elimination phase.  For the 1- and 20-mg/kg dose groups, the mean apparent clearance 
and the mean volume of distribution at steady state had a range of 3.503.55 mL/day/kg 
and 48.1 to 65.7 mL/kg, respectively, which is consistent with the expected PK profile of 
an IgG1 antibody in humans.  Atezolizumab exhibited non-linear pharmacokinetics at 
doses of 1 mg/kg (i.e., 0.03−0.3 mg/kg), which is likely due to target-mediated 
clearance at lower concentrations.  Refer to the Atezolizumab Investigator’s Brochure for 
additional details. 
1.3.2.3
Summary of Clinical Activity of Atezolizumab
Patients with multiple tumor types were included in Study PCD4989g, with the largest 
cohorts consisting of patients with NSCLC, renal cell carcinoma (RCC), and urothelial 
bladder cancer (UBC).  Clinical activity of atezolizumab monotherapy was observed in a 
broad range of malignancies, including NSCLC, RCC, melanoma, bladder cancer, 
colorectal cancer, head and neck cancer, gastric cancer, breast cancer, and sarcoma.  
Analyses of response by PD-L1 expression status in tumor-infiltrating immune cells (ICs) 
and tumor cells in baseline tumor tissue were also conducted. 
Efficacy results, based on a data cutoff of 15 December 2015, are summarized below for 
the NSCLC, RCC, and UBC cohorts.  See the Atezolizumab Investigator’s Brochure for 
clinical activity in combination studies, and additional details.  
Patients with NonSmall Cell Lung Cancer
Objective responses were reported in 20 of 88 (22.7%) efficacy-evaluable patients with 
locally advanced or metastatic NSCLC; responses were seen in squamous and 
non-squamous histologies (4 of 21 and 16 of 67, respectively).  Higher response rates 
were associated with higher PD-L1 expression (50.0% in TC3 or IC3 versus 33.3% in 
TC2/3 or IC2/3 versus 22.7% in all patients).
Patients with Urothelial Bladder Cancer
Objective responses were reported in 24 of 94 (25.5%) efficacy-evaluable patients with 
locally advanced or metastatic UBC.  Responses were observed in all PD-L1 subgroups, 
with higher response rates associated with higher PD-L1 expression in ICs (ORRs 
ranged from 20.8% in patients with IC0/1 to 31.8% in patients with IC2/3).  Median PFS 
and 1-year PFS also appeared to be associated with PD-L1 IC status.
Patients with Renal Cell Carcinoma
Objective responses were reported in 10 of 65 (15.4%) efficacy-evaluable patients with 
clear cell RCC.  Higher response rates were associated with higher PD-L1 expression, 
ranging from 9.1% in IC0 patients to 19.4% in patients with IC1, IC2, or IC3.  Duration of 
response also varied by IC score.  The small sample size limits further interpretation.


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Patients with Hematologic Malignancies
Eleven patients with refractory or relapsed hematologic malignancies have been treated 
with atezolizumab in Study PCD4989g.  This includes patients with multiple myeloma 
(n4), FL (n3), cutaneous T-cell lymphoma (n2), DLBCL (n1), and Hodgkin’s 
lymphoma (n1).  Among the 10 patients who were evaluable for response, the best 
response was PR for the 2 patients with cutaneous T-cell lymphoma; stable disease for 
the 3 patients with FL, the 1 patient with Hodgkin’s lymphoma, and 2 patients with 
multiple myeloma; and progressive disease for the remaining 2 patients with 
multiple myeloma.
Please refer to the Atezolizumab Investigator’s Brochure for details on clinical activity in 
patients treated to date.
1.4
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
Despite significant therapeutic progress with the addition of rituximab to chemotherapy 
for first-line treatment of patients with B-cell NHL, FL remains an area of high medical 
need (see Section 1.1).  Patients ultimately relapse, and subsequent active and 
well-tolerated therapies are needed.  Emerging evidence of the activity of new drugs that 
target the cell surface (e.g., monoclonal antibodies), microenvironment 
(immunomodulatory drugs such as lenalidomide), and checkpoint inhibitors that target 
the PD-1/PD-L1 axis opens the way to chemotherapy-free approaches as a new 
treatment paradigm.  This study will evaluate the activity of a novel triplet combination of 
obinutuzumab, atezolizumab, and lenalidomide.
1.4.1
PD-L1/PD-1 Pathway in Lymphoma
The PD-L1/PD-1 pathway serves as an immune checkpoint to temporarily dampen 
immune responses in states of chronic antigen stimulation, such as chronic infection or 
cancer.  PD-L1 is an extracellular protein that downregulates immune responses through 
binding to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on 
T cells following T-cell activation, and expression is sustained in states of chronic 
stimulation (Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on 
antigen-presenting cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 
inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, 
leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007).  
Overexpression of PD-L1 on tumor cells has been reported to impede anti-tumor 
immunity, resulting in immune evasion (Blank and Mackensen 2005).  Therefore, 
interruption of the PD-L1/PD-1 pathway represents an attractive strategy for restoring 
tumor-specific T-cell immunity.
Antibody-mediated PD-1 blockade has already been successfully exploited as a 
therapeutic strategy in solid tumors (Brahmer et al. 2012; Topalian et al. 2012; 
Herbst et al. 2013) and is currently being evaluated in hematologic malignancies 
(see Section 1.4.2).  Increased PD-L1 expression has been reported on tumor cells and 


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on immune or microenvironment cells in various lymphoid malignancies.  In FL, PD-L1 is 
expressed on tumor-infiltrating lymphocytes (TILs), macrophages, peripheral blood 
T cells, and monocytes but not on tumor cells (Myklebust et al. 2013).
1.4.2
Clinical Experience with PD-L1/PD-1 Pathway Inhibitors 
in Lymphoma
Several PD-1 and PD-L1 inhibitors are currently being investigated in various lymphoma
malignancies.
Pidilizumab (CT-011), a humanized IgG-1monoclonal antibody that targets PD-1, has 
been tested in Phase I and II clinical trials in hematologic malignancies.  Pidilizumab 
administered as a single agent after autologous stem cell transplantation (SCT) in 
patients with DLBCL (Armand et al. 2013) or in combination with rituximab in patients 
with relapsed FL (Westin et al. 2014) was well tolerated and showed potential clinical 
benefit.  No autoimmune- or treatment-related Grade 3 or 4 adverse events have been 
reported in these studies.  Among patients with relapsed FL who received pidilizumab in 
combination with rituximab (n32), responders have been shown to express higher 
levels of PD-L1 on peripheral blood T cells and monocytes at baseline relative to 
non-responders.  Additionally, in this study, gene expression profile (GEP) analysis 
performed on baseline tumor biopsy specimens from 18 patients showed a correlation 
between PFS and gene expression signature of activated T cells.  GEP studies identified 
41 genes more highly expressed in Teffs compared with follicular helper T cells (TFHs).  
Low expression of this signature suggests a higher number of TFHs and lower number 
of Teffs within the tumor.  Consistent with the expectation that Teffs are likely to have 
anti-tumor effects, whereas TFHs are likely to have pro-tumor effects, a low expression 
of this signature is predictive of less tumor shrinkage and resulted in a shorter PFS in 
this study. Median PFS was 12.7 months (95% CI: 6.5, 21.6) for patients with low 
signature expression; median PFS was not reached for patients with high signature 
expression (Westin et al. 2014). 
Nivolumab (BMS-936558), a fully human IgG4 monoclonal antibody that targets PD-1, 
was recently evaluated in a Phase I dose-escalation study that tested doses of 1 and 
3 mg/kg in patients with relapsed or refractory lymphoid malignancies.  Preliminary data 
indicate that 1 patient experienced DLTs of Grade 3 pneumonia and pneumonitis at the 
1-mg/kg dose, and 1 patient experienced DLTs of Grade 3 eosinophilia and diplopia 
at the 3-mg/kg dose (expansion is in progress at this dose; Lesokhin et al. 2014).  
The ORR and CR rate in patients with B-cell NHL were 28% and 7%, respectively, 
including an ORR of 36% in patients with DLBCL and 40% in patients with FL 
(Armand et al. 2014; Lesokhin et al. 2014).
Atezolizumab, a first-in-class PD-L1 inhibitor being tested in multiple tumor types 
(which will be included in the regimen administered in the current study), has also shown 
activity in lymphoma (see Section 1.3.2 for a summary of results).  


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1.4.3
Rationale for Treatment Combination
1.4.3.1
Nonclinical Data
Obinutuzumab and Atezolizumab
As presented in Section 1.2.1, nonclinical xenograft experiments consistently 
demonstrated superiority of obinutuzumab over rituximab.
Obinutuzumab and atezolizumab have complementary mechanisms of action, acting at 
different steps of the anti-tumor immune response.  Obinutuzumab induces direct 
tumor-cell killing with subsequent release of tumor antigens for immune presentation 
(immunogenic cell death).  Additionally, obinutuzumab was engineered to augment 
antibody-dependent cellular cytotoxicity, resulting in enhanced binding to FcRIIIA/B 
(CD16a/b).  Thus, obinutuzumab has the ability to enhance T-cell priming and 
immune-cell activation through interactions with NK cells, T cells, 
monocytes/macrophages, dendritic cells, and neutrophils cells carrying FcRIIIA or 
FcRIIIB.  Atezolizumab affects primarily the effector phase of the immune response by 
restoring cytotoxic T-cell function.  
Studies of obinutuzumab plus atezolizumab have not been performed in nonclinical 
murine models because there are no suitable models for testing the combination.  
However, synergism was exhibited when the combination of a surrogate anti-mouse 
PD-L1 antibody, and an anti-mouse CD20-depleting antibody was tested using a 
syngeneic A20 lymphoma model in immune-competent mice (see Section 1.3.1).  
Although the anti-CD20 agent used in this study is not completely identical to 
obinutuzumab, the results provide compelling proof of concept for exploring this 
combination in clinical trials.
Lenalidomide
Lenalidomide, a thalidomide analogue, is a potent immunomodulatory agent with activity 
in lymphoid malignancies occurring primarily through immune modulation and direct 
anti-tumor effects.  Currently, lenalidomide is approved for the treatment of multiple 
myeloma, deletion 5q myelodysplastic syndromes, and mantle cell lymphoma.
Nonclinical studies demonstrated that T-cell immune synapse dysfunction in FL can be 
restored with lenalidomide (Ramsay et al. 2009).  In addition, lenalidomide has been 
shown to reduce T regulatory cells and activate CD8 T cells (Kater et al. 2014).  
E3 ligase protein cereblon (encoded by the CRBN gene) is the molecular target of 
lenalidomide.  Lenalidomide binding to CRBN mediated its direct anti-tumor effects and 
is also required for T-cell production of interleukin-2 (IL-2) and tumor necrosis factor 
(Lopez-Girona et al. 2012).
In nonclinical studies, lenalidomide combined with rituximab resulted in anti-tumor 
effects via increased NK cell function, enhanced antibody-dependent cell-mediated 
cytotoxicity, and improved NK cellmediated synapse formation (Wu et al. 2008; 
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The combination of obinutuzumab with lenalidomide has been evaluated in nonclinical 
studies using the mantle cell lymphoma Z138 xenograft model in severe combined 
immunodeficient-beige mice.  Results from these studies demonstrated greater 
anti-tumor efficacy than either drug as a single agent and superior activity to the 
combination of lenalidomide with rituximab (data available on request [RDR 1064289]).
1.4.3.2
Available Clinical Data
BO29562 is the only study currently evaluating the combination of atezolizumab, 
obinutuzumab, and lenalidomide in lymphoma. 
A Phase Ib study of atezolizumab in combination with obinutuzumab in patients with 
relapsed or refractory FL and DLBCL (Study GO29383) is currently in progress,
sponsored by Roche.  Preliminary results indicated that atezolizumab combined with 
obinutuzumab is well tolerated with evidence of clinical activity in this patient population 
(Palomba et al. 2016).   A total of 49 patients were enrolled and dosed: 26 with FL and 
23 with DLBCL. The doublet combination appears to be safe and tolerable, and is 
consistent with what has been observed with the respective single agents and the 
diseases under study.  As of the 14 June 2017 data cutoff, a review of safety data in 
GO29383 in FL (n=26) and DLBCL (n=23) did not reveal any new safety signals. 
The most commonly reported (>20%) treatment-emergent adverse events included the 
preferred terms (PTs): fatigue, pyrexia, nausea, diarrhea, abdominal pain, cough, and 
decreased appetite.  The most common Grade 34 treatment-related adverse events 
were neutropenia (8%), diarrhea (8%), and pain (8%).  There were no adverse events 
with fatal outcomes reported in FL. Atezolizumab + obinutuzumab demonstrated 
encouraging signs of response in heavily pretreated and refractory patients with 
relapsed/refractory FL. The ORR at the end of induction assessment (Lugano 2014 
Response Criteria by PET-CT) was 56.5%, with a CR rate of 26.1%. The median 
duration of response and median PFS at time of clinical cutoff were 15.0 and 
15.1 months, respectively. Although preliminary, these data may support the hypothesis 
that the addition of obinutuzumab to atezolizumab has the potential to reduce the 
incidence of autoimmune side effects observed with atezolizumab monotherapy by 
depleting B cells.
Clinical activity of lenalidomide has been demonstrated in the treatment of both relapsed 
or refractory indolent and aggressive NHL as a single agent (Wiernik et al. 2008;
Witzig et al. 2011) and in combination with rituximab (see Section 1.1).
Obinutuzumab in combination with lenalidomide is currently being evaluated in an 
ongoing Phase Ib/II study sponsored by the Lymphoma Academic Research 
Organisation (Study MO28005 [GALEN]) in patients with relapsed or refractory FL and 
aggressive lymphoma (DLBCL and mantle cell lymphoma), and supported by Roche in 
the form of an investigator-initiated study model.  The recommended dose of 
lenalidomide was established at 20 mg/day on the basis of an increased incidence of 
Grade 3 or 4 neutropenia between Cycles 2 and 6 at the next higher dose of 25 mg/day 


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(Morschhauser et al. 2014).  The most common (occurring in 20% patients) adverse 
events observed during the dose escalation phase (all grades) in the 19 patients were 
neutropenia and constipation (10; 53% each), asthenia and upper respiratory tract 
infection (7; 37% each), rash/cutaneous eruption and cough (5; 26% each), and diarrhea 
and fever (4; 21% each). The only Grade 3 or 4 adverse event that occurred in 2 or 
more patients was neutropenia (8/19; 42%). IRRs occurred in 3 patients and did not 
exceed Grade 2.  Preliminary efficacy data available from the dose-escalation phase of 
the study are encouraging, with an overall response according to Cheson 1999 criteria of 
68% (13 of 19 evaluable patients), including 7 patients with a CR; 3 patients with a CR, 
unconfirmed; and 3 patients with a PR (Morschhauser et al. 2014). 
The Phase II portion of the GALEN study is currently ongoing. Data for the 89 patients 
enrolled in the relapsed/refractory FL cohort (cutoff date: 22 November 2016) were 
presented at the 14th ICML conference (Morschhauser et al. 2017). The expansion 
phase at 20 mg/day of lenalidomide for the first-line FL cohort is currently in progress. 
Eighty-eight patients with relapsed/refractory FL were evaluable for safety and 86 for 
efficacy. With a median follow-up of 18.1 months, 75 patients (87.2%) completed 
induction and 67 (78%) entered maintenance. The median induction treatment duration 
was 5.3 months (0.26.7), with a median number of cycles received of 5.4 (16). 
The median dose intensity for both drugs was >98% during induction. 
Preliminary results from the GALEN study suggest that the addition of lenalidomide to 
obinutuzumab represents an effective and safe combination in patients with relapsed or 
refractory FL. The overall response according to Cheson 2007 criteria was 74% 
(CR/CRu rate of 44%) and the 1-year PFS rate was 75.5% (95% CI: 64.2-83.7). 
The most common adverse events (>20% of patients) during induction (all grades) were 
gastrointestinal disorders (76%), infections (63%), asthenia (52%), neutropenia (31%), 
muscle spasms (30%), and cough (21%). The most common Grade 3/4 adverse events
were infections (7%) and neutropenia (28%). Febrile neutropenia occurred in 3.4% of 
patients. Six second primary malignancies were reported in 3 patients (5 basal 
carcinoma and 1 myelodysplastic syndrome), and there were 3 fatal adverse events
reported (3.4%): febrile neutropenia, pneumonia, and atypical pneumonia.
Currently available data continue to provide a strong rationale for an improved 
benefitrisk ratio with the addition of atezolizumab to the combination of obinutuzumab 
and lenalidomide in patients with FL.  Strengthening the immunotherapy component of 
the combination is expected to result in deeper and long-lasting anti-tumor responses.  
Additionally, overlapping toxicities are expected to be manageable in the clinical setting 
and drugdrug interactions (DDIs) are unlikely to occur (see Section 5.1.4).


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2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the safety, efficacy, pharmacokinetics, and immunogenicity of 
induction treatment consisting of atezolizumab in combination with obinutuzumab plus 
lenalidomide (AtezoGLen) in patients with relapsed or refractory FL, followed by 
maintenance treatment with AtezoGLen in patients who achieve a CR, a PR, or 
stable disease at EOI (see Section 3.1 for details).  Specific objectives and 
corresponding endpoints for the study are outlined below.  
In this study, “study treatment” refers to the combination of all study treatment 
components.
2.1
SAFETY OBJECTIVES
The safety objectives for this study are as follows:

To determine the recommended Phase II dose (RP2D) for lenalidomide when given 
in combination with fixed doses of obinutuzumab and atezolizumab on the basis of 
the following endpoint:
Incidence of DLTs during Cycle 2 of study treatment

To evaluate the safety and tolerability of AtezoGLen on the basis of the following 
endpoints:
Nature, frequency, severity, and timing of adverse events 
Changes in vital signs, ECGs, and clinical laboratory results during and 
following study treatment administration
2.2
EFFICACY OBJECTIVES
Response will be determined through use of the PET-CT scans or CT scans alone,
using Revised Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014; 
see Appendix 3), hereinafter referred to as Lugano 2014 criteria.  Response will be 
determined by an Independent Review Committee (IRC) and by the investigator.
2.2.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of induction 
treatment with AtezoGLen on the basis of the following endpoint:

CR at EOI as determined by the IRC on the basis of PET-CT scans 
2.2.2
Secondary Efficacy Objectives
The secondary efficacy objective for this study is to evaluate the efficacy of induction 
and maintenance treatments with AtezoGLen on the basis of the following endpoints:

CR at EOI as determined by the investigator on the basis of PET-CT scans

CR at EOI as determined by the IRC and by the investigator on the basis of CT 
scans alone


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
Objective response (defined as a CR or PR) at EOI as determined by the IRC and 
by the investigator on the basis of PET-CT scans

Objective response (defined as a CR or PR) at EOI as determined by the IRC and 
by the investigator on the basis of CT scans alone

Best response of CR or PR during the study as determined by the investigator on 
the basis of CT scans alone
2.2.3
Exploratory Efficacy Objectives
The exploratory efficacy objective for this study is to evaluate the long-term efficacy of 
AtezoGLen on the basis of the following endpoints:

For patients who have positive PET scans at EOI:  CR at 12 months as determined 
by the IRC and by the investigator on the basis of PET-CT scans

PFS, defined as the time from initiation of study treatment to first occurrence of 
disease progression or relapse, as determined by the investigator on the basis of 
CT scans alone or death from any cause

Event-free survival (EFS), defined as the time from initiation of study treatment to 
any treatment failure, including disease progression or relapse, as determined by 
the investigator on the basis of CT scans alone; initiation of new anti-lymphoma 
therapy; or death from any cause, whichever occurs first

Disease-free survival (DFS), defined as the time from the first occurrence of a 
documented CR to relapse among patients achieving a CR, as determined by the 
investigator on the basis of CT scans alone or death from any cause, whichever 
occurs first

Duration of objective response (DOR), defined as the time from the first occurrence 
of a documented objective response to the time of disease progression or relapse, 
as determined by the investigator on the basis of CT scans alone or death from any 
cause, whichever occurs first.

Overall survival (OS), defined as the time from initiation of study treatment to death 
from any cause
2.3
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to characterize the pharmacokinetics of atezolizumab, 
obinutuzumab, and lenalidomide, when given in combination, on the basis of the 
following endpoints:

Observed serum obinutuzumab concentration at specified timepoints

Observed serum atezolizumab concentration at specified timepoints

Observed plasma lenalidomide concentration at specified timepoints


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2.4
IMMUNOGENICITY OBJECTIVES
The immunogenicity objective for this study is to evaluate the immune response to 
obinutuzumab and to atezolizumab on the basis of the following endpoints:

Incidence of human anti-human antibodies (HAHAs) to obinutuzumab during the 
study relative to the prevalence of HAHAs at baseline

Incidence of anti-therapeutic antibodies to atezolizumab during the study relative to 
the prevalence of anti-therapeutic antibodies at baseline
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
HAHAs or anti-therapeutic antibodies on the basis of the following endpoint:

Correlation between HAHA or anti-therapeutic antibody status and efficacy, safety, 
or PK endpoints
2.5
BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify non-inherited biomarkers 
that are predictive of response to study treatment (i.e., predictive biomarkers), are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), 
are associated with acquired resistance to study treatment, are associated with 
susceptibility to developing adverse events, can provide evidence of study treatment
activity, can increase the knowledge and understanding of lymphoma biology or study 
treatment mechanism of action, or can contribute to improvement of diagnostic assays, 
on the basis of the following endpoint:

Association between non-inherited biomarkers (listed in Section 4.5.7) and efficacy, 
safety, PK, or immunogenicity endpoints
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study
This Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study will 
evaluate the safety, efficacy, pharmacokinetics, and immunogenicity of AtezoGLen in 
patients with relapsed or refractory FL.  The study will include an initial dose-escalation 
phase designed to determine the RP2D for lenalidomide in this treatment combination 
(see Section 3.1.2) followed by an expansion phase in which lenalidomide will be given 
at the RP2D (see Section 3.1.3).  All patients will receive induction treatment with 
AtezoGLen for six cycles.  Patients achieving a CR, a PR, or stable disease at EOI 
will be eligible to receive extended dosing of AtezoGLen as maintenance treatment 
(refer to Sections 3.1.2.2 and 3.1.3 for details on treatment regimens).  A study schema 
is provided in Figure 1.
Overall, it is planned to have approximately 46 patients enrolled in this study at
approximately 15 investigative sites around the world, mainly in Europe and 
North America. 


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All patients will be closely monitored for adverse events throughout the study and for at 
least 35 days after the last dose of study treatment (see Section 5.3.1).  Adverse events 
will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) v4.0.  An Internal Monitoring Committee (IMC) will be 
established to monitor patient safety throughout the study (see Section 3.1.4).
To characterize the PK properties of obinutuzumab, atezolizumab, and lenalidomide as 
well as the immunogenicity of obinutuzumab and atezolizumab when given in 
combination, blood samples will be taken at various timepoints before and during dosing 
(see Appendix 2).
Response will be determined by the IRC (see Section 3.1.5) and the investigator using 
the Lugano 2014 criteria (see Appendix 3).  The primary efficacy endpoint will be based 
on IRC assessment of response.  Refer to Section 4.5.5 for details on tumor 
assessments.
During induction treatment, all patients will have a CT scan performed at the end of 
Cycle 2 to confirm absence of early disease progression.  Because of the potential for 
tumor flares with immunotherapies, which result in early apparent radiographic 
progression (pseudoprogression/tumor immune infiltration), including the appearance of 
new lesions followed by delayed response (Wolchok et al. 2009), patients whose CT 
scans meet criteria for disease progression may continue to receive study treatment at 
the discretion of the investigator and following discussion with the Medical Monitor if a 
moderate increase is seen in one lesion only or if at least two of the following criteria are 
met:

Absence of symptoms and signs, including worsening of laboratory values 
(e.g., increased LDH) that indicate unequivocal disease progression

No decline in Eastern Cooperative Oncology Group (ECOG) Performance Status

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions
Patients with radiographic evidence of progression at the end of Cycle 2 who continue to 
receive study treatment per the above criteria should have a CT scan repeated 
48 weeks later.
3.1.2
Dose-Escalation Phase
The purpose of the dose-escalation phase is to identify the RP2D for lenalidomide when 
combined with fixed doses of obinutuzumab and atezolizumab as induction treatment
(see Section 3.3.1).
Approximately 612 patients will be enrolled in the dose-escalation phase.  Dosing 
groups of 36 patients each will be treated in accordance with the treatment regimens 
and the dose-escalation rules described in Section 3.1.2.2.


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Patients will be closely monitored for adverse events during a DLT assessment window, 
defined as Cycle 2.  Adverse events meeting the criteria for DLT, as defined below 
(see Section 3.1.2.1), will be reported to the Sponsor within 24 hours (see Section 5.4.2).
Patients who discontinue from the study prior to completing the DLT assessment window 
for reasons other than a DLT will be considered non-evaluable for dose-escalation 
decisions and for RP2D assessments and will be replaced by an additional patient at 
that same dose level.  Patients who miss one or more doses of atezolizumab or 
obinutuzumab or five consecutive daily doses of lenalidomide during the DLT 
assessment window for reasons other than a DLT will also be replaced.
3.1.2.1
Definition of Dose-Limiting Toxicity
In this study, a DLT is defined as any one of the following events occurring during 
Cycle 2 of treatment and assessed by the investigator as related to study treatment:

Adverse event of any grade that leads to a delay of more than 14 days at the start of 
the next treatment cycle 

Hematologic adverse event that meets any of the following criteria:
Grade 3 or 4 neutropenia in the presence of sustained fever of 38C 
(lasting 5 days) or a documented infection 
Grade 4 neutropenia lasting 7 days
Grade 3 or 4 thrombocytopenia that results in significant bleeding per 
investigator judgment
Grade 4 thrombocytopenia lasting 7 days

Grade 3 or 4 non-hematologic adverse event, with the following exceptions:
Grade 3 or 4 IRRs
Note that IRRs may occur even after a small amount of drug has been 
administered (i.e., IRRs are not dose dependent).
Grade 3 diarrhea that responds to therapy within 72 hours
Grade 3 nausea or vomiting that occurs in the absence of premedication and 
responds to adequate therapy within 72 hours
Other toxicities occurring during Cycle 2 that are considered to be clinically relevant and 
related to study treatment, as determined by the investigator and the Medical Monitor, 
may also be considered DLTs.
3.1.2.2
Treatment Regimens and Dose-Escalation Rules
A 33 dose-escalation schema will be used.  Induction treatment will be administered in 
28-day cycles, as outlined in Table 1.  Obinutuzumab and atezolizumab will remain at 
fixed doses during the dose-escalation phase.  For induction treatment, the starting dose 
for lenalidomide is 15 mg, which is one dose level below 20 mg, the RP2D identified for 
lenalidomide when given in combination with obinutuzumab in a Phase Ib/II study 


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(MO28005 [GALEN]).  If the 15-mg dose is safe and tolerable, the lenalidomide dose will 
be escalated to 20 mg.  Intrapatient dose escalation is not allowed.
Table 1
Induction Treatment for Dose-Escalation Phase
Cycle(s)
Atezo G Len (28-Day Cycles)
1

Lenalidomide 15 or 20 mg a PO once daily on Days 121

Obinutuzumab 1000 mg IV on Days 1, 8, and 15
26

Lenalidomide 15 or 20 mg a PO once daily on Days 121

Obinutuzumab 1000 mg IV on Day 1

Atezolizumab 840 mg IV on Days 1 and 15
IVintravenous; POby mouth.
a Dose may be de-escalated to 10 mg.
Dose escalation will occur in accordance with the rules listed below.
First Dosing Group (15 mg of Lenalidomide)

A minimum of 3 patients will initially be enrolled in the first dosing group (15 mg of 
lenalidomide).  Patients within the dosing group may be treated in parallel.

If none of the first 3 DLT-evaluable patients experiences a DLT, enrollment of the 
second dosing group (i.e., 20 mg of lenalidomide) may proceed.

If 1 of the first 3 DLT-evaluable patients experiences a DLT, the dosing group will be 
expanded to at least 6 patients.  If there are no further DLTs in the first 
6 DLT-evaluable patients, enrollment of the second dosing group may proceed. 

If 2 or more of the first 3 DLT-evaluable patients experience a DLT, the RP2D will 
have been exceeded, and dose escalation will stop.  The Medical Monitor, in 
discussion with the Principal Investigator and participant investigators, may decide 
to proceed with dose de-escalation and enroll patients at 10 mg of lenalidomide, 
following the same 33 design.

If 2 or more of the first 6 DLT-evaluable patients experience a DLT, the RP2D will 
have been exceeded, and dose escalation will stop.  The Medical Monitor, in 
discussion with the Principal Investigator and participant investigators, may decide 
to proceed with dose de-escalation and enroll patients at 10 mg of lenalidomide, 
following the same 33 design.
Second Dosing Group (20 mg of lenalidomide)

A minimum of 3 patients will initially be enrolled in the second dosing group (20 mg
of lenalidomide).  Patients within the dosing group may be treated in parallel.

If none of the first 3 DLT-evaluable patients experiences a DLT, the dosing group 
will be expanded to 6 patients to confirm the dose of 20 mg as the RP2D for 
lenalidomide.


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
If 1 of the first 3 DLT-evaluable patients experiences a DLT, the dosing group will be
expanded to at least 6 patients.  If there are no further DLTs in the first 
6 DLT-evaluable patients, 20 mg will be declared the RP2D for lenalidomide.

If 2 or more of the first 3 DLT-evaluable patients experience a DLT, the RP2D will 
have been exceeded, and 15 mg will be declared the RP2D for lenalidomide.

If 2 or more of the first 6 DLT-evaluable patients experience a DLT, the RP2D will 
have been exceeded, and 15 mg will be declared the RP2D for lenalidomide.
The highest dose at which 33% of the DLT-evaluable patients (i.e., fewer than 2 of 
6 patients) experiences a DLT will be declared the RP2D for lenalidomide that will be 
used in the expansion phase.
On the basis of a review of real-time safety data and available preliminary PK data, dose 
escalation may be halted or modified by the Sponsor as deemed appropriate.
Relevant demographic, adverse event, laboratory, and PK (if available) data will be 
reviewed prior to dose-escalation decisions, by the Medical Monitor in consultation with 
the Principal Investigator and participant investigators.  
Although the DLT assessment window is defined as Cycle 2, cumulative toxicities 
occurring beyond Cycle 2 may be considered when determining the RP2D.
Patients who achieve a CR, a PR, or stable disease at EOI may receive maintenance 
treatment with AtezoGLen, as outlined in Table 3.  Maintenance treatment should 
start 8 weeks (1 week) after Day 1 of Cycle 6 and will continue until disease 
progression or unacceptable toxicity for up to 24 months.
3.1.3
Expansion Phase
The expansion phase is designed to further assess the safety and efficacy of the 
combination of atezolizumab with obinutuzumab plus lenalidomide when given as 
induction and maintenance treatment. 
Approximately 40 patients with FL will be enrolled during the expansion phase and 
treated as described below.  Patients who received lenalidomide at the RP2D during the 
dose-escalation phase will be pooled with patients treated in the expansion phase.  
All patients will receive induction treatment as outlined in Table 2.


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Table 2
Induction Treatment for Expansion Phase
Cycle(s)
Atezo G Len (28-Day Cycles)
1

Lenalidomide at RP2D PO once daily on Days 121

Obinutuzumab 1000 mg IV on Days 1, 8, and 15
26

Lenalidomide at RP2D PO once daily on Days 121

Obinutuzumab 1000 mg IV on Day 1

Atezolizumab 840 mg IV on Days 1 and 15
IVintravenous; PO by mouth; RP2Drecommended Phase II dose.
Patients who achieve a CR, a PR, or stable disease at EOI will receive maintenance 
treatment with AtezoGLen, as outlined in Table 3.  Maintenance treatment should 
start 8 weeks (1 week) after Day 1 of Cycle 6 and will continue until disease 
progression or unacceptable toxicity for up to 24 months. 
Table 3
Maintenance Treatment 
Patients with 
FL
Maintenance treatment consisting of the following, administered for 24 months
(from Months 124 a):

Lenalidomide 10 mg PO once daily on Days 121 of each month for a 
maximum of 12 months

Obinutuzumab 1000 mg IV on Day 1 of every other month (i.e., every 
2 months), starting with Month 1

Atezolizumab 840 mg IV on Days 1 and 2 of each month
FLfollicular lymphoma; IVintravenous; PO by mouth.
a
1 month28 days.
In the event that any one of the stopping rules criteria (refer to Section 6.11 for further 
details) occurs at any time in the expansion phase, enrollment of patients will be paused 
while an IMC is immediately convened to review and provide a recommendation on 
further conduct of the study (e.g., consider study discontinuation).
A schedule of assessments is provided in Appendix 1, and a study schema is provided 
in Figure 1.




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3.1.4
Internal Monitoring Committee 
An IMC will monitor patient safety throughout the study.  The IMC will include the 
Sponsor representatives from Clinical Science, Drug Safety, Biostatistics, and Statistical 
Programming and Analysis.  In addition to the ongoing assessment of the incidence and 
nature of adverse events (particularly, Grade 3 events), serious adverse events, deaths, 
and laboratory abnormalities performed by the investigator and the Medical Monitor, the 
IMC will review data supporting the determination of the RP2D and cumulative data at 
regular intervals, every 4 months for safety and efficacy, and ad-hoc if safety concerns 
arise between the planned regular 4-month intervals, during the expansion phase. 
Predefined stopping rules for excess toxicity, including fatal adverse events, have been 
included in Section 6.11. In the event that any of the stopping rules criteria are met at 
any time during the course of the study, enrollment of patients will be paused while an 
IMC meeting is immediately convened to review and provide a recommendation on 
further conduct of the study (e.g., consider study discontinuation).
At the time of each review, the IMC will make appropriate recommendations (e.g., the
study should continue as planned, additional analyses should be performed, enrollment 
should be held pending further safety evaluations).  
Decisions will be made in consideration of the totality of the available data.  Ad hoc 
meetings may be called in addition to scheduled meetings, as necessary, to provide 
recommendations on management of any potential new safety signals.  At the time when 
all patients have completed or discontinued the maintenance treatment, regular IMC
assessments will no longer take place.  Ad hoc meetings may be called at the discretion 
of the Medical Monitor in case of newly identified safety signals.   Specific operational 
details such as the committee’s composition, frequency and timing of meetings, 
members' roles and responsibilities, and data to be reviewed will be detailed in an 
IMC charter.
3.1.5
Independent Review Committee 
An IRC will assess all patients for response on the basis of imaging results and bone 
marrow biopsy results.  The IRC will consist of radiologists, nuclear medicine experts, 
and a board-certified oncologist with experience in malignant lymphoma.  Specific 
methodological and operational details will be specified in the IRC charter.
3.1.6
Post-Treatment Follow-Up and Survival Follow-Up
Patients who complete treatment or discontinue treatment for reasons other than 
disease progression will undergo assessments every 3 months during the post-treatment 
follow-up period, which will continue until disease progression, the start of new 
anti-lymphoma treatment, or the end of the study (as defined below), whichever occurs 
first.  Patients who experience disease progression will be evaluated for survival status 
and initiation of new anti-lymphoma treatment every 3 months until the end of the study.  
Details are provided in the schedule of assessments (see Appendix 1).


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3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the time when all enrolled patients have completed or 
discontinued study treatment (including induction treatment and maintenance treatment 
as applicable).
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.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Patient Population
As discussed in Section 1.1, despite significant therapeutic progress with the use of 
chemoimmunotherapy as first-line treatment, FL remains essentially an incurable 
disease.  Patients ultimately relapse, and subsequent active and well-tolerated agents 
are needed.  The combination of lenalidomide with rituximab has shown promising 
results in Phase II clinical trials in patients with relapsed or refractory FL, with an overall 
response and a CR of 74%75% and 32%44%, respectively (Leonard et al. 2012; 
Tuscano et al. 2014) and an mPFS of 16.2 months (Tuscano et al. 2014).
On the basis of the biologic and clinical rationale presented in Section 1.4, the addition 
of atezolizumab to obinutuzumab and lenalidomide is a promising approach to expand 
the number of patients with relapsed or refractory FL who achieve remission and to 
decrease the relapse rate in these patients.
3.3.2
Rationale for Dose and Schedule
3.3.2.1
Rationale for Atezolizumab Dose and Schedule
Atezolizumab will be administered at a flat dose consisting of one of the following:  
1) 840 mg Q2W (840 mg on Days 1 and 15 of Cycles 26, given in 28-day cycles with 
G-Len as induction treatment) or 2) 1680 mg every 4 weeks (Q4W) (840 mg on Days 1 
and 2 of each month, given with G-Len as maintenance treatment.  Both dosages are 
equivalent to an average body weightbased dose of 15 mg/kg Q3W.
The dosage of 15 mg/kg Q3W was selected as the RP2D of atezolizumab on the basis 
of both nonclinical studies and available clinical data from Study PCD4989g, as 
described below.
The target exposure for atezolizumab was projected on the basis of clinical and 
nonclinical parameters, including nonclinical tissue distribution data in tumor-bearing 
mice, target-receptor occupancy in the tumor, and observed atezolizumab interim 
pharmacokinetics in humans.  The target trough concentration (Ctrough) was projected to 
be 6 g/mL on the basis of several assumptions, including the following:  
1) 95% tumor-receptor saturation is needed for efficacy and 2) the tumor interstitial 
concentration-to-plasma ratio is 0.30 on the basis of tissue distribution data in 
tumor-bearing mice.


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In Study PCD4989g, the first-in-human study in patients with advanced solid tumors and 
hematologic malignancies, 30 patients were treated with atezolizumab at doses ranging 
from 0.01 to 20 mg/kg Q3W during the dose-escalation stage and 247 patients were 
treated with atezolizumab at doses of 10, 15, or 20 mg/kg Q3W during the 
dose-expansion stage.  Anti-tumor activity has been observed across all dose cohorts.  
There was no evidence of dose-dependent toxicity in this study.  The MTD of 
atezolizumab was not reached, and no DLTs were observed at any dose.  
Anti-therapeutic antibodies to atezolizumab were associated with changes in 
pharmacokinetics for some patients in the lower dose cohorts (0.3, 1, and 3 mg/kg), but 
patients treated at 10, 15, and 20 mg/kg maintained the expected target trough levels of 
drug despite the detection of anti-therapeutic antibodies.  To date, no relationship has 
been observed between the development of measurable anti-therapeutic antibodies and 
safety or efficacy.  After review of available PK and anti-therapeutic antibody data for a 
range of doses, 15 mg/kg Q3W was identified as the lowest atezolizumab dosing 
regimen that would maintain Ctrough at 6 g/mL while further safeguarding against 
interpatient variability and the potential effect of anti-therapeutic antibodies that could 
lead to subtherapeutic levels of atezolizumab.
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in 
exposure following a fixed dose compared with a body weightadjusted dose.  On the 
basis of this analysis, a fixed dose of 1200 mg Q3W (equivalent to a weight-based dose 
of 15 mg/kg Q3W) was defined as the RP2D.
For the Q2W dosing interval, the fixed dose of 840 mg Q2W is the equivalent of a 
weight-based dose of 15 mg/kg Q3W.  This dosing schedule is currently being evaluated 
in patients with advanced solid tumors in combination with chemotherapy or biologic 
agents (see Section 1.3.2.1).
For the Q4W dosing interval, the fixed dose of 1680 mg Q4W is the equivalent of a 
weight-based dose of 15 mg/kg Q3W.  Population PK modeling suggests that the area 
under the concentration-time curve (AUC) would be comparable to that of 1200 mg Q3W
(data available on request).  The current manufacturing process considers 1200 mg the 
maximum daily dose for clearance of manufacturing process-derived impurities (such as 
host-cell DNA and endotoxins) to safe levels.  The manufacturing processes for 
atezolizumab are capable of clearing such impurities to safe levels, and tests for 
impurities are performed as a part of the manufacturing processes. However, the total 
dose of 1680 mg will be split into two daily doses to minimize the theoretical risk of 
exceeding safe limits.
In Study PCD4989g, atezolizumab was safely administered to 11 patients with various 
hematologic malignancies (including 7 patients with lymphoma) at doses of 15 mg/kg 
Q3W (n1) or 20 mg/kg Q3W (n10).  Atezolizumab 1200 mg Q3W is currently being 
evaluated in combination with obinutuzumab in an ongoing Phase Ib study (GO29383) in 
patients with relapsed or refractory DLBCL or FL (see Section 1.4.3.2).  Atezolizumab is 


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added to obinutuzumab starting with Cycle 2 to avoid overlapping IRRs during the first 
infusion of obinutuzumab, which is known to be associated with the highest incidence 
and risk of severe IRRs.  The combination has been safely administered in the first 
6 patients who were evaluable for DLTs.  Consistent with the dosing schedule used in 
Study GO29383, in this study, atezolizumab will be added to G-Len starting with Cycle 2.
3.3.2.2
Rationale for Obinutuzumab and Lenalidomide Dose 
and Schedule
Obinutuzumab in combination with lenalidomide is currently being evaluated in an 
ongoing Phase Ib/II study (MO28005 [GALEN]) in patients with relapsed or refractory FL 
and aggressive lymphoma (DLBCL and mantle cell).  A total of 20 patients with relapsed 
or refractory FL have been enrolled in the dose-escalation phase of the study and have 
received escalating doses of oral lenalidomide ranging from 10 to 25 mg/day on 
Days 121 of a 28-day cycle in combination with obinutuzumab at a fixed dose of 
1000 mg on Days 8, 15, and 22 of Cycle 1 and on Day 1 of Cycles 26.  The RP2D of 
lenalidomide was established as 20 mg/day on the basis of an increased incidence of 
Grade 3 or 4 neutropenia between Cycles 2 and 6 at the next higher dose of 25 mg/day 
(Morschhauser et al. 2014).  The enrollment in the expansion phase at 20 mg/day is in 
progress.  As of 30 September 2014, 45 patients were evaluable for safety during 
induction treatment (Cycles 16).  Preliminary data demonstrate a manageable safety 
profile (see Section 1.4.3.2).  In this study, the starting dose for lenalidomide during 
induction treatment is 15 mg/day on Days 121 of a 28-day cycle, which is one dose 
level below the RP2D of 20 mg/dose defined in Study MO28005 (GALEN).
During maintenance treatment, the lenalidomide dose will be 10 mg/day on Days 1–21, 
every month for 12 months.  The use of lenalidomide at this dosing regimen in the 
maintenance setting in lymphoma is currently being evaluated in ongoing Phase Ib/II and 
Phase III studies in patients with FL, both as a single agent (e.g., RELEVANCE 
ClinicalTrial.gov, number NCT01476787) and in combination with obinutuzumab 
(Study MO28005 [GALEN]).  The proposed dosing regimen for lenalidomide as 
maintenance treatment is also supported by the available clinical data from randomized 
studies in multiple myeloma that evaluate lenalidomide maintenance in patients following 
stem-cell transplantation (Attal et al. 2013; McCarthy et al. 2012) and in patients 
ineligible for transplantation (Palumbo et al. 2012).  Results from these studies 
demonstrate a favorable benefit-risk profile of lenalidomide 10-mg maintenance therapy, 
allowing for continuous long-term treatment in this setting.
3.3.2.3
Rationale for Treatment Duration
In this study, patients with relapsed or refractory FL will receive six cycles of induction 
treatment followed by extended dosing with AtezoGLen as maintenance treatment in 
patients who achieve a CR, a PR, or have stable disease at the EOI. 
Despite recent improvements in therapy for FL, including demonstrated benefit from 
2-year rituximab maintenance in patients responding to first-line immunochemotherapy 


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(Study MO18264), FL is still not considered curable, with a 6-year PFS of 59.2% 
(Salles et al. 2013).  A Phase III study, GAO4753g, investigated obinutuzumab plus
bendamustine (GB) compared with bendamustine alone in patients with 
rituximab-refractory iNHL (n396).  Patients in the GB group who had not experienced 
disease progression at the EOI received obinutuzumab monotherapy every 2 months for 
up to 2 years.  On the basis of positive results from this study, demonstrating significant 
improvement in PFS in the GB arm, with a median PFS of 29 versus 14 months
(HR: 0.52; 95% CI: 0.39, 0.70; p0.0001) (Sehn et al. 2015), the Independent Data
Monitoring Committee recommended that the study be unblinded to the Sponsor.  These 
data support further investigation of obinutuzumab in combination with new targeted 
drugs in the setting of induction and maintenance treatment for patients with FL.
The objective of maintenance treatment is to improve the response to induction therapy, 
either by improving the quality of clinical response (e.g., converting a PR to a CR) or by 
eradicating minimal residual disease (MRD) to achieve a molecular response, thus 
reducing the relapse risk.  In this study, MRD levels will be measured during the 
maintenance period as an additional means of evaluating the benefits of the triple 
combination as a maintenance treatment.  On the basis of the nonclinical rationale 
(presented in Section 1.4.3.1), it is hypothesized that the addition of atezolizumab and 
lenalidomide to obinutuzumab may enhance and prolong the anti-tumor immune 
response and provide significant clinical benefit to patients.  
In the ongoing Phase Ib/II Study MO28005 (GALEN), evaluating the combination of 
obinutuzumab and lenalidomide in patients with relapsed or refractory FL, maintenance 
treatment consists of obinutuzumab administered every 2 months for 2 years and 
lenalidomide administered on Days 121 of each 28-day cycle for 1 year.  Building upon 
this basis, the same obinutuzumab and lenalidomide dosing schedule will be employed 
in this study.  Nonclinical data demonstrating synergism between obinutuzumab and 
atezolizumab, associated with a low risk of overlapping toxicities, provide the rationale 
for administering atezolizumab as maintenance treatment on a monthly basis for the 
same period of 2 years.
3.3.3
Rationale for PET-CT–Based Complete Response as the 
Primary Efficacy Endpoint
In DLBCL, the prognostic value of the post-treatment fluorodeoxyglucose (FDG) PET-CT 
scan has been well documented (Thomas et al. 2010; Vitolo et al. 2010).  PET-CT scans 
have been implemented in the Lugano 2014 criteria (Cheson et al. 2014) and are 
commonly used to assess efficacy in medical practice and clinical trials in lymphoma.  
More recently, the value of post-induction PET-CT status has been investigated as a 
prognostic marker for long-term outcome in patients with FL.  In the first-line setting, 
results from a pooled analysis of 246 patients enrolled in three studies and having 
PET-CT scans available at the end of chemoimmunotherapy showed, with a median 
follow-up of 55 months, a 4-year PFS in PET-CTpositive and PET-CTnegative 


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patients of 23.2% (95% CI: 11.1%, 37.9%) versus 63.4% (95% CI: 55.9%, 70.0%; 
p0.001), respectively, and a 4-year survival of 87.2% (95% CI: 71.9%, 94.5%) versus 
97.1% (95% CI: 93.2%, 98.8%; p0.0001), respectively (Trotman et al. 2014).  In the 
relapsed FL setting, results from the preliminary analysis of a Phase II study (BO21003) 
comparing obinutuzumab versus rituximab monotherapy demonstrated that the 
post-induction PET-CT status is strongly prognostic of PFS.  With a median follow-up of 
32.1 months, the risk of disease progression was significantly reduced in 
PET-CTnegative patients compared with that in PET-CTpositive patients, regardless 
of the assessment criteria, either International Harmonization Project criteria (HR, 0.25; 
95% CI: 0.191, 0.807; p0.0083) or European Organization for Research and Treatment 
of Cancer (EORTC) criteria (HR, 0.39; 95% CI: 0.191, 0.807; p0.0083)
(Kostakoglu et al. 2014).
In response to developments involving PET-CT status, the 11th International Conference 
of Malignant Lymphoma imaging group provided updated guidance for the use of 
PET-CT scan results for lymphoma staging and response assessment (Lugano 2014 
criteria; Cheson et al. 2014).  
3.3.4
Rationale for Biomarker Assessments 
3.3.4.1
Rationale for Assessment of Immune-Mediated Biomarkers
Over the last decade, tumor microenvironment and host immunity have emerged as 
critical determinants of cancer development and response to therapy.  There is an 
increasing body of evidence regarding the prognostic value of TILs in B-cell NHL.  More 
recently, analysis of peripheral T cellreceptor repertoire demonstrated impaired T-cell 
diversity in B-cell NHL, with expansion of oligoclonal clusters of CD8-positive T cells and 
expansion of T-regulatory cells associated with an increased degree of skewing 
observed within the CDR3 region (Fozza et al. 2014).  A recent study of 12 melanoma 
patients treated with ipilimumab, a blocker of the immunologic checkpoint CTLA-4, 
showed a correlation between T cellreceptor diversity in the peripheral blood at 
baseline and patient outcomes (Postow et al. 2014).
This study will investigate the potential correlation of TIL signature and the status of 
peripheral T cellreceptor repertoire (diversity and quantity of receptors) with response 
to study treatment.  
Increase in T cellactivation biomarkers has been observed in peripheral blood following 
atezolizumab administration in cancer patients (Herbst et al. 2014).  Cytokines that are 
characteristic of activated T cells (e.g., IL-18, interferon gamma [IFN-]) and potential 
correlation with response to treatment will be assessed in this study.
A recent publication (Rosille et al. 2014) described the prognostic effect of soluble PD-L1 
in DLBCL.  The value of soluble PD-L1 in FL is unknown.  Soluble PD-L1 levels at 
baseline will be assessed in this study to support an exploratory biomarker analysis.  
Any correlation with PK parameters may also be examined.


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DLBCL subtypes (Activated B-cell, ABC and Germinal Centre B-cell) have been shown 
to be prognostic (Alizadeh et al. 2000). Furthermore, a subtype specific activity of 
lenalidomide in ABC DLBCL has been reported (Nowakowski et al. 2015). Therefore, 
DLBCL subtypes will be determined in the study.
Similarly, expression of Bcl-2 and concomitant Bcl-2 and Myc was shown to be 
prognostic (Johnson et al. 2012). To understand the prevalence and impact of
upregulated expression of Bcl-2 and Bcl-2/Myc, these markers will be assessed.
3.3.4.2
Rationale for Assessment of Minimal Residual Disease
MRD measurement is an increasingly recognized tool for response assessment in B-cell 
malignancies.  Circulating lymphoma cells and circulating tumor DNA can be detected 
and quantified at low levels as MRD to assess depth of response and to monitor patients 
for possible disease recurrence.  
In FL, MRD at end of treatment is likely to be prognostic (Ladetto et al. 2013).  
In addition, MRD assessment may complement the response assessment, particularly in 
immune treatmentbased regimens, and mitigate potential false-positive PET-CT results 
caused by infiltration of metabolically active immune cells into the tumor.
In this study, MRD will be quantified by circulating lymphoma cells and circulating tumor 
DNA as an exploratory endpoint.  The lymphoma clone will be identified in DNA from 
the lymphoma tissue specimen.  MRD levels will be determined in blood samples 
collected prior to dosing and during treatment to explore a pharmacodynamic 
relationship.  MRD assessments will be performed at the EOI to allow for an evaluation 
of the depth of response and during maintenance treatment to allow for an evaluation of 
long-term response or possible disease recurrence.
4.
MATERIALS AND METHODS
4.1
PATIENTS
This study will enroll patients with FL who meet the eligibility criteria presented below.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years

ECOG Performance Status of 0, 1, or 2 (see Appendix 4)

Relapsed or refractory FL after treatment with at least one prior 
chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody and 
for which no other more appropriate treatment option exists as determined by the 
investigator


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
Histologically documented CD20-positive lymphoma as determined by the local 
laboratory

FDG-avid lymphoma (i.e., PET-positive lymphoma)

At least one bi-dimensionally measurable lesion (1.5 cm in its largest dimension by 
CT scan or magnetic resonance imaging [MRI])

Availability of a representative tumor specimen and the corresponding pathology 
report for retrospective central confirmation of the diagnosis of FL
If archival tissue is unavailable or unacceptable, a pretreatment core-needle, 
excisional or incisional tumor biopsy is required.  Cytological or fine-needle
aspiration samples are not acceptable.
If the available biopsy was performed more than 12 months prior to Day 1 of 
Cycle 1 for patients with FL, or the patient received anti-lymphoma treatment 
between the time of the most recent available biopsy and Day 1 of Cycle 1, a 
core-needle biopsy is strongly recommended.
Further details are provided in Section 4.5.7.

Agreement to comply with all local requirements of the lenalidomide risk 
minimization plan
In every country where lenalidomide has been approved, a risk minimization 
plan, which includes a pregnancy prevention program, is in place.  The risk 
minimization plan should be followed by patients using lenalidomide.  
In addition, because lenalidomide will be administered in combination with 
atezolizumab and obinutuzumab, patients must comply with contraceptive 
measures designed to ensure safe administration of all three study treatments, 
as outlined below.  

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate methods of contraception, including 
at least one method with a failure rate of 1% per year, for at least 28 days prior to 
Day 1 of Cycle 1, during the treatment period (including periods of treatment 
interruption), and for at least 18 months after the last dose of study treatment
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of non-hormonal contraceptive methods with a failure rate of 1%
per year include bilateral tubal ligation, male sterilization, established and
proper use of progestogen-only hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.  
Combined oral contraceptives are not recommended because of the increased 
risk of venous and arterial thromboembolism (TE) in patients taking 
lenalidomide.


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The reliability of sexual abstinence should 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.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures and agreement to refrain from donating sperm, as 
defined below:
With female partners of childbearing potential or 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 to avoid exposing the 
embryo.  Men must refrain from donating sperm during this same period.
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:

Grade 3b follicular lymphoma

History of transformation of indolent disease to DLBCL

Known CD20-negative status at relapse or progression

CNS lymphoma or leptomeningeal infiltration

Prior allogeneic SCT

Completion of autologous SCT within 100 days prior to Day 1 of Cycle 1 

History of resistance to lenalidomide or response duration of 1 year (for patients 
who had a response to a prior lenalidomide-containing regimen) 

Prior standard or investigational anti-cancer therapy as specified below:
Lenalidomide, fludarabine, or alemtuzumab within 12 months prior to Day 1 of 
Cycle 1
Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1
Monoclonal antibody or antibody-drug conjugate within 4 weeks prior to Day 1 
of Cycle 1
Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule 
therapy within 2 weeks prior to Day 1 of Cycle 1
AntiPD-1, antiPD-L1, anti-CTLA4, antiCD137/41-BB agonist, or anti-CD40 
agonist antibodies

Clinically significant toxicity (other than alopecia) from prior treatment that has not 
resolved to Grade 2 (per NCI CTCAE v4.0) prior to Day 1 of Cycle 1


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
Treatment with systemic immunosuppressive medications, including, but not limited 
to, prednisone, azathioprine, methotrexate, thalidomide, and antitumor necrosis 
factor agents within 2 weeks prior to Day 1 of Cycle 1
Treatment with inhaled corticosteroids and mineralocorticoids is permitted.
If corticosteroid treatment is urgently required for lymphoma symptom control 
prior to the start of study treatment, 100 mg of prednisone or equivalent can be 
given for a maximum of 5 days, but all tumor assessments must be completed 
prior to initiation of corticosteroid treatment.

History of solid organ transplantation

History of severe allergic or anaphylactic reaction to humanized, chimeric or murine
monoclonal antibodies

Known sensitivity or allergy to murine products

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab, obinutuzumab, or lenalidomide 
formulation, including mannitol

History of erythema multiforme, Grade 3 rash, or blistering following prior 
treatment with immunomodulatory derivatives such as thalidomide and lenalidomide

Known history of idiopathic pulmonary fibrosis, organizing pneumonia 
(e.g., bronchiolitis obliterans), drug-induced pneumonitis or evidence of active 
pneumonitis on screening chest CT scan.
History of radiation pneumonitis in the radiation field (fibrosis) is allowed.

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
Caution should be exercised when considering the use of obinutuzumab in 
patients with a history of recurring or chronic infections.

Positive for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody 
(HBcAb), or hepatitis C virus (HCV) antibody at screening

Known history of HIV positive status
For patients with unknown HIV status, HIV testing will be performed at 
screening if required by local regulations.

History of progressive multifocal leukoencephalopathy

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

History of other malignancy that could affect compliance with the protocol or 
interpretation of results, with the exception of the following:
Any of the following malignancies, previously curatively treated:  carcinoma in 
situ of the cervix, good-prognosis ductal carcinoma in situ of the breast, or
basal or squamous cell skin cancer


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Stage I melanoma, low-grade; early-stage localized prostate cancer; or any 
other previously treated malignancy that has been in remission without 
treatment for 5 years prior to enrollment

History of autoimmune disease, including, but not limited to, myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 8 for a 
comprehensive list of autoimmune diseases)
Patients with a history of autoimmune-related hypothyroidism on a stable dose 
of thyroid-replacement hormone may be eligible for this study.
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen 
may be eligible for this study.

Contraindication to treatment for TE prophylaxis (see Section 4.3.2.6)

Grade 2 neuropathy

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)

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

Inadequate hematologic function (unless due to underlying lymphoma), defined as 
follows:
Hemoglobin 9 g/dL
ANC 1.5109/L
Platelet count 75109/L

Any of the following abnormal laboratory values (unless due to underlying 
lymphoma):
Calculated creatinine clearance 60 mL/min (using the Cockcroft-Gault formula; 
see Appendix 9)
AST or ALT 2.5 times the upper limit of normal (ULN)
Serum total bilirubin 1.5ULN (or 3ULN for patients with Gilbert syndrome)
INR or PT 1.5ULN in the absence of therapeutic anticoagulation
PTT or aPTT 1.5ULN in the absence of a lupus anticoagulant


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
Pregnant or lactating or intending to become pregnant during the study
Women of childbearing potential must have two negative serum pregnancy test 
results (minimum sensitivity, 25 mIU/mL) prior to initiating therapy:  at 
1014 days prior to Day 1 of Cycle 1 and within 24 hours prior to Day 1 of 
Cycle 1.

Life expectancy 3 months

Unable to comply with the study protocol, in the investigator’s judgment
4.2
METHOD OF TREATMENT ASSIGNMENT
This is a Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study of 
AtezoGLen in patients with relapsed or refractory FL.  During the dose-escalation 
phase, an interactive voice or web-based response system (IxRS) will be used to assign 
patients to dosing groups that vary according to the dose of lenalidomide given during 
induction treatment.  During the expansion phase, patients will receive lenalidomide at 
the RP2D during induction treatment.  All patients will receive lenalidomide at a dose of 
10 mg during maintenance treatment.  Atezolizumab and obinutuzumab will be given at 
stable doses to all patients, during both induction and maintenance treatment.
Enrollment tracking will be performed through use of the IxRS.  Prior to initiating 
screening, the study site should confirm via the IxRS that slots are available for 
enrollment.  After written informed consent has been obtained and preliminary eligibility 
has been established, the study site will submit documentation supporting eligibility to 
the Sponsor and obtain the Sponsor’s approval to enroll the patient.  Once the Sponsor 
reviews and approves the patient for enrollment, the patient number will be assigned and 
the patient will be enrolled via the IxRS.  The Sponsor will communicate to the sites 
impending closure of screening.
4.3
STUDY TREATMENT
4.3.1
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.


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4.3.1.2
Atezolizumab
Atezolizumab will be supplied by the Sponsor as an IMP.  Atezolizumab drug product is 
formulated as 60 mg/mL of atezolizumab in 20 mM histidine acetate, 120 mM sucrose, 
pH 5.8 with 0.04% (w/v) polysorbate 20.  Atezolizumab is provided in a single-use, 
20-mL USP/Ph. Eur. Type 1 glass vial as a colorless to slightly yellow, sterile, 
preservative-free clear liquid solution intended for IV administration.  The vial is designed 
to deliver 20 mL (1200 mg) of atezolizumab solution but may contain more than the 
stated volume to enable delivery of the entire 20-mL volume.  Extraction of 14 mL of 
atezolizumab solution will contain an 840-mg dose.  For information on the formulation 
and handling of atezolizumab, see the Atezolizumab Investigator’s Brochure and the 
Pharmacy Manual.
4.3.1.3
Lenalidomide
Lenalidomide will be supplied by the Sponsor as an IMP.  Lenalidomide will be provided 
as 5-, 10-, 15-, and 20-mg capsules.  
Female caretakers of patients taking lenalidomide who are of childbearing potential 
should not handle or administer lenalidomide unless they are wearing gloves.  
Lenalidomide should be stored at room temperature away from direct sunlight and 
should be protected from excessive heat and cold.
For information on the formulation and handling of lenalidomide, see the local 
prescribing information for lenalidomide.
4.3.2
Dosage, Administration, and Compliance
The treatment regimens are summarized in Table 4 and Table 5 (see Sections 4.3.2.4
and 4.3.2.5).
Premedication and treatment for TE prophylaxis should be administered as described in 
Section 4.3.2.6.
Any overdose or incorrect administration of any of the study treatments should be noted 
on the Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of any of the study treatments 
should be recorded on the Adverse Event eCRF.
4.3.2.1
Obinutuzumab
Obinutuzumab will be administered by IV infusion at an absolute (flat) dose of 1000 mg
on Days 1, 8, and 15 of the first cycle and on Day 1 of each subsequent cycle during 
induction treatment, and on Day 1 of every other month (i.e., every 2 months) during 
maintenance treatment.


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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 infusions will be 
administered per the instructions outlined in Figure 2 and Figure 3.  For patients with 
bulky lymphadenopathy, the infusion may be given slowly over a longer period of time, 
or the dose may be split and given over more than 1 day.
No dose modification for obinutuzumab is allowed.  Guidelines for treatment delays or 
discontinuation are provided in Section 5.1.
Premedication with a corticosteroid, analgesic/antipyretic, and antihistamine, as outlined 
in Section 4.3.2.6 (see Table 6), is required to reduce the incidence and severity of IRRs.  
For anaphylaxis precautions, see Appendix 7.


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Figure 2
Guidelines for Obinutuzumab Infusions:  First Infusion
IRR infusion-related reaction.
a All patients should receive full premedication with an oral corticosteroid, oral analgesic/anti-pyretic, and antihistamine prior to the first obinutuzumab infusion.  
Refer to Section 4.3.2.6 for details.
b Supportive treatment should include acetaminophen/paracetamol and an antihistamine such as diphenhydramine, if not administered within the previous 4 hours.  
Intravenous saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may require antihistamines, oxygen, corticosteroids (e.g., 100 mg oral 
prednisone or equivalent), and/or bronchodilators.  For anaphylaxis precautions, see Appendix 7.


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Figure 3
Guidelines for Obinutuzumab Infusions:  Second and Subsequent Infusions
IRR infusion-related reaction.
a
Patients should receive full premedication with an oral corticosteroid, oral analgesic/anti-pyretic, and antihistamine prior to the obinutuzumab infusion.  Refer to 
Section 4.3.2.6 for details.  In the case of a recurrent Grade 3 IRR, obinutuzumab may be discontinued at the discretion of the investigator, following an 
individual benefit-risk assessment.
b
Patients who experience wheezing, urticaria, or other symptoms of anaphylaxis must receive full premedication prior to all subsequent doses.


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4.3.2.2
Atezolizumab
Atezolizumab will be administered at a flat dose consisting of one of the following:  
a) 840 mg Q2W (840 mg on Days 1 and 15 of Cycles 26, given in 28-day cycles as 
induction treatment) and b) 1680 mg Q4W (840 mg on Days 1 and 2 of each month, 
given as maintenance treatment).  Detailed atezolizumab dosing regimens are provided 
in Table 4 for induction treatment and in Table 5 for maintenance treatment 
(see Sections 4.3.2.4 and 4.3.2.5).
Atezolizumab infusions will be administered as follows: 

The initial dose of atezolizumab will be delivered over 60 (15) minutes.  If the first 
infusion is tolerated without infusion-associated adverse events, the second infusion 
may be delivered over 30 (10) minutes.  If the 30-minute infusion is well tolerated, 
all subsequent infusions may be delivered over 30 (10) minutes.

In the event that a patient experiences a mild (NCI CTCAE Grade 1) IRR, the 
infusion rate should be reduced to half the rate being given at the time of event 
onset.  Once the event has resolved, the investigator should wait for 30 minutes 
while delivering the infusion at the reduced rate.  If tolerated, the infusion rate may 
then be increased to the original rate.

In the event that a patient experiences a moderate (NCI CTCAE Grade 2) IRR or 
flushing, fever, or throat pain, the infusion should be immediately interrupted and the 
patient should receive aggressive symptomatic treatment.  The infusion should be 
restarted only after the symptoms have adequately resolved.  The infusion rate at 
restart should be half of the infusion rate being given at the time of event onset.

In the event of a severe or life-threatening (NCI CTCAE Grade 3 or 4) IRR, the 
infusion should be stopped immediately and aggressive resuscitation and supportive 
measures should be initiated.  In the event of a life-threatening IRR, atezolizumab 
should be permanently discontinued.
For anaphylaxis precautions, see Appendix 7.
No dose modification for atezolizumab is allowed.  Guidelines for treatment delays or 
discontinuation are provided in Section 5.1.
4.3.2.3
Lenalidomide
Lenalidomide will be administered orally once daily on Days 121 of Cycles 16 
(28-day cycles) during induction treatment and on Days 121 of each month during 
maintenance treatment.  During the dose-escalation phase, lenalidomide will be 
administered at a dose of 15 or 20 mg (dose may be de-escalated to 10 mg) during 
induction treatment and at 10 mg during maintenance treatment.  During the expansion 
phase, lenalidomide will be administered at the RP2D during induction treatment and at 
10 mg during maintenance treatment.


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Lenalidomide capsules should be swallowed whole with water and should not be broken, 
chewed, or opened.  The capsules may be taken with or without food, except on 
lenalidomide PK sampling days (see Appendix 2), when the patient should fast 
(water allowed) at least 2 hours before and at least 1 hour after the lenalidomide dose.  
On lenalidomide PK sampling visits, lenalidomide dose will be taken in the clinic.  
Lenalidomide should be administered at approximately the same time each day.  If a 
dose of lenalidomide is missed and it has been 12 hours since the time of the 
scheduled dose, the patient may take the missed dose.  If it has been 12 hours, the 
dose should be skipped and the next dose should be taken at the regularly scheduled 
time.  Two doses should not be taken at the same time.  If a dose had been vomited, the 
dose should not be re-taken.
At each cycle, each patient will be supplied with only enough lenalidomide for that cycle.  
A drug diary will be provided to the patient to record oral administration of doses, 
including the date and time. Patients will be instructed to return empty bottles or unused 
capsules.  The investigator is responsible for monitoring patient compliance by 
monitoring the patient diary and counting unused capsules.
4.3.2.4
Induction Treatment with Atezolizumab, Obinutuzumab, and 
Lenalidomide (AtezoGLen)
Patients will receive induction treatment, administered in 28-day cycles as follows:

Patients will receive six cycles of induction treatment consisting of obinutuzumab 
and lenalidomide for Cycles 16 and atezolizumab for Cycles 26 as outlined in 
Table 4.
Lenalidomide may be administered before or concomitantly with obinutuzumab.  
After completion of the obinutuzumab infusion, the line will be flushed (unless there is a 
central line with more than one line/port), after which atezolizumab will be administered.
For patients at increased risk for IRRs (high tumor burden), the obinutuzumab infusion 
may be split and administered over 2 days, with 100 mg given on Day 1 and 900 mg
given on Day 2.
For patients who experience an IRR during obinutuzumab infusion, administration of 
atezolizumab may be delayed by 1 day if clinically required.


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Table 4
Induction Treatment
Treatment
Dose
Route
Regimen (28-Day Cycles)
Cycle 1
Cycles 26
Lenalidomide
Dose-escalation phase:  
15 or 20 mg a
Expansion phase:  RP2D
PO
Days 121
Days 121
Obinutuzumab
1000 mg
IV
Days 1, 8, and 15
Day 1
Atezolizumab
840 mg
IV

Days 1 and 15
IVintravenous; POby mouth; RP2Drecommended Phase II dose.
a Dose may be de-escalated to 10 mg.
4.3.2.5
Maintenance Treatment with Atezolizumab, Obinutuzumab, 
and Lenalidomide (AtezoGLen)
Patients who achieve a CR, a PR, or stable disease at EOI are eligible for maintenance 
treatment with atezolizumab and obinutuzumab for 24 months and lenalidomide for 
12 months, as outlined in Table 5.
Lenalidomide will be given before other agents are administered on the same day.  
Obinutuzumab will be administered next, followed by a line flush (unless there is a 
central line with more than one line/port), after which atezolizumab will be administered.
Maintenance treatment should start 8 weeks (1 week) after Day 1 of Cycle 6 and will 
continue until disease progression or unacceptable toxicity for up to 24 months. 
Table 5
Maintenance Treatment
Treatment
Dose
Route
Regimen (Months 124)
Lenalidomide
10 mg
PO
Days 121 of each month for a maximum of 
12 months
Obinutuzumab
1000 mg
IV
Day 1 of every other month (i.e., every 2 months), 
starting with Month 1
Atezolizumab
840 mg
IV
Days 1 and 2 of each month
IVintravenous; PO by mouth.
4.3.2.6
Premedication and Other Prophylaxis Treatment
Patients should receive premedication as outlined in Table 6.
Granulocyte colony-stimulating factor (G-CSF) may be administered in each cycle of 
therapy as primary prophylaxis for neutropenia, per American Society of Clinical 
Oncology, EORTC, and European Society for Medical Oncology guidelines 
(Smith et al. 2015) or per each site’s institutional standards.


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Prophylactic treatment with antibiotics should be administered as per standard practice.  
Lenalidomide increases the risk of TE.  Anticoagulation prophylaxis should be given after 
a careful assessment of a patient’s underlying risk factors.  All patients will receive daily 
low-dose aspirin (81100 mg) during lenalidomide treatment and until 28 days after the 
last dose of lenalidomide.  Patients who are unable to tolerate aspirin, who have a 
history of TE, and who are at high risk of TE should receive warfarin or 
low-molecular-weight heparin (LMWH).  


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Table 6
Premedication
Timepoint
Patients Requiring Premedication
Premedication
Administration
Cycle 1, 
Day 1
All patients
Oral corticosteroid a
Administer 1 hour prior to obinutuzumab infusion
All patients
Oral analgesic/anti-pyretic b
Antihistamine drug c
Administer30 minutes prior to obinutuzumab infusion
Patients at risk for TLS 
(e.g., because of bulky disease 
or renal impairment (creatinine 
clearance 70 mL/min)
Allopurinol or suitable alternative 
such as rasburicase, along with 
adequate hydration
Administer prior to obinutuzumab infusion
Cycle 1, 
Days 8 and 15
Cycles 2 and 
beyond,
Day 1
Patients with Grade 1 or 2IRR 
or no IRR during the previous 
infusion
Antihistamine drug b
Oral analgesic/anti-pyretic c
Administer at least 30 minutes prior to obinutuzumab 
infusion
Patients with Grade 3 IRR, 
wheezing, urticaria, or other 
symptoms of anaphylaxis
during the previous infusion
Patients with bulky disease
Oral corticosteroid a
Administer 1 hour prior to obinutuzumab infusion
Oral analgesic/anti-pyretic b
Antihistamine drug c
Administer 30 minutes prior to obinutuzumab infusion
Patients still at risk for TLS
Allopurinol or suitable alternative 
such as rasburicase, along with 
adequate hydration
Administer prior to obinutuzumab infusion
IRRinfusion-related reaction; TLStumor lysis syndrome.
a Treat with 100 mg of prednisone or prednisolone, 20 mg of dexamethasone, or 80 mg of methylprednisolone.  Hydrocortisone should not be 
used because it has not been effective in reducing rates of IRR.
b For example, 1000 mg of acetaminophen/paracetamol.
c For example, 50 mg of diphenhydramine.


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4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (atezolizumab, obinutuzumab, and 
lenalidomide) will be provided by the Sponsor.  The study site will acknowledge receipt 
of IMPs 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 returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any 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.
4.3.4
Post-Trial Access to Atezolizumab and Obinutuzumab
Patients may continue to receive study treatment and undergo scheduled assessments 
as part of an extension study.  Currently, the Sponsor does not have any plans to 
provide post-trial access to any IMP or interventions to patients who do not qualify for 
the extension study.  The Roche Global Policy on Continued Access to Investigational 
Medicinal Product is available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to the screening period to the visit at the EOI or at the end of maintenance 
(EOM) treatment, whichever occurs later.  All such medications should be reported to 
the investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy
Prophylaxis treatment and premedication should be administered as described in 
Section 4.3.2.6.
Patients who use oral contraceptives, hormone replacement therapy, or other 
maintenance therapy should continue their use.  However, it must be noted that 
erythropoietic agents or other agents that may increase the risk of thrombosis, such as 
estrogen-containing therapies (e.g., oral contraceptives), are not recommended because 
of the increased risk of TE in patients taking lenalidomide.  Suitable methods of 
contraception are presented in Section 4.1.1.


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Patients using concomitant medication that could possibly worsen 
thrombocytopenia-related events (e.g., platelet inhibitors and anticoagulants) may be at 
a greater risk of bleeding.  When possible, replace prior vitamin K antagonist therapy 
with LMWH prior to Day 1 of Cycle 1.
Prophylactic treatment with antibiotics should be administered as per standard practice.
Necessary supportive measures for optimal medical care will be given throughout the 
study according to institutional standards.
4.4.2
Prohibited Therapy
Use of the following therapies (excluding protocol-specified treatments) is prohibited 
during the study:

Receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor (denosumab)
for a period of 10 weeks after the last dose of atezolizumab
RANKL inhibition could potentially alter the activity and safety of atezolizumab.  
Thus, patients receiving a RANKL inhibitor prior to enrollment must be willing 
and eligible to receive a bisphosphonate instead of a RANKL inhibitor.

Any anti-cancer therapy, approved or investigational, other than intrathecal CNS
prophylaxis

Hormonal therapy other than contraceptives, stable hormone replacement therapy, 
or megestrol acetate

Biologic agents other than G-CSF (as described in Section 4.3.2.6)

Immunostimulatory agents, including, but not limited to, interferon alpha, IFN-, or 
IL-2
Immunostimulatory agents, in combination with atezolizumab, could potentially 
increase the risk for autoimmune conditions.  Patients should not receive other 
immunostimulatory agents for 10 weeks after the last dose of atezolizumab.

Vaccines, as outlined below:
Any live, attenuated vaccine (e.g., FluMist) while the patient is receiving 
atezolizumab and for a period of 5 months after discontinuation of 
atezolizumab. Inactivated influenza vaccines are allowed only during flu 
season. 
Vaccination with live vaccines is not recommended during treatment with 
obinutuzumab until B-cell recovery. 
4.5
STUDY ASSESSMENTS
See Appendix 1 for the schedule of assessments performed during the study.


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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.  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.  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.
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent, and within the defined window, may be used as screening and baseline 
assessments (see Appendix 1); such tests do not need to be repeated for screening 
purposes (e.g., screening tumor assessment).
Study treatment should be initiated within 28 days after the Informed Consent Form has 
been signed.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, reproductive status, 
smoking history, and alcohol and drug abuse.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the patient within 7 days prior to the screening period 
and until the EOI or EOM visit, whichever occurs later, will 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 4)

B symptoms (unexplained fever 38C, night sweats, unexplained weight loss 10% 
of body weight over 6 months)

Ann Arbor staging (see Appendix 5)

Follicular Lymphoma International Prognostic Index (FLIPI) and Follicular 
Lymphoma International Prognostic Index 2 (FLIPI2) (see Appendix 6)

Prior anti-lymphoma treatment, as well as response to prior treatment, date of 
disease progression in relation to start date of prior treatment, and date of last dose 
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4.5.3
Physical Examinations
A complete physical examination should be performed at screening and on Cycle 1 
Day 1 and should include an evaluation of the head, eyes, ears, nose, and throat and 
the cardiovascular, dermatological, musculoskeletal, respiratory, GI, genitourinary, and 
neurological 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 subsequent visits (or as clinically indicated), 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; see Section 4.5.5).
Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, body temperature, 
and systolic and diastolic blood pressures while the patient is in a seated position.  
Vital sign measurements will be performed as outlined in the schedule of assessments 
(see Appendix 1), but the associated data, other than the data collected at screening, do 
not need to be recorded on the eCRF (except in the case of an adverse event as 
presented in Section 5.3.6.6).
4.5.5
Tumor and Response Evaluations
All evaluable or measurable disease must be documented at screening and re-assessed
at each subsequent tumor evaluation.  Response will be assessed by the IRC and the
investigator on the basis of PET and CT scans, using the Lugano 2014 criteria.  In this 
study, the Lugano 2014 criteria for a PET-CTbased CR have been slightly modified to 
require normal bone marrow for patients with bone marrow involvement at screening.  
Additionally, designation of PET-CTbased PR requires that CT-based response criteria 
for a CR or PR be met in addition to the PET-CTbased response criteria for a PR
(see Appendix 3).
4.5.6
Radiographic Assessments
PET scans should include skull-base to mid-thigh.  Full body PET scans should be 
performed when clinically appropriate.


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CT scans with oral and IV contrast should include chest, abdomen, and pelvic scans.  
CT scans of the neck should be included if clinically indicated (i.e., if evidence of disease 
upon physical examination) and must be repeated throughout the study if there is 
disease involvement at baseline.
PET-CT scans and diagnostic CT scans should be acquired according to a standardized 
imaging manual, which will be provided to all sites.
If contrast is medically contraindicated (e.g., patients with contrast allergy or impaired 
renal clearance), MRI scans of the chest, abdomen, and pelvis (and neck, if clinically 
indicated) and a non-contrast CT scan of the chest may be performed.  If MRI scans 
cannot be obtained, CT scans without contrast are permitted as long as these allow 
consistent and precise measurement of the targeted lesions during the study 
treatment period.
The same radiographic assessment modality must be used for all response evaluations 
to ensure consistency across different timepoints (including unscheduled assessments).
A full tumor assessment, including radiographic assessment, must be performed any 
time disease progression or relapse is suspected. Additional details regarding imaging 
procedures will be provided in the Imaging Manual.
4.5.6.1
Bone Marrow Assessments
Bone marrow examinations are required at screening for staging purposes in all patients 
and should be performed within approximately 3 months prior to Day 1 of Cycle 1.
If bone marrow infiltration is present at screening, a bone marrow biopsy is required at 
the EOI response assessment for all patients who may have achieved a CR.  In patients 
with a PR at the EOI, a bone marrow examination may be required at a later timepoint
during maintenance treatment or at the EOM to confirm a CR that was achieved after the 
EOI response assessment.
Any additional (unscheduled) bone marrow examinations performed during the study will 
be at the discretion of the investigator. 
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Local Laboratory Assessments
Samples for the following laboratory tests will be analyzed at the study site's local 
laboratory for analysis:

Hematology:  hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
percent or absolute WBC differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells)


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
Chemistry panel (serum or plasma):  sodium, potassium, glucose, BUN or urea, 
creatinine, calculated creatinine clearance, calcium, total bilirubin, direct bilirubin, 
total protein, albumin, ALT, AST, alkaline phosphatase (ALP), amylase, lipase, LDH, 
uric acid

Urinalysis (dipstick) 

Thyroid-stimulating hormone (TSH), triiodothyronine, thyroxine (T4)

2 microglobulin

Coagulation:  INR, aPTT (or PTT), PT

Pregnancy test
All women of childbearing potential must have two negative serum pregnancy 
test results (minimum sensitivity, 25 mIU/mL) prior to initiating therapy:  at 
1014 days prior to Day 1 of Cycle 1 and within 24 hours prior to Day 1 of 
Cycle 1.  Urine pregnancy tests will be performed at specified subsequent visits 
(see Appendix 1).  If a urine pregnancy test is positive, it must be confirmed by 
a serum pregnancy test.

Viral serology 
Hepatitis B testing includes HBsAg and total HBcAb.
Hepatitis C testing includes HCV antibody.

Quantitative immunogloblulins: IgA, IgG, IgM
Central Laboratory Assessments
The following samples will be sent to one or several Sponsor-designated central 
laboratories or to the Sponsor for analysis:

Serum samples for obinutuzumab PK analysis using a validated assay

Serum samples for atezolizumab PK analysis using a validated assay

Plasma samples for lenalidomide PK analysis using a validated assay.  Relevant 
biotransformation products of lenalidomide may also be analyzed at the discretion of 
the Sponsor.

Serum samples for assessment of HAHAs to obinutuzumab using a validated assay

Serum samples for assessment of anti-therapeutic antibodies to atezolizumab using 
validated assays

Tumor tissue samples and the corresponding pathology report for retrospective 
central confirmation of the diagnosis of FL, and for exploratory research on 
candidate biomarkers (see Table 7)
The specimen must contain adequate evaluable tumor cells (20% for 
excisional biopsy and 50% for core biopsy).
Formalin-fixed paraffin-embedded tissue blocks are preferred over slides.  
Tissue blocks that are not formalin fixed will be accepted in countries that use a 
fixative other than paraformaldehyde, but information on the type of fixative 
should be included.  If a tissue block is not available, 1520 serial, freshly cut, 


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unstained slides accompanied by a punch biopsy may be sent.  A tumor block 
or punch biopsy is required for construction of a tissue microarray.  If fewer than 
1520 unstained serial slides are available, the study site should consult the 
Sponsor (or delegate) regarding the acceptability of a fewer number of slides.
If archival tissue is unavailable, a pretreatment core-needle, excisional, or 
incisional tumor biopsy is required.  Cytological or fine-needle aspiration
samples are not acceptable.
If the available biopsy was performed more than 12 months prior to Day 1 of 
Cycle 1, or the patient received anti-lymphoma treatment between the time of 
the most recent available biopsy and Day 1 of Cycle 1, a core-needle biopsy is 
strongly recommended.
The sample should be shipped according to instructions provided in the 
laboratory manual.  The remainder of the tissue blocks will be returned to the 
local pathology laboratory, according to country-specific procedures.
Analysis methods will be detailed in the Biomarker Analysis Plan.

Tumor biopsy samples obtained prior to the start of Cycle 2 and at the time of 
progression (unless no adequate tumor site is accessible) for exploratory research 
on candidate biomarkers (see Table 7)

Serum samples for exploratory research on candidate biomarkers (see Table 7)

Whole blood samples for exploratory research on candidate biomarkers 
(see Table 7)

Whole blood samples for isolation of peripheral blood mononuclear cells for 
exploratory research on candidate biomarkers (see Table 7)
Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in Table 7.
Table 7
Proposed Non-Inherited Biomarkers
Sample Type
Timing
Proposed 
Non-Inherited Biomarkers
Archival or fresh tumor 
tissue
Prior to study (archival) or 
baseline (fresh)
Lymphoma-related genetic changes 
(DNA) and gene expression (mRNA)
PD-L1, HLA-1
CD8 and other biomarkers of T-cell 
subpopulations
Biomarkers of other immune cells (such 
as macrophages)
Cytokines, drug transporters, and genes 
related to regulation of apoptosis


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Table 7
Proposed Non Inherited Biomarkers (cont.)
Sample Type
Timing
Proposed 
Non-Inherited Biomarkers
Tumor tissue biopsy
Prior to the start of Cycle 2 
and at the time of 
progression (unless no 
adequate tumor site is 
accessible)
Immune infiltrate, PD-L1, CD8 and other 
biomarkers of T-cell subpopulations, 
cytokines, drug transporters, and genes 
related to regulation of apoptosis
Plasma
Baseline
Soluble PD-L1
Plasma
Baseline and subsequent 
timepoints during treatment
Cytokines characteristic of T-cell 
activation (e.g., IL-18, IFN-)
Whole blood 
(separated into PBMCs 
and plasma)
Baseline and subsequent 
timepoints during treatment
Detection of minimal residual disease:
Cell-free circulating tumor DNA in 
plasma
Circulating lymphoma cells in PBMCs
PBMCs isolated from 
whole blood
Baseline and subsequent 
timepoints during treatment
T cell-receptor repertoire
Whole blood
Baseline and subsequent 
timepoints during and after 
treatment
Lymphocyte immunophenotyping, 
including B-cell counts (CD19), T-cell 
counts (CD3, CD4, and CD8), and 
NK cell counts (CD16 and CD56)
HLA human lymphocyte antigen; IFN-interferon gamma; ILinterleukin; NKnatural killer; 
PBMCs peripheral blood mononuclear cells; PD-L1programmed death-ligand 1.
Note:  Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in this table.
Samples collected for PK and immunogenicity analyses may be used for assay 
development purposes and additional safety and immunogenicity assessments, as 
appropriate.
Biological samples will be destroyed when the final Clinical Study Report has been 
completed, unless the patient gives specific consent for the leftover samples to be stored 
for optional exploratory research (see Section 4.5.9).
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.


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4.5.8
Electrocardiograms 
Single, resting, 12-lead ECG recordings will be obtained at specified timepoints, as 
outlined in the schedule of assessments (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.
4.5.9
Samples for Roche Clinical Repository 
4.5.9.1
Overview of the Roche Clinical Repository
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized 
therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection and submission of biological samples to the RCR are contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site’s Institutional Review Board (IRB) or Ethics Committee (EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (Section 4.5.9) will not be 
applicable at that site.


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4.5.9.3
Sample Collection
The following samples will be collected for research purposes, including, but not limited 
to, research on dynamic (non-inherited) biomarkers related to atezolizumab, 
obinutuzumab, or NHL:

Peripheral blood (i.e., whole blood, plasma, and serum)

Leftover tumor tissue from lymph node biopsy (archival and/or fresh biopsy)

Leftover peripheral blood
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual.  
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.9.4
Confidentiality
Confidentiality for All RCR Specimens
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RCR specimens 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.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and the Sponsor’s monitors, 
representatives, and collaborators, as appropriate.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Sponsor policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
Additional Confidentiality for Specimens Used for Genetic Research
Given the sensitive nature of genetic data, the Sponsor has implemented additional 
processes to ensure patient confidentiality for RCR specimens collected for genetic 
research.  Upon receipt by the RCR, specimens for genetic research are “double-coded”


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by replacing the patient identification number with a new independent number.  
Data generated from the use of these specimens and all clinical data transferred from 
the clinical database and considered relevant are also labeled with this same 
independent number.  A “linking key” between the patient identification number and this 
new independent number is stored in a secure database system.  Access to the linking 
key is restricted to authorized individuals and is monitored by audit trail.  Legitimate 
operational reasons for accessing the linking key are documented in a standard 
operating procedure.  Access to the linking key for any other reason requires written 
approval from the Pharma Repository Governance Committee and the Sponsor’s Legal 
Department, as applicable.
4.5.9.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient’s agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.  In the 
event of an RCR participant's death or loss of competence, the participant's specimens 
and data will continue to be used as part of the RCR research.
4.5.9.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  After withdrawal of consent, any 
remaining samples will be destroyed or will no longer be linked to the patient.  If a 
patient wishes to withdraw consent to the testing of his or her specimens, the 
investigator must inform the Medical Monitor in writing of the patient’s wishes through 
use of the RCR Subject Withdrawal Form and, if the trial is ongoing, must enter the date 
of withdrawal on the RCR Research Sample Withdrawal of Informed Consent eCRF.  If 
a patient wishes to withdraw consent to the testing of his or her RCR samples after 
closure of the site, the investigator must inform the Sponsor by emailing the study 
number and patient number to the following email address:
global_rcr-withdrawal@roche.com
A patient’s withdrawal from Study BO29562 does not, by itself, constitute withdrawal of 
specimens from the RCR.  Likewise, a patient’s withdrawal from the RCR does not 
constitute withdrawal from Study BO29562.


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4.5.9.7
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice (GCP) 
by a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  The Sponsor’s monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RCR samples.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
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 withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance (e.g., consistent failure to show up for scheduled visits)
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal 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.  Study personnel may use a public 
information source (e.g., county records) to obtain information about survival status.
4.6.2
Study Treatment Discontinuation
Study treatment should be permanently discontinued in patients who experience any of 
the following:

Anaphylaxis, acute respiratory distress, or Grade 4 IRR
If a Grade 3 IRR is recurrent during the second and subsequent cycles, study 
treatment may be discontinued at the discretion of the investigator, following an 
individual benefit-risk assessment.  

Life-threatening adverse event

Grade 3 nonimmune-mediated adverse event that is considered to be related to 
study treatment and does not resolve to Grade 2 within 21 days


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
Nonimmune-mediated adverse event that is considered to be treatment related and 
requires study treatment to be withheld for 21 days

Immune-mediated adverse event that requires atezolizumab to be withheld 
for 42 days, unless approved by the Medical Monitor

Any adverse event that meets criteria for permanent discontinuation per guidelines 
provided in Section 5.1

Disease progression
Because of the potential for tumor flares with immunotherapies, resulting in 
early apparent radiographic progression (pseudoprogression/tumor immune 
infiltration), including the appearance of new lesions followed by delayed 
response (Wolchok et al. 2009), patients whose CT scans at the end of Cycle 2
meet criteria for disease progression may continue to receive study treatment at 
the discretion of the investigator and following discussion with the Medical 
Monitor, if certain criteria are met (see Section 3.1.4 for details).  Cases of 
delayed pseudoprogression have also been described in patients with solid 
tumors treated with immunotherapies.  In case of CT- findings suggestive for 
pseudoprogression in patients with persistent clinical benefit, the investigator 
should contact the Medical Monitor to discuss further patient management.
Patients who continue to receive study treatment should have a CT scan 
repeated 48 weeks later.  

Pregnancy
In case of toxicity solely attributable to one drug of the combination requiring 
discontinuation, the other two drugs may be continued for patients experiencing clinical 
benefit as determined by the investigator after discussion with the Medical Monitor.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.
Patients who discontinue study treatment will not be replaced, except as outlined below:

During the dose-escalation phase, patients who discontinue study treatment prior to 
completing the DLT assessment window for reasons other than a DLT will be 
replaced by an additional patient at that same dose level.

During the expansion phase, patients who discontinue study treatment prior to 
receiving at least one dose of each component of the combination will be replaced.
4.6.3
Study and Site 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 (see Section 6.11, Stopping Rules for 
Safety) in this or other studies indicates a potential health hazard to patients.

Patient enrollment is unsatisfactory.


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The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.
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 Conference on Harmonisation (ICH) guideline 
for GCP

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 study 
treatment components in completed and ongoing studies.  The anticipated important 
safety risks of IMPs in this study (i.e., obinutuzumab, atezolizumab, and lenalidomide) 
are outlined below.  
Several measures will be taken to ensure the safety of patients participating in this trial.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities 
(see Section 4.1).  In addition, patients will undergo adequate safety monitoring during 
the study, as described in this section and in Section 4.5.  Finally, guidelines for 
managing adverse events, including criteria for dosage modification and treatment 
delays or discontinuation, have been provided (see Section 5.1.5).
5.1.1
Risks Associated with Obinutuzumab
As of 12 July 2017, the following adverse events are considered to be important risks 
associated or potentially associated with obinutuzumab:  IRRs and hypersensitivity 
reactions, TLS, thrombocytopenia (including acute thrombocytopenia), neutropenia 
(including prolonged and late onset neutropenia), infections (including progressive 
multifocal leukoencephalopathy and HBV reactivation), prolonged B-cell depletion, 
impaired immunization response, worsening of preexisting cardiac conditions, GI 
perforation, immunogenicity, and second malignancies.  These events, with the 
exception of prolonged B-cell depletion, immunogenicity, and second malignancies, 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, IRRs were mild or moderate and resolved with the
slowing or interruption of the infusion and supportive care.  The commonly experienced 


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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 or anaphylactic 
reactions; anaphylaxis has been reported in patients treated with obinutuzumab.
Hypotension may occur during obinutuzumab IV infusions.  Therefore, withholding of 
anti-hypertensive treatments should be considered for 12 hours prior to and throughout 
each 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.
Patients who have preexisting cardiac or pulmonary conditions should be monitored 
carefully throughout the infusion and the post-infusion period.
Guidelines for medical management of IRRs and anaphylaxis are provided in 
Section 4.3.2.1 and Appendix 7.
Hypersensitivity reactions with immediate (e.g., anaphylaxis) and delayed (e.g., serum 
sickness) onset have been reported in patients treated with obinutuzumab.  
Hypersensitivity reactions typically occur after previous exposure and very rarely with the 
first infusion.  In 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.  
Patients at risk for TLS (e.g., because of bulky disease or renal insufficiency) should 
receive adequate hydration and premedication with allopurinol or an alternative 
uricostatic agent as indicated in Section 4.3.2.6 (see Table 6).  Additional guidelines for 
management of TLS in this study are provided in Section 5.1.5 (see Table 11).
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/L occurring 28 days after obinutuzumab 
treatment has been completed or stopped) or prolonged neutropenia 
(ANC 1000 cells/L that does not resolve after 28 days without obinutuzumab 
treatment) have also been reported.  The use of G-CSF is allowed for the treatment of 
neutropenia per institutional guidelines in this study.  Prophylactic treatment with 
antibiotics should be administered as per standard practice.  Guidelines for primary 
prophylaxis with G-CSF are provided in Section 4.3.2.6.


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5.1.1.4
Thrombocytopenia
Severe and life-threatening thrombocytopenia, including acute thrombocytopenia 
(occurring within 24 hours after the infusion), has been observed during treatment with 
obinutuzumab.  In patients with CLL 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 a 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.  
5.1.1.5
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 FL studies, a high incidence of infections was observed in all phases of the studies, 
including follow-up, with the highest incidence seen in maintenance. 
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 
increased particularly when anti-CD20 antibodies are administered with 
immunosuppressive therapies, such as steroids or chemotherapy.  Patients positive for 
HBsAg and HBcAb are not eligible for this study.
John Cunningham (JC) viral infection resulting in progressive multifocal 
leukoencephalopathy has been reported in patients treated with obinutuzumab.  
The diagnosis of progressive multifocal leukoencephalopathy should be considered in 
any patient presenting with new-onset neurologic manifestations.  The symptoms of 
progressive multifocal leukoencephalopathy 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.  


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Evaluation of progressive multifocal leukoencephalopathy includes, but is not limited to, 
consultation with a neurologist, brain MRI, and lumbar puncture (cerebrospinal fluid 
testing for JC viral DNA).  Additional guidelines for medical management of progressive 
multifocal leukoencephalopathy in this study are provided in Section 5.1.5.
5.1.1.6
Immunizations
The safety of immunization with live virus vaccines following obinutuzumab therapy has 
not been studied.  Thus, vaccination with live virus vaccines is not recommended during 
treatment and until B-cell recovery.
5.1.1.7
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.
5.1.1.8
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.
5.1.2
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, and myositis.  Immune-mediated reactions may involve any 
organ system and may lead to hemophagocytic lymphohistiocytosis and macrophage 
activation syndrome (considered to be potential risks for atezolizumab).  Refer to 
Section 6 of the Atezolizumab Investigator's Brochure and Appendix 10 for a detailed 
description of anticipated safety risks for atezolizumab. 
5.1.3
Risks Associated with Lenalidomide
5.1.3.1
Embryo-Fetal Toxicity
Lenalidomide, a thalidomide analogue, is structurally related to thalidomide, a known 
human teratogenic active substance that causes severe life-threatening birth defects.  In 
a developmental study in monkeys, lenalidomide caused limb abnormalities similar to 
birth defects caused by thalidomide in humans.  If taken during pregnancy, lenalidomide 
is expected to have a teratogenic effect in humans.
Lenalidomide must not be taken by patients who are pregnant.  In every country where 
lenalidomide has been approved, a risk minimization plan, which includes a pregnancy 


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prevention program, is in place.  Investigators must ensure that all specific local 
requirements that are applicable to the safe and effective use of lenalidomide are fulfilled 
prior to administration to patients.  The risk minimization plan should be followed by 
prescribers and by patients using lenalidomide.  In addition, because lenalidomide will 
be administered in combination with atezolizumab and obinutuzumab, patients must 
comply with contraceptive measures designed to ensure safe administration of all three 
study treatments, as outlined in Section 4.1.1.  Pregnancy testing and counseling should 
be performed if a patient misses her period or has unusual menstrual bleeding.  
Treatment with lenalidomide must be discontinued until it is confirmed that the patient is 
not pregnant.
5.1.3.2
Hematologic Toxicity
Lenalidomide can cause significant neutropenia and thrombocytopenia.  Patients should 
have their CBCs monitored weekly for the first 8 weeks and at least monthly thereafter. 
5.1.3.3
Venous and Arterial Thromboembolism
Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary 
embolism) have occurred in patients treated with lenalidomide.  Prophylactic 
anti-thrombotic medicines are recommended, especially in patients with additional 
thrombotic risk factors.  The decision to take prophylactic measures should be made 
after a careful assessment of a patient’s underlying risk factors. Thromboprophylaxis is 
presented in Section 4.3.2.6.
Patients with known risk factors for TE, including prior thrombosis, should be closely 
monitored.  Action should be taken to try to minimize all modifiable risk factors 
(e.g., smoking, hypertension, and hyperlipidemia).  Concomitant administration of 
erythropoietic agents or previous history of thromboembolic events may also increase 
thrombotic risk in these patients.  Therefore, erythropoietic agents, or other agents that 
may increase the risk of thrombosis (such as hormone replacement therapy), should be 
used with caution.  A hemoglobin concentration of 12 g/dL should lead to 
discontinuation of erythropoietic agents.
Patients and physicians are advised to be observant of the signs and symptoms of TE.  
Patients should be instructed to seek medical care if they develop symptoms such as 
shortness of breath, chest pain, or arm or leg swelling. 
5.1.3.4
Tumor Flare Reaction
Tumor flare reaction (TFR) has occurred during investigational use of lenalidomide for 
treatment of CLL and lymphoma, and is characterized by tender lymph node swelling, 
low grade fever, pain, and rash.  Monitoring and evaluation for TFR is recommended in 
patients taking lenalidomide. TFR may mimic disease progression.  Guidelines for the 
management of TFR are presented in Table 10.


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5.1.3.5
Severe Skin Reactions
Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome 
and toxic epidermal necrolysis have been reported during treatment with lenalidomide.  
These events can be fatal.  Guidelines for the management of severe skin reactions are 
presented in Table 10.  Patients with a history of erythema multiforme, Grade 3 rash, 
or blistering following prior treatment with immunomodulatory derivatives (such as 
thalidomide and lenalidomide) will not be enrolled in the study.
5.1.3.6
Tumor Lysis Syndrome
Fatal instances of TLS have been reported during treatment with lenalidomide.  Patients 
at risk for TLS are those with high tumor burden prior to treatment.  These patients 
should be monitored closely, and appropriate precautions should be taken.
5.1.3.7
Hepatotoxicity
Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide 
in combination with dexamethasone.  The mechanism of drug-induced hepatotoxicity is 
unknown.  Preexisting viral liver disease, elevated baseline liver enzymes, and 
concomitant medications may be risk factors.  Liver enzymes are to be monitored 
periodically.  Guidelines for the management of hepatotoxicity are presented in Table 10. 
5.1.3.8
Renal Impairment
Lenalidomide is substantially excreted by the kidney.  Patients with renal impairment 
(i.e., calculated creatinine clearance 60 mL/min) will not be enrolled in this study.  
Renal function will be monitored during the study, and the lenalidomide dose may be 
adjusted as outlined in Section 5.1.5 (see Table 10).
5.1.3.9
Thyroid Disorders
Cases of hypothyroidism and cases of hyperthyroidism have been reported during 
treatment with lenalidomide.  Optimal control of comorbid conditions influencing thyroid 
function is recommended before initiating lenalidomide treatment.  Baseline and ongoing 
monitoring of thyroid function is recommended.
5.1.3.10
Peripheral Neuropathy
Lenalidomide is structurally related to thalidomide, which is known to induce severe 
peripheral neuropathy.  There was no increase in peripheral neuropathy observed with 
long-term use of lenalidomide for the treatment of newly diagnosed multiple myeloma.
5.1.3.11
Second Primary Malignancies
Patients with multiple myeloma treated with lenalidomide in studies that included 
melphalan and SCT had a higher incidence of second primary malignancies (SPM), 
particularly acute myelogenous leukemia and Hodgkin’s lymphoma.  Patients are to be 
monitored for the development of second malignancies. A regular reminder will be sent 
to study investigators every 6 months in order to collect any new cases of SPMs.


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5.1.3.12
Drug-Drug Interactions
Patients who are receiving digoxin should undergo periodic monitoring of digoxin plasma 
levels, due to increased maximum concentration observed and AUC with concomitant 
lenalidomide therapy
Co-administration of multiple dose lenalidomide (10 mg) with single dose warfarin 
(25 mg) had no effect on the pharmacokinetics of lenalidomide or warfarin. Expected 
changes in laboratory assessments of PT and INR were observed after warfarin 
administration, but these changes were not affected by concomitant lenalidomide 
administration. However, a close monitoring of PT and INR is recommended in patients 
receiving warfarin.
5.1.4
Risk of Overlapping Toxicities and Drug-Drug Interactions
The anticipated toxicities from the combined administration of atezolizumab with 
obinutuzumab and lenalidomide are expected to be manageable in the clinical setting. 
Hematologic toxicity (mainly neutropenia) is the most common toxicity associated with 
G-Len.  Of interest, the risk of overlapping hematologic toxicity with the addition of 
atezolizumab to G-Len appears very low.  Considering the risk associated with each 
individual component of the combination (Sections 5.1.1, 5.1.2, and 5.1.3), the expected 
overlapping non-hematologic toxicities summarized in Table 8 are IRRs, infections, 
cutaneous toxicity, GI toxicity, and elevated liver transaminases.  Additionally, 
hypothyroidism is a toxicity associated with both atezolizumab and lenalidomide, 
reported in 4% of patients treated with atezolizumab (mild to moderate in severity) and 
with unknown frequency in lymphoma patients treated with lenalidomide.  In one study of 
lenalidomide single agent in patients with myelodysplastic syndromes, hypothyroidism 
was reported in 6.8% of patients (RevlimidU.S. Package Insert).
Lenalidomide is primarily excreted in the urine.  Lenalidomide is not a substrate, 
inhibitor, or inducer of cytochrome P450 (CYP) group of enzymes (Kumar et al. 2009).  
Obinutuzumab and atezolizumab do not interact directly with CYP isoforms or other drug 
metabolizing enzymes or drug transporters.  Cytokine modulation may be considered as 
an indirect mechanism through which a monoclonal antibody could alter CYP expression, 
but would only be relevant for drugs that are significantly metabolized via CYP enzymes.  
Therefore, clinically relevant PK DDIs are unlikely to occur between lenalidomide, 
obinutuzumab, and atezolizumab.  


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Table 8
Summary of Potentially Overlapping Adverse Events
Event
Atezolizumab a Obinutuzumab b, c Lenalidomide d
G-Len e
Hematologic Toxicity
Neutropenia, Grade 3 or 4
0
5%14%
33%43%
26.1%
Febrile neutropenia
0
25%
2%7%
3.4%
Thrombocytopenia, Grade 3
or 4
0
5%8%
20%30%
10.2%
Anemia, Grade 3 or 4
4.6%
3%
6%12%
1.1%
Non-Hematologic Toxicity
IRRs
All grades
1.2% 
73%75%
0
14.8%
Grade 3 or 4
0
11%
0
0
Infections
All grades
0
5%41%
10%27%g
25.0%
Grade 3 or 4
0
10%
8%10%
3.4%
Rash
All grades
13%
7% 
18%27%
12.5%
Grade 3 or 4
0
0
1%4%
0
Diarrhea
All grades
22.4% f
5%8%
25%31%
14.8%
Grade 3 or 4
0
0
2%6%
0
Vomiting
All grades
19.7%
5%
12%
2.3%
Grade 3 or 4
0.2%
0
0
0
Nausea
All grades
27.8%
5%9%
18%30%
13.6%
Grade 3 or 4
0.2%
0
2%
0
SGOT/SGPT 
increase
Grade 3 or 4
1.7% f
3%
2%
1.1%
IRRinfusion-related reaction.
a Atezolizumab Investigator’s Brochure, Version 9, August 2016.
b BO21003 Clinical Study Report (No. 1056428).
c BO20999 Clinical Study Report (No. 1036614) (high dose, NHL cohorts).
d Goy et al. 2013, Wiernik et al. 2008, Witzig et al, 2011, and Zinzani et al. 2013.
e Data from relapsed/refractory FL cohort from (Study MO28005 [GALEN]), events related to 
any study drug during the induction phase of treatment.
f
Grade 2 immune colitis and Grade 3 or 4 immune hepatitis were documented in 0.4% and 
0.7% of patients, respectively.
g Pneumonia was the most common Grade 3 or 4 infection.
5.1.5
Management of Specific Adverse Events
Study treatment may be delayed for toxicity for a maximum amount of time, as specified 
in the tables below.  If study treatment is delayed for longer than the specified maximum, 
study treatment will be permanently discontinued. Treatment delays apply to all 
toxicities described below; dose modifications apply only to toxicities that are considered 


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to be related to lenalidomide.  There will be no dose reductions of obinutuzumab or 
atezolizumab.
The lenalidomide dose may be reduced in 5-mg increments one or two times, depending 
on the starting dose, as outlined in Table 9.  There will be no more than one dose 
reduction per treatment cycle.  If the lenalidomide dose is reduced, re-escalation is 
not permitted.
Table 9
Lenalidomide Dose Reduction
Starting Dose
First Reduction
Second Reduction
20 mg
15 mg
10 mg
15 mg
10 mg
5 mg
10 mg
5 mg

If a lenalidomide-related toxicity occurs during lenalidomide treatment (i.e., before 
Day 21 of the cycle), lenalidomide must be withheld until criteria for recovery have been 
met (i.e., improves to Grade 2 or baseline values).
If recovery is observed prior or on Day 15 of the cycle, lenalidomide may be resumed at 
the same dose for the remainder of the cycle (through Day 21; missed doses will not be 
made up) at the discretion of the investigator.  If the investigator considers that resuming 
lenalidomide at the same dose within the cycle represents an unacceptable risk for the 
patient, lenalidomide shall be resumed at reduced dose or withheld for the remainder of 
the cycle.  For subsequent cycles, lenalidomide will be resumed at reduced doses.
If recovery is observed after Day 15 of the cycle, lenalidomide will not be resumed 
for the current cycle.  For subsequent cycles, lenalidomide will be resumed at 
reduced doses.
Guidelines for management of toxicities during induction are provided in Section 5.1.5.1.  
Guidelines for management of toxicities during maintenance are provided in 
Section 5.1.5.2.
5.1.5.1
Toxicities during Induction Treatment
Hematologic Toxicities during Induction Treatment
Table 10 provides guidelines for management of hematologic toxicities that occur during 
induction treatment.  Hematologic toxicity is defined as neutropenia, anemia, or 
thrombocytopenia. Lymphopenia is not considered a hematologic toxicity but rather an 
expected outcome of therapy. 


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Table 10 Guidelines for Management of Hematologic Toxicities that Occur 
during Induction Treatment 
Event
Action To Be Taken
Grade 3 or 
4 
hematologic 
toxicity a,b
For patients on any dose of lenalidomide:

If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, these doses of 
obinutuzumab will not be skipped but given after resolution of toxicity. 
For patients on a lenalidomide dose 10 mg who have had one or no prior 
lenalidomide dose reductions

Withhold study treatment (except atezolizumab).c

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 receiving primary thromboprophylaxis who develop platelet count 
of 20,000/L, reduce the dose of LMWH or consider temporarily withholding 
platelet inhibitors, as applicable.  If patient’s condition doesn’t allow interruption 
of the anticoagulant/anti-aggregant treatment, adequate platelet transfusion 
support and close monitoring of the hematologic and coagulation functions are 
required.

For lenalidomide dose reductions, refer to guidelines presented in Section 5.1.5.

If the event is ongoing on Day 1 of the next cycle but improves to Grade 2 or 
baseline 14 days after the scheduled date of the cycle, resume obinutuzumab 
at full dose and resume lenalidomide at current dose or reduced dose if the 
patient received 21 days of lenalidomide due to toxicity (see Section 5.1.5).

If the event is ongoing on Day 1 of the next cycle but improves to Grade 2 or 
baseline 1521 days after the scheduled date for the next cycle, resume 
obinutuzumab at full dose and resume lenalidomide at a reduced dose a, b per 
guidelines in Section 5.1.5a,b for current and subsequent cycles.

If study treatment is withheld for 21 days, permanently discontinue 
lenalidomide.  Obinutuzumab may be continued for patients experiencing clinical 
benefit as determined by the investigator after discussion with the Medical 
Monitor.

Permanently discontinue study treatment if any of the following events occur:
Grade 3 or 4 thrombocytopenia that results in significant bleeding per 
investigator judgment
Recurrent Grade 3 or 4 neutropenia associated with fever 38°C lasting 
5 days or documented infection despite use of G-CSF and after one 
lenalidomide dose reduction
Recurrent Grade 4 neutropenia or thrombocytopenia lasting 7 days despite 
use of G-CSF (for neutropenia) and after one lenalidomide dose reduction
For patients on a lenalidomide dose of 5 mg and patients who have had two 
prior lenalidomide dose reductions:

Permanently discontinue lenalidomide.  Obinutuzumab may be continued for 
patients experiencing clinical benefit as determined by the investigator after 
discussion with the Medical Monitor.
G-CSFgranulocyte colony-stimulating factor; LMWHlow-molecular-weight heparin.
a Dose modifications apply only to events that are considered to be related to lenalidomide.
b If cytopenia is thought to be caused mainly by non-Hodgkin’s lymphoma infiltration of the bone 
marrow, the investigator may decide not to reduce the dose of lenalidomide.
c For Grade 3 neutropenia, only if sustained ( 7 days) Grade 3 or Grade 3 associated with 
fever (temperature 38.5C).


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Non-Hematologic Toxicities during Induction Treatment
Table 11 provides guidelines for management of non-hematologic toxicities that occur 
during induction treatment.
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.  
For detailed information regarding management of adverse events associated with 
atezolizumab, please refer to the Appendix 10.


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Table 11 Guidelines for Management of Non-Hematologic Toxicities
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, these doses of obinutuzumab will not be skipped but given 
after resolution of toxicity. 

When a treatment cycle is delayed because of a toxicity resulting from any component of the regimen, all study 
treatment should generally be held and resumed together to remain synchronized.

If it is anticipated that atezolizumab will be delayed by 21 days, obinutuzumab and lenalidomide should be given 
without atezolizumab if there is no contraindication. 

If one drug is discontinued, treatment with the other two drugs may be continued for patients experiencing clinical 
benefit as determined by the investigator after discussion with the Medical Monitor.

Permanently discontinue study treatment if any of the following events occur:
–
Grade 3 nonimmune-mediated adverse event that is considered to be related to study treatment and does not 
resolve to Grade 2 within 21 days
–
Nonimmune-mediated adverse event that is considered to be treatment related and requires study treatment to be 
withheld for 21 days
–
Immune-mediated adverse event that requires atezolizumab to be withheld for 42 days, unless approved by the 
Medical Monitor
IRRs and anaphylaxis

Guidelines for management of IRRs are provided in Sections 4.3.2.1 (obinutuzumab) and 4.3.2.2 (atezolizumab). 

Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its potential for causing 
agranulocytosis.

In case of anaphylaxis, study treatment should be permanently discontinued. 
Renal toxicity

Adjust the dose of lenalidomide a as outlined below:
–
If creatinine clearance is 30 but 60 mL/min, lenalidomide should be given at a dose of 10 mg/day.
–
If creatinine clearance is 30 mL/min and dialysis is not required, lenalidomide should be given at a dose of 10 mg 
every other day.
–
If creatinine clearance is 30 mL/min and dialysis is required, lenalidomide should be given at a dose of 5 mg/day.  
On dialysis days, the dose should be administered after dialysis.


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Table 11 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action to Be Taken
TLS
Clinical TLS b

Withhold study treatment.

Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive 
care, including dialysis as indicated.  Rasburicase therapy (if approved by the local health authority) may 
be administered as needed to reduce hyperuricemia.

If symptoms resolve completely, resume atezolizumab and obinutuzumab at full dose and resume 
lenalidomide at a reduced dose a per guidelines in Section 5.1.5 for current and subsequent cycles.

Perform chemistry panel every other day for the first week after re-initiation of lenalidomide.
Laboratory TLS b

Withhold study treatment.

Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive 
care as clinically indicated.

If laboratory abnormalities have resolved completely, resume atezolizumab and obinutuzumab at full 
dose and resume lenalidomide either at current dose or at a reduced dose a per guidelines in 
Section 5.1.5 for current and subsequent cycle, at the investigator’s discretion.
Peripheral 
neuropathy
Grade 4 or 
Myasthenia gravis 
(any grade) or 
Guillain-Barre (any 
grade)

Permanently discontinue study treatment.

Initiate treatment as per institutional guidelines.
Grade 2 or 3

Withhold study treatment and evaluate patient at least every 7 days.

If neurotoxicity is considered likely related to lenalidomide and there is improvement to Grade 1 or 
baseline, resume atezolizumab and obinutuzumab at full dose and resume lenalidomide at a reduced 
dose a per guidelines in Section 5.1.5 for current and subsequent cycles.

Permanently discontinue atezolizumab for life-threatening immune-mediated neuropathy.
New-onset neurologic manifestations 
suggestive of progressive multifocal 
leukoencephalopathy

Withhold study treatment. a

Consult with a neurologist if progressive multifocal leukoencephalopathy is suspected (refer to 
Section 5.1.1.5 for guidance on investigations).

If progressive multifocal leukoencephalopathy is ruled out, resume atezolizumab and obinutuzumab at 
full dose and resume lenalidomide at current dose. 

If progressive multifocal leukoencephalopathy is confirmed, permanently discontinue study treatment. 


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Table 11 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action to Be Taken
Immune-mediated 
meningoencephalitis

Withhold study treatment.

Refer patient to neurologist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and convert to 12 mg/kg/day 
oral prednisone or equivalent upon improvement. If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1:
‒
Resume obinutuzumab at full dose and lenalidomide at current dose.
‒
Taper corticosteroids over 1 month. Contact Medical Monitor before resuming atezolizumab.
Immune-mediated 
nephritis
Grade 3 or 4

Permanently discontinue study treatment.

Refer patient to renal specialist.

Consider renal biopsy and supportive measures.

Corticosteroids and/or additional immunosuppressive agents should be administered as clinically 
indicated.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset.d  Contact Medical Monitor.

Refer patient to renal specialist.

Consider renal biopsy and supportive measures as indicated.

Corticosteroids and/or additional immunosuppressive agents should be administered as clinically 
indicated.

If event resolves to Grade 1 or better, resume atezolizumab. e

If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. f
Grade 1

Continue study treatment.

Monitor kidney function, including creatinine, closely until values resolve to within normal limits or to 
baseline values.


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Table 11 Guidelines for Management of Non-Hematologic Toxicities (cont.)
AST, ALT, or 
bilirubin 
increase
Grade 3 
(or 10 ULN for 
patients with liver 
involvement)

Withhold study treatment and monitor liver enzymes at least every 7 days.

Investigate etiology.  Consult with a hepatologist if immune etiology is suspected (refer to Appendix 10
for guidance in case of suspected immune-mediated hepatitis).

For immune-mediated hepatopathy:
- Treat with corticosteroids following guidance provided in the Appendix 10.
- Permanently discontinue atezolizumab
-  Obinutuzumab may be resumed at full dose and lenalidomide at reduced dose for current and 
subsequent cycles as specified below, at investigator’s discretion and after approval by the Medical 
Monitor.  

If immune etiology is unlikely and there is improvement to Grade1, resume obinutuzumab and 
atezolizumab at full dose and resume lenalidomide at a reduced dose a per guidelines in Section 5.1.5
for current and subsequent cycles. 
Grade 2 lasting 57 
days

Withhold atezolizumab.

If immune etiology is suspected, treat with corticosteroids according to guidance provided in the 
Appendix 10.

If there is improvement to Grade 1, resume atezolizumab after corticosteroids have been tapered 
(refer to Appendix 10 for guidance). Contact Medical Monitor before resuming atezolizumab.
Amylase or 
lipase increase
+/- abdominal 
pain 
Grade 3

Withhold study treatment.

Investigate etiology.  Consult with a gastroenterologist if immune etiology is suspected.

For isolated increase of lipase or amylase that is asymptomatic and considered related to atezolizumab, 
obinutuzumab/rituximab and lenalidomide may be continued at current dose at the investigator’s 
discretion and in discussion with the Medical Monitor.

If no improvement, consider treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.

If there is improvement to Grade 2 and patient is asymptomatic, resume obinutuzumab at full dose 
and resume lenalidomide at current dose. Atezolizumab may be resumed at full dose after approval by 
the Medical Monitor.

For recurrent Grade 3 lipase or amylase increase that is isolated and asymptomatic, atezolizumab may 
be resumed following an individual benefit/risk assessment and in discussion with the Medical Monitor.


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Table 11 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action to Be Taken
Amylase or 
lipase increase
+/- abdominal 
pain (cont.)
Grade 2 long lasting 
(e.g., 3 weeks)
Amylase and/or lipase 1.52.0 ULN:

Continue study treatment. 

Consider oral prednisone 10 mg daily or equivalent.
Asymptomatic with amylase and/or lipase 2.05.0 ULN:

Treat as a Grade 3 event.
Immune-
mediated 
pancreatitis
Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. f

Refer patient to gastrointestinal specialist.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV methylprednisolone and 
convert to 12 mg/kg/day oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.

If event resolves to Grade 1, taper corticosteroids over 1 month.
Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset. d

Refer patient to gastrointestinal specialist.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV methylprednisolone and 
convert to 12 mg/kg/day oral prednisone or equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. e

If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab and contact Medical Monitor. f

For recurrent events, permanently discontinue atezolizumab and contact Medical Monitor. f
Ocular toxicity 
Grade 3 or 4

Withhold study treatment.

Investigate etiology.  Consult with an ophthalmologist.

Treat immune-mediated toxicity attributable to atezolizumab with systemic corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If there is improvement to Grade1, resume obinutuzumab at full dose and resume lenalidomide at 
current dose. Taper corticosteroids over 1 month.

Permanently discontinue atezolizumab.


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Table 11 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action to Be Taken
Ocular toxicity
(cont.)
Grade 2

Withhold study treatment for up to 12 weeks after event onset. d

Consult with an ophthalmologist.

Treat with topical corticosteroid eye drops and topical immunosuppressive therapy.

If event resolves to Grade 1, resume study treatment. e

If event event does not resolve to Grade 1 while withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. f
Grade 1

Continue study treatment.

Consult with an ophthalmologist.

Treat with topical corticosteroid eye drops. If symptoms persist, topical immunosuppressive therapy may 
also be considered.

If symptoms persist, treat as a Grade 2 event.
Diarrhea/Colitis Grade 4

Permanently discontinue study treatment.

Investigate etiology. Consult with a gastroenterologist (refer to Appendix 10 for guidance in case of 
suspected immune-mediated colitis).

Treat with corticosteroids following guidance provided in the Appendix 10.
Grade 2 or 3

Withhold study treatment.

Investigate etiology.  Consult with a gastroenterologist if immune etiology is suspected.

Treat immune diarrhea/colitis with corticosteroids following guidance provided in the Appendix 10. 

If diarrhea improves to Grade 1, resume obinutuzumab at full dose and resume lenalidomide at a 
reduced dose a per guidelines in Section 5.1.5. In case of immune-mediated event, atezolizumab may 
be resumed at full dose if colitis has cleared as confirmed by sigmoidoscopy (or colonoscopy, if 
appropriate) with colonic biopsy. Discuss with Medical Monitor before resuming atezolizumab.
Note:  If colitis is treated with corticosteroids, atezolizumab should not be resumed until the 
corticosteroids have been tapered to 10 mg/day of prednisone or equivalent (refer to Appendix 10 for 
guidance).


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Table 11 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action to Be Taken
Pneumopathy, 
non-infectious 
(i.e., dyspnea, 
hypoxia, 
pulmonary 
infiltrates)
Grade 3 or 4

Permanently discontinue atezolizumab. Withhold obinutuzumab and lenalidomide.

Investigate etiology.  Consult with a pulmonologist if immune etiology is suspected (refer to Appendix 10
for guidance).

Treat immune-mediated pneumopathy with corticosteroids following guidance provided in the 
Appendix 10.

If symptoms have resolved and CT lung findings are clear, resume obinutuzumab at full dose and 
resume lenalidomide at current dose. 
Grade 2

Withhold atezolizumab for immune-mediated pneumopathy.

Treat with corticosteroids following guidance provided in the Appendix 10. 

If there is improvement to Grade 1, resume atezolizumab after corticosteroids have been tapered
(refer to Appendix 10 for guidance). Discuss with Medical Monitor before resuming atezolizumab.

Treat as Grade 34 if recurrent episode of immune pneumopathy.
Tumor flare 
reaction
Grade 34 c

Withhold study treatment.

Administer corticosteroids, NSAIDs, and/or narcotic analgesics at investigator's discretion.

If there is improvement to Grade1, resume obinutuzumab and atezolizumab at full dose and resume 
lenalidomide at a reduced dose per guidelines in Section 5.1.5 for current and subsequent cycles.
Grade 12 c

Continue study treatment.

Administer corticosteroids, NSAIDs, and/or narcotic analgesics at investigator's discretion.


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Table 11 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action to Be Taken
Dermatologic 
toxicity:
Grade 2
Grade 3 with 
blistering or 
Grade 4

Permanently discontinue study treatment.
Grade 2 or Grade 3 
without blistering
First occurrence:

Withhold study treatment and evaluate patient at least every 7 days.

Investigate etiology.  Consult with a dermatologist.

Topical corticosteroids may be required.

If immune etiology is suspected, consider oral prednisone 10 mg or equivalent. If event is unresolved 
after 4872 hours, administer oral prednisone 60 mg or equivalent.

If there is improvement to Grade1, resume obinutuzumab at full dose and resume lenalidomide at a 
reduced dose a per guidelines in Section 5.1.5 for current and subsequent cycles. Atezolizumab may be 
resumed at full dose if the event is resolved and systemic corticosteroids dose is 10 mg/day of oral 
prednisone or equivalent. Contact Medical Monitor before resuming atezolizumab.
Second occurrence:

Permanently discontinue study treatment.
Hypothyroidism

Investigate etiology.  Consult with an endocrinologist (refer to the Appendix 10 for guidance if immune 
etiology is suspected).

Start thyroid replacement hormone.

Monitor TSH weekly.
Asymptomatic elevation of TSH

Continue study treatment.
Symptomatic elevation of TSH

Withhold study treatment.

If symptoms are controlled and TSH levels are decreasing, resume obinutuzumab and atezolizumab at 
full dose and lenalidomide at current dose.

Permanently discontinue atezolizumab for Grade 3 hypothyroidism.


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Table 11 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action to Be Taken
Hyperthyroidism (cont.)
For asymptomatic patients with TSH 0.5 mU/L:

Perform TSH, free T4, and T3 tests every 4 weeks.
For asymptomatic patients with TSH 0.1 mU/L or symptomatic patients:

Withhold study treatment.

Consider consultation with an endocrinologist.

Administer methimazole as needed.

Resume atezolizumab when symptoms are controlled by thyroid hormone replacement.

Permanently discontinue atezolizumab for life-threatening hyperthyroidism.
Hypophysitis 
(pan-hypopituitarism)
Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor.

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

Initiate hormone replacement if clinically indicated.
Grade 2 or 3

Withhold atezolizumab.

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

Initiate hormone replacement if clinically indicated.

Resume atezolizumab e if event resolves to Grade 1 or better, and patient is stable on replacement 
therapy (if required) within 12 weeks.

If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab and contact Medical Monitor.

For recurrent hypophysitis, treat as a Grade 4 event.


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Table 11 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action to Be Taken
Hyperglycemia  
Grade 34

Withhold atezolizumab.

Initiate treatment with insulin.

Monitor for glucose control.

Resume atezolizumab when symptoms resolve and glucose levels are stable.
Grade 1 or 2 
Continue atezolizumab.

Investigate for diabetes.  If patient has Type 1 diabetes, treat as a Grade 3 event.  If patient does not 
have Type 1 diabetes, treat as per institutional guidelines.

Monitor for glucose control.
Symptomatic adrenal 
insufficiency
Grade 24

Withhold atezolizumab.

Refer patient to endocrinologist.

Perform appropriate imaging.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and convert to 12 mg/kg/day 
oral prednisone or equivalent upon improvement.

Resume atezolizumab if event resolves to Grade ≤1 and patient is stable on replacement therapy 
(if required) within 12 weeks. If corticosteroids have been initiated, they must be tapered over 1 month 
to 10 mg/day oral prednisone or equivalent before atezolizumab can be resumed. Contact Medical 
Monitor before resuming atezolizumab.
Immune-mediated 
myocarditis
Grade 34

Permanently discontinue study treatment and contact Medical Monitor.

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider antiarrhythmic drugs, temporary pacemaker, 
ECMO, or VAD as appropriate.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and convert to 12 mg/kg/day 
oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.


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Table 11 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action to Be Taken
Immune-mediated 
myocarditis (cont.)
Grade 2

Withhold study treatment.

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider antiarrhythmic drugs, temporary pacemaker, 
ECMO, or VAD as appropriate.

Consider treatment with 12 mg/kg/day IV methylprednisolone or equivalent and convert to 12 mg/kg/day 
oral prednisone or equivalent upon improvement.

If event resolves to Grade 1 or better, resume study treatment. If corticosteroids have been initiated, they 
must be tapered over 1 month to 10 mg/day oral prednisone or equivalent before atezolizumab can be 
resumed.  Contact Medical Monitor before resuming atezolizumab.

If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor.
Grade 1

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines.
Venous thrombosis or embolism

Withhold lenalidomide.

Start anticoagulation treatment.

After patient has been stabilized on anticoagulants and any complications of the thromboembolic event have 
been managed, lenalidomide may be resumed at current dose at investigator’s discretion, dependent upon a 
benefitrisk assessment. 

Anticoagulants should be continued during the course of lenalidomide treatment.
Immune-mediated 
myositis
Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor (refer to Appendix 10 for further 
guidance).
Grade 3

Withhold atezolizumab for up to 12 weeks after event onset d and contact Medical Monitor (refer to 
Appendix 10 for further guidance).
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset d and contact Medical Monitor (refer to 
Appendix 10 for further guidance).
Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.


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Table 11 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action to Be Taken
Suspected HLH or MAS

Permanently discontinue atezolizumab and contact Medical Monitor (refer to Appendix 10 for further 
guidance).
Other non-hematologic 
toxicities (i.e., not 
described above), 
excluding alopecia, 
nausea, and vomiting 
Grade 3 or 4 Grade 4 events

Permanently discontinue study treatment.
Grade 3 events

Withhold study treatment.

If there is improvement to Grade 1 or baseline, resume obinutuzumab and atezolizumab at full dose and, if 
the event is considered related to lenalidomide, resume lenalidomide at a reduced dose per guidelines in 
Section 5.1.5 for current and subsequent cycles; if the event is not related to lenalidomide, resume 
lenalidomide at current dose.

For Grade 3 laboratory abnormalities that are isolated, asymptomatic and considered not clinically 
significant, study treatment may be either continued or delayed and resumed at the current dose, upon 
improvement to at least Grade 2 at the investigator’s discretion and in agreement with the Medical Monitor.
Grade 2

Withhold study treatment.

If there is improvement to Grade 1 or baseline, resume obinutuzumab and atezolizumab at full dose and 
resume lenalidomide at current dose.

For Grade 2 laboratory abnormalities that are isolated, asymptomatic and considered not clinically 
significant treatment may be continued at the current dose at the investigator’s discretion.
CTcomputed tomography; FLfollicular lymphoma; G-CSFgranulocyte colony-stimulating factor; HLH hemophagocytic lymphohistiocytosis; 
IRRinfusion-related reaction; IVintravenous; LMWHlow-molecular-weight heparin; MAS macrophage activation syndrome; 
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; NHLnon-Hodgkin's lymphoma; NSAIDnonsteroidal
anti-inflammatory drug; TLStumor lysis syndrome; TSHthyroid-stimulating hormone; ULNupper limit normal.
a Dose modifications apply only to events that are considered to be related to lenalidomide.
b According to Cairo-Bishop classification system.
c Graded according to NCI CTCAE Version 3.0.
d Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced 
to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
e If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before atezolizumab 
can be resumed.
f
Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated event.  
Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor.


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5.1.5.2
Toxicities during Maintenance Treatment
Table 12 provides guidelines for management of toxicities that occur during 
maintenance treatment.
Table 12 Guidelines for Management of Toxicities That Occur during 
Maintenance Treatment
Event
Action To Be Taken
Hematologic toxicity:
Grade 3 or 4
For all patients:

Atezolizumab may be continued at the discretion of the 
investigator.

Withhold obinutuzumab and lenalidomide.

Administer G-CSF for neutropenia per institutional guidelines.

Administer RBCs or platelets as required.

If there is improvement to Grade 2, resume obinutuzumab and 
lenalidomide at same dose.

If study treatment is withheld for 42 days, permanently 
discontinue study treatment.
Non-hematologic toxicity:
Grade 2
For atezolizumab-related toxicities with possible immune 
etiology:

Follow guidelines presented in Table 11 for the management of 
atezolizumab-related toxicities with possible immune etiology 
(i.e., autoimmune colitis, hepatitis, pancreatitis, hypothyroidism, 
pneumopathy, skin, toxicity, or ocular toxicity).
For all other non-hematologic toxicities:

Withhold study treatment.

If there is improvement to Grade 1 or baseline, administer study 
treatment at full dose.

If study treatment is withheld for 42 days, permanently 
discontinue study treatment.
G-CSFgranulocyte colony-stimulating factor.
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.


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5.2.1
Adverse Events
According to the ICH guideline for GCP, 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), except as described in 
Section 5.3.6.10

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 treatment

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 in-patient hospitalization (see Section 5.3.6.11)

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 treatment

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 
NCI CTCAE v3.0; see Section 5.3.4); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).


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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).
SPMs should be also reported as Serious Adverse Events.  This requirement includes 
any SPM, regardless of causal relationship to study treatment occurring at any time
during the study, from the time of signing the informed consent form up to 3 years after 
the last dose of lenalidomide.
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 
include the following:

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 5.3.6.7)

Suspected transmission of an infectious agent by the study treatment, 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 any of the study treatment components is suspected.

TLS of any grade, irrespective of causality

Second malignancies
Adverse events of special interest to atezolizumab are as follows:

Pneumonitis

Colitis

Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency,
hyperthyroidism, and hypophysitis

Hepatitis, including AST or ALT > 10 x ULN

Systemic lupus erythematosus

Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or
myasthenia gravis, and meningoencephalitis


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
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release
syndrome, influenza-like illness, and systemic inflammatory response syndrome

Nephritis

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)

Myositis

Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis
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 (except for TLS and second malignancies).
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 progressive multifocal leukoencephalopathy

Neutropenia, including prolonged neutropenia (neutropenia 1000 cells/L that 
does not resolve after 28 days without obinutuzumab treatment) and late-onset 
neutropenia (neutropenia 1000 cells/L occurring 28 days after obinutuzumab 
treatment has been completed or stopped) 

GI perforation
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 5.3.4), and causality (see Section 5.3.5).  


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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 treatment, 
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 treatment, all adverse events will be reported until 35 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 up to 2 years after the last dose of study treatment; and 
for SPMs (related and unrelated), which should be reported as serious adverse events 
until up to 3 years after the last dose of lenalidomide.
Similarly, second malignancies (related and unrelated to study treatment) will be 
reported indefinitely (even if the study has been closed) for patients who received 
obinutuzumab (see Section 5.6).
5.3.2
Dose-Limiting Toxicities (Immediately Reportable to the 
Sponsor)
During the DLT assessment window (Cycle 2), adverse events identified as DLTs, as 
defined in Section 3.1.2.1, 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).
5.3.3
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:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”
5.3.4
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE v4.0 will be used for 
assessing adverse event severity, with the exception of TFRs that will be graded using 
NCI CTCAE v3.0.  Table 13 will be used for assessing severity for adverse events that 
are not specifically listed in the NCI CTCAE.


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Table 13 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 (v4.0), 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.
5.3.5
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 or 
not an adverse event is considered to be related to any of the study treatment 
components, indicating "yes" or "no" accordingly.  The following guidance should be 
taken into consideration:

Temporal relationship of event onset to the initiation of study treatment

Course of the event, considering especially the effects of study treatment 
modifications or discontinuation, or reintroduction of study treatment (as applicable)

Known association of the event with the study treatment 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


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For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.6
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.
5.3.6.1
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after the end of study treatment 
infusion and are judged to be related to infusion of any of the study treatment 
components 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.
5.3.6.2
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.
5.3.6.3
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.


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
If a severe GI 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.
5.3.6.4
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.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes 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.
5.3.6.5
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

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.


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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP 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 5.3.6.4 for 
details on recording persistent adverse events).
5.3.6.6
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.
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 5.3.6.4 for 
details on recording persistent adverse events).


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5.3.6.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) 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baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value 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 5.3.6.2) 
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).
5.3.6.8
Deaths
For this protocol, mortality is an efficacy endpoint.  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 lymphoma should be recorded only on the 
Study Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study treatment, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).  An 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").
During survival follow-up, deaths attributed to progression of lymphoma should be 
recorded only on the Study Completion/Early Discontinuation eCRF.
5.3.6.9
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.


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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").
5.3.6.10
Lack of Efficacy or Worsening of Lymphoma
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on the Lugano 2014 criteria (see Appendix 3).  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.
5.3.6.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient 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 treatment
administration or insertion of access device for study treatment administration) 

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


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5.3.6.12
Adverse Events Associated with an Overdose or Error in 
Treatment Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  Additionally, all adverse 
events associated with an overdose or incorrect administration of study treatment should 
be recorded 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).
No experience with overdosage is available from human clinical trials.  In clinical trials 
with obinutuzumab doses ranging from 50 mg up to and including 2000 mg per infusion 
have been administered.  The incidence and intensity of adverse reactions reported in 
these studies did not appear to be dose-dependent.
Patients who experience overdose should have immediate interruption or reduction of 
their infusion and should be closely supervised.  Consideration should be given to the 
need for regular monitoring of blood cell count and for increased risk of infections while 
patients are B-cell depleted.
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 any of the study treatments:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Adverse events identified as DLTs

Pregnancies (see Section 5.4.3 for further details)
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


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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
Medical Monitor Contact Information for All Sites
Medical Monitor:
, Ph.D.
Telephone No.:
Mobile Telephone No.:
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, Adverse 
Events of Special Interest, and Dose-Limiting Toxicities
5.4.2.1
Events That Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The 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 Treatment Initiation
After initiation of study treatment, all adverse events will be reported until 35 days after 
the last dose of study treatment.  DLTs will be reported during the DLT assessment 
window.  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 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.


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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 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 and counsel the patient, discussing the risks of 
the pregnancy and the possible effects on the fetus.  The patient should be referred to 
an obstetrician or gynecologist, preferably one who is experienced in reproductive 
toxicity, for further evaluation and counseling.  The patient shall be instructed to return 
any unused portion of the study drug to the Investigator. 
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 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.  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 treatment.  
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
Exposure of Pregnant Female to Lenalidomide
If a pregnant female not enrolled in the study (e.g., caregiver or pharmacist) is exposed 
to lenalidomide, the Adverse Event Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 


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after learning of the exposure), either by faxing or by scanning and emailing the form 
using the fax number or email address provided to investigators.  The woman should be 
referred to an obstetrician or gynecologist, preferably one who is experienced in 
reproductive toxicity, for further evaluation and counseling.  
5.4.3.4
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. 
5.4.3.5
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment 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 
serious adverse events considered to be related to study treatment 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.


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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, electronic mail, 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
After the end of the adverse event reporting period (defined as 35 days after the last 
dose of study treatment), all deaths, regardless of cause, should be reported through 
use of the Long-Term Survival Follow-Up eCRF.
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug, the event should be reported through use 
of the Adverse Event eCRF.
An exception is made for Grade 34 infections (related and unrelated to study treatment), 
which should be reported until up to 2 years after the last dose of study treatment.  
In addition, SPMs (related and unrelated to study treatment) should be reported as 
serious adverse events until up to 3 years after the last dose of lenalidomide.
The Sponsor should also be notified of events of second malignancies indefinitely (even 
if the G+Atezo+len treatment group or the overall study has been closed) 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 

Atezolizumab Investigator’s Brochure

Lenalidomide Summary of Product Characteristics
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 study will include an initial dose-escalation phase followed by an expansion phase.  
The dose-escalation phase is designed to determine the RP2D for lenalidomide when 
combined with fixed doses of obinutuzumab and atezolizumab.  During the expansion 
phase, patients will undergo treatment with lenalidomide at the RP2D, obinutuzumab, 
and atezolizumab.
6.1
DETERMINATION OF SAMPLE SIZE
Limited dose finding will be conducted during the dose-escalation phase of this study.  
The estimated sample size follows from the dose-escalation rules for a 33 algorithm, 
as outlined in Section 3.1.  It is anticipated that enrollment of two dosing groups of 
36 patients each, for a total of 612 patients with relapsed or refractory FL, will be 
required to establish the RP2D during the dose-escalation phase.
Approximately 40 patients will be enrolled during the expansion phase.
The primary efficacy analysis will be the estimation of the true proportion of patients 
expected to obtain a PET-CTdefined CR at EOI. 
Data from completed and ongoing studies in similar disease settings will be used as 
historical controls for comparison.  Currently available data from the GALEN study 
(Morschhauser et al. 2017) indicate that the historical CR rate based on PET-CT scans 
is approximately 40% in relapsed or refractory setting, as assessed by Cheson 2007 
criteria.  
A sample size of 40 patients is deemed sufficient to provide adequate precision for the 
point estimate and for the lower bound of the two-sided 90% CI to rule out a clinically 
uninteresting probability of response of 46%, assuming an observed PET-CTdefined 
CR rate of 60%.  Updated estimates of the proportion of patients expected to achieve a 


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PET-CTdefined CR are expected to be available from ongoing studies by the time of 
the first interim analysis and will be used as reference data.  
Table 14 lists the two-sided 90% Clopper-Pearson exact CI for the true probability of 
achieving a PET-CTdefined CR at the EOI for a range of observed proportions based 
on a sample of 40 patients.  
Table 14 Potential 90% CI for the True Probability of Achieving a 
PET-CT–Defined Complete Response at EOI
Observed Proportion of Patients
Achieving a PET-CTDefined CR at EOI
(n40)
Two-Sided 90% Clopper-Pearson CI a for 
True Population PET-CTDefined CR
(n40)
0.32
(0.20, 0.46)
0.50
(0.36, 0.64)
0.55
(0.40. 0.68)
0.60
(0.46, 0.73)
0.65
(0.51, 0.77)
0.70
(0.56, 0.82)
0.72
(0.58, 0.83)
0.75
(0.61, 0.86)
0.80
(0.66, 0.89)
0.85
(0.72, 0.93)
CIconfidence interval; CR complete response; CT computed tomography; EOI end of 
induction; PET positron emission tomography.
a Note that the lower limit of a two-sided 90% CI is equivalent to a one-sided 95% CI.
6.2
DEFINITION OF ANALYSIS POPULATIONS
The following populations are defined:

The primary population will include patients who received at least one dose of each 
component of the combination.

The intent-to-treat (ITT) population will include all patients enrolled in the study.
6.3
SUMMARIES OF CONDUCT OF STUDY
Enrollment, protocol violations, and discontinuations from the study will be listed.  The 
incidence of treatment discontinuation for reasons other than disease progression will be 
tabulated.  
Data related to the administration of study treatment components as well as any dose 
modifications will be listed.  The number of doses, treatment cycles, average dose 
received, for each treatment component will be summarized using descriptive statistics 
(mean, standard deviation, median, and range).


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6.4
SUMMARIES OF DEMOGRAPHIC AND BASELINE
CHARACTERISTICS
Demographic and baseline characteristics, such as age, sex, race, and duration of 
malignancy, will be summarized using descriptive statistics (mean, standard deviation, 
median, and range) for continuous variables and frequencies and percentages for 
categorical variables.
6.5
SAFETY ANALYSES
The safety analysis will be performed on the primary population; additional safety 
analysis will be performed on the ITT population.
The safety analyses will be performed separately for each study phase (i.e., dose
escalation and expansion).
Safety will be assessed through summaries of adverse events, changes from baseline in 
laboratory test results, laboratory data with values outside of the normal ranges, ECGs, 
and vital signs.
All adverse events occurring on or after the first study treatment will be summarized by 
mapped term, appropriate thesaurus levels, and NCI CTCAE v4.0 grade.  All serious 
adverse events, adverse events of special interest, and selected events will be 
summarized and listed.  
Deaths reported during the treatment period and during post-treatment follow-up will be 
listed.
Relevant laboratory and vital sign data will be displayed by time, with Grade 3 and 4 
values identified as appropriate.
6.6
EFFICACY ANALYSES
6.6.1
Primary Efficacy Endpoint
The efficacy analysis will be performed on the primary population.  Additional efficacy 
analysis will be performed on the ITT population.  
Patients who received lenalidomide at the RP2D during the dose-escalation phase will 
be pooled with patients treated in the expansion phase.
The primary efficacy analysis will be estimation of the proportion of patients achieving a 
CR at EOI, as determined by the IRC through use of the PET-CTbased Lugano 2014 
criteria (see Appendix 3).  Point estimates will be presented, along with the 
corresponding two-sided 90% Clopper-Pearson exact CIs.  Patients without an EOI 
tumor assessment will be considered non-responders.


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6.6.2
Secondary Efficacy Endpoints
The secondary efficacy analyses will be estimation of the proportion of patients 
achieving each of the following endpoints: 

CR at EOI, as determined by the investigator on the basis of PET-CT scans

CR at EOI, as determined by the IRC and by the investigator on the basis of CT 
scans alone 

Objective response (defined as a CR or PR) at EOI, as determined by the IRC and 
by the investigator on the basis of PET-CT scans

Objective response (defined as a CR or PR) at EOI, as determined by the IRC and 
by the investigator on the basis of CT scans alone

Best response of CR or PR during the study, as determined by the investigator on 
the basis of CT scans alone.
For all secondary efficacy endpoints, point estimates will be presented, along with the 
corresponding two-sided 90% Clopper-Pearson exact CIs.  Patients without a 
post-baseline tumor assessment will be considered non-CRs and non-responders, 
respectively.
6.6.3
Exploratory Efficacy Endpoints
For patients who have positive PET scans at EOI:  CR at 12 months, as determined by 
the IRC and by the investigator on the basis of PET-CT scans.
Point estimates will be presented, along with the corresponding two-sided 90% 
Clopper-Pearson exact CIs.  Patients without a post-baseline tumor assessment will be 
considered non-CRs and non-responders, respectively.
PFS, EFS, DFS, DOR, and overall survival (OS) will be summarized descriptively using 
the Kaplan-Meier method (Kaplan and Meier 1958). For the PFS, EFS, and DFS 
analyses, data for patients without an event of interest will be censored at the date of the 
last tumor assessment.  For EFS and PFS analysis, data for patients without 
post-baseline tumor assessments will be censored at the date of initiation of study 
treatment plus 1.  For the DFS analysis, data for patients without post-first CR tumor 
assessments will be censored at the date of first CR tumor assessments1 day.  
OS analyses, data for patients who have not died will be censored at the date the patient 
was last known to be alive.  Where medians are reached, the corresponding estimated 
median will be provided, along with the 95% CI using the method of Brookmeyer and 
Crowley (1982).  In addition, estimates of the proportion of patients who are event free at 
6 months, 9 months, 1 year, and 2 years will be provided, along with 95% asymptotic CIs 
using Greenwood’s formula for standard errors.


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6.7
PHARMACOKINETIC ANALYSES
Plasma/serum concentrations of obinutuzumab, atezolizumab, and lenalidomide will be 
tabulated, summarized, and plotted after appropriate grouping.  As appropriate, PK
parameters (e.g., AUC, time to maximum concentration, maximum concentration, and 
half-life) may also be calculated, tabulated, and summarized after appropriate grouping.  
Additional PK and PK/PD analyses (e.g., population modelling, including pooled 
analyses across studies) may also be performed as appropriate.  If done, these 
additional analyses may be reported separately from the Clinical Study Report.  
At the discretion of the Sponsor, all analyses may be extended to include 
relevant-biotransformation products of lenalidomide.
6.8
IMMUNOGENICITY ANALYSES
The numbers and proportions of post-treatment HAHA- or anti-therapeutic 
antibody-positive patients and HAHA- or anti-therapeutic antibody-negative patients at 
baseline and during both the treatment and follow-up periods will be summarized.  
The relationship between HAHA or anti-therapeutic antibody status and safety, efficacy, 
and PK endpoints will be explored as appropriate.
6.9
BIOMARKER ANALYSES
Exploratory analyses of biomarkers related to tumor biology and study treatment 
mechanisms of action will be conducted.  Analyses will assess the prognostic and/or 
predictive value of candidate biomarkers with respect to both IRC- and 
investigator-assessed outcomes.  Specifically, the association between candidate 
biomarkers and PET-CTdefined CR rate and OR rate, and potentially other measures 
of efficacy and safety, will be explored to assess potential prognostic or predictive value.  
These analyses may not be included in the final study report because of their exploratory 
nature.  In addition to analysis in the context of this study, data will also be explored in 
aggregate with data from other studies.  
6.10
INTERIM ANALYSES
It is anticipated that at least one interim analysis will be conducted during the expansion 
phase of the study, when at least 15patients treated at the RP2D of lenalidomide have 
been evaluated for PET-CTdefined CR at the EOI.  Additional analyses will be 
conducted every 4 months to guide early stopping of enrollment for safety on the basis 
of observed toxicities. Stopping rules for excess toxicity, including fatal adverse events,
have been included (see Section 6.11).
During the expansion phase, a modified version of the predictive probability design 
(Lee and Lui 2008) may be used to guide early stopping for futility by comparing the 
observed proportion of patients who achieve a PET-CTdefined CR at EOI with that in 
historical controls.  The earliest interim analysis would occur after at least 15 patients 
have been evaluated for PET-CTdefined CR at EOI.  


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If, at any time, an interim analysis suggests that the proportion of patients achieving a 
PET-CTdefined CR is lower or higher than expected, the IMC will review the data and 
decide whether to recommend an early decision to stop enrollment.  Interim analysis 
decision rules will be based on the modified version of the predictive probability that the 
trial will have a positive outcome if carried out to completion and will use the historical 
control data available at the time of analysis.
Additional review of safety and/or efficacy data by the IMC may be requested by and 
carried out at the discretion of the Medical Monitor.  Further details regarding the rules 
and guidelines of data review will be provided in an IMC charter.
6.11
STOPPING RULES FOR SAFETY
In the event that any of the following criteria are met at any time in the course of the 
study, the IMC will be immediately convened to review and provide a recommendation 
for further conduct of the study:

Fatal adverse events ≥ 10% 

Grade 34 adverse events ≥ 75% 
The fatal adverse event threshold of 10% is derived from the completed GADOLIN study
(Sehn et al. 2015) and the ongoing external study GALEN (Morschhauser et al. 2017), in 
which the occurrence rates of Grade 5 adverse events were 6% and 3.4%, respectively.
Based on these two studies, the assumed historical control fatal adverse event rate is 
5%, and with a 5% addition as a trigger for IMC review, a threshold rate of 10% is 
used for the stopping rules. The fatal adverse events will be continuously monitored 
during the conduct of the study and if the number of fatal adverse events reach the 
pre-specified threshold, the IMC will be immediately convened to decide whether to 
continue or stop the study (see Table 15). For each of these incidence rates, the 
minimized false positive probabilities and the true positive probability of correctly
triggering an IMC safety review when the observed fatal adverse event rates are 5% 
higher than the historical control rate are presented.
Table 15 Early Stopping Rules Based on Number of Fatal Adverse Events
Interim 
look, n
# (rate, %) of fatal 
(Grade 5) AE(s) 
required for an IMC 
review
Probability of early stopping a
Probability of correct stop if 
true experimental regimen 
fatal AE rate =10%
(historical control rate + 5%)
Probability of incorrect stop 
if true experimental
regimen fatal AE rate =5%
2730
2 (7%)
59%
19%
3140
2 (5%)
78%
32%
4145
3 (7%)
67%
19%
AEadverse event; IMCInternal Monitoring Committee.
Note:  The assumed historical control fatal adverse event rate is 5%.
a Assessed for upper limit of the interim look sample size (i.e., for n=30, 40, 45).


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In addition to fatal adverse events, Grade 3/4 adverse events, which represent severe 
non-fatal events, will be closely monitored. The threshold of 75% for Grade 3/4 adverse 
events is derived from the external study GALEN (Morschhauser et al. 2017) and the 
completed study GADOLIN (Sehn et al. 2015), where the occurrence rates of Grade 3/4 
adverse events were 57% and 62%, respectively.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for 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 Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and any other 
externally-generated electronic study data will be sent directly to the Sponsor, using 
the Sponsor’s standard procedures to handle and process the electronic transfer of 
these 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.
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 Sponsor.
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 on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification 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, 


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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 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 on 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, 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, electronic patient-reported outcome data (if applicable), 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 Clinical Study Report has been 
completed 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 GCP 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. Food and Drug Administration (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 a Child’s Informed Assent Form or Home 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.


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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 
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.
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
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 (defined as the time 
when all enrolled FL patients have completed or discontinued study treatment.
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 
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 Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 


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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.
EDC will be used for this study.  An IxRS will be used to assign patient numbers.  
A central laboratory will be used for a subset of laboratory assessments as specified in 
Section 4.5.7; otherwise, local laboratories will be used.  A central independent review 
facility will be used to collect PET-CT and CT scans, and the IRC will perform 
independent assessments of response for all patients enrolled in the study (separate 
IRC charter will contain all details).  
9.5
PUBLICATION 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 details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Trials Data at the following Web site:
http://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.


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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 Assessments (cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
140/Protocol BO29562, Version 8
Screening a
Induction (6 months; 28-day cycles)
EOI
Maint. (24 months)
EOM b
Post-
Treatment
FU Period 
(Q3M) d
Survival 
FU 
Period 
(Q3M) d
D28 
to 
D1
D14 
to 
D1
Cycle 1 
(1 days)
Cycles 26
(2 days)
After Last 
Induction 
Dose c
Monthly
Every 
2 months 35 days
after 
Last 
Dose
(3 days)
D1
D8
D15
D22 D1 D8 D15 D22
D1
D1
Urinalysis (dipstick)
x
As clinically indicated
Pregnancy test q
x q
x q
x q
x q
x q
x q
Hepatitis B and C testing r
x
TSH, T3, T4
x
Every 3 months
Quantitative IgA, IgG, IgM
x
x
x s
x
x t
HAHA sample for 
obinutuzumab
x u
Anti-therapeutic antibody
sample for atezolizumab
x u
PK sample for obinutuzumab
x u
PK sample for atezolizumab
x u
PK sample for lenalidomide
x u
Plasma for soluble PD-L1
x n
Whole blood for MRD v
x n,v
x v
x s,v
Whole blood for lymphocyte 
immunophenotyping w
x n
x n
x
x s
x
x t
Whole blood for T-cell 
receptor repertoire in PBMCs
x n
x
n,o
x
x x


Appendix 1
Schedule of Assessments (cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
141/Protocol BO29562, Version 8
Screening a
Induction (6 months; 28-day cycles)
EOI
Maint. (24 months)
EOM b
Post-
Treatment
FU Period 
(Q3M) d
Survival 
FU 
Period 
(Q3M) d
D28 
to 
D1
D14 
to 
D1
Cycle 1 
(1 days)
Cycles 26
(2 days)
After Last 
Induction 
Dose c
Monthly
Every 
2 months 35 days
after 
Last 
Dose
(3 days)
D1
D8
D15
D22 D1 D8 D15 D22
D1
D1
Plasma for soluble PD-L1
x n
x n
x
n,o
x n,o
Optional peripheral blood 
sample for RCR y
x n
Tumor tissue specimen 
(leftover tissue may be used 
for optional RCR specimen y)
x z
x aa
x aa
Concomitant medications bb
x bb
To be recorded continually until end of treatment bb
Adverse events cc
x
To be assessed continually cc
PET-CT scan
x dd
x ee
x ff
CT scan gg
x gg
x hh
x ee
x hh
x ii
x jj
Bone marrow biopsy and 
aspirate 
x kk
x ee,ll
x ll
x ii,ll
Study 
treatment 
administration
Obinutuzumab
mm
x
x
x
x
x
Atezolizumab
mm
x
x
D1, D2
Lenalidomide
mm
D121
D121
D121


Appendix 1
Schedule of Assessments (cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
142/Protocol BO29562, Version 8
Screening a
Induction (6 months; 28-day cycles)
EOI
Maint. (24 months)
EOM b
Post-
Treatment
FU Period 
(Q3M) d
Survival 
FU 
Period 
(Q3M) d
D28 
to 
D1
D14 
to 
D1
Cycle 1 
(1 days)
Cycles 26
(2 days)
After Last 
Induction 
Dose c
Monthly
Every 
2 months 35 days
after 
Last 
Dose
(3 days)
D1
D8
D15
D22 D1 D8 D15 D22
D1
D1
New anti-lymphoma treatment
x
x
Survival follow-up
x
CTcomputed tomography; Dday; ECOGEastern Cooperative Oncology Group; eCRF electronic Case Report Form; EOIend of induction; 
EOMend of maintenance; FLIPIFollicular Lymphoma International Prognostic Index; FU follow-up; HAHA human anti-human antibody;
IgA immunoglobulin A; IgGimmunoglobulin G; Maint. maintenance; MRDminimal residual disease; MRImagnetic resonance imaging; 
NKnatural killer; PBMCperipheral blood mononuclear cell; PD-L1programmed deathligand 1; PET positron emission tomography; 
PKpharmacokinetic; Q3M every 3 months; RCRRoche Clinical Repository; SPMsecond primary malignancies; T3triiodothyronine; 
T4thyroxine; TSHthyroid-stimulating hormone; wk week.
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  Assessments shaded in gray should 
be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the case of an adverse event).  
a The screening period starts with the signing of the Informed Consent Form.  Results of standard-of-care tests or examinations performed prior to 
obtaining informed consent and within the defined window may be used as screening and baseline assessments; such tests do not need to be 
repeated for screening purposes.
b Patients who complete maintenance treatment or discontinue maintenance treatment prematurely will undergo assessments at EOM.
c EOI assessments should be performed 68 weeks after Day 1 of the last induction cycle.  As an exception, patients who discontinue induction 
treatment prematurely because of an adverse event may undergo EOI assessments 48 weeks after their last dose of study treatment.
d Patients who complete treatment or discontinue treatment for reasons other than disease progression will undergo assessments every 3 months 
during the post-treatment FU period, which will continue until disease progression, the start of new anti-lymphoma treatment, or the end of the 
study, whichever occurs first.  The first post-treatment FU visit is 3 months after the EOI visit for patients who do not receive maintenance 
treatment and 3 months after the last dose for patients who receive maintenance treatment.  Patients who experience disease progression will 
be evaluated for survival status and new anti-lymphoma treatment every 3 months until the end of the study.  The end of the study is defined as 
the time when all enrolled patients have completed or discontinued study treatment (including induction treatment and maintenance treatment as 
applicable).


Appendix 1
Schedule of Assessments (cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
143/Protocol BO29562, Version 8
e Informed consent must be documented before any study-specific screening procedure is performed.  
f
Vital signs include respiratory rate, pulse rate, body temperature, and systolic and diastolic blood pressures while the patient is in a seated 
position.  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.  For obinutuzumab infusions:  For the first cycle and for 
patients who experience an infusion-related reaction, vital signs will be measured prior to the infusion, every 15 (5) minutes for the first 
90 minutes of the infusion, and then every 30 (10) minutes until 1 hour after completion of the infusion.  For the second and subsequent cycles, 
vital signs will be measured every 30 minutes during the infusion, except in patients who had experienced an infusion-related reaction during a 
prior infusion.  For atezolizumab infusions:  Vital signs should be determined up to 60 (15) minutes before each atezolizumab infusion.  Vital 
signs should also be obtained during or after the atezolizumab infusion if clinically indicated.
g Perform only in patients who will not be receiving maintenance treatment.
h Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions 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 Unexplained fever 38C, night sweats, and unexplained weight loss 10% of body weight over 6 months.
l
Includes hemoglobin, hematocrit, platelet count, RBC count, WBC count, and percent or absolute WBC differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).
m Screening laboratory assessments may be used for Day 1 of Cycle 1 if performed within 72 hours prior to Day 1 of Cycle 1.
n Perform hematology and chemistry tests within 72 hours prior to Day 1 of each cycle during induction or each month during maintenance, and 
within 24 hours prior to other timepoints during induction treatment.  Samples for exploratory biomarker research should be collected at the same 
time as hematology and chemistry samples. 
o Cycles 2 and 3 only.
p Includes sodium, potassium, glucose, BUN or urea, creatinine, calculated creatinine clearance, calcium, total bilirubin, direct bilirubin, 
total protein, albumin, ALT, AST, alkaline phosphatase, amylase, lipase, LDH, and uric acid.


Appendix 1
Schedule of Assessments (cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
144/Protocol BO29562, Version 8
q All women of childbearing potential will have two negative serum pregnancy test results prior to initiating treatment:  at 1014 days prior to Day 1 
of Cycle 1 and within 24 hours prior to Day 1 of Cycle 1.  Urine pregnancy tests are required after treatment initiation (including times of 
treatment interruption) as follows:  every week during the first cycle and then every 4 weeks during treatment for women with regular menstrual 
cycles or every 2 weeks during treatment for women with irregular menstrual cycles, any time the patient misses her period or has unusual 
menstrual bleeding, at the time of treatment discontinuation, and at least 35 days after the last dose of study treatment.  If a urine pregnancy test 
is positive, it must be confirmed by a serum pregnancy test.
r
Includes hepatitis B surface antigen, total hepatitis B core antibody, and hepatitis C virus antibody.
s Perform at the same time as tumor assessments at 12, 18, and 24 months after initiation of induction treatment.
t
Perform every 3 months until disease progression, or the start of new anti-lymphoma treatment, whichever occurs first.
u See Appendix 2 for detailed PK collection schedule.
v Includes circulating lymphoma cells and/or cell-free circulating tumor DNA.
w Includes B-cell counts (CD19), T-cell counts (CD3, CD4, and CD8), and NK cell counts (CD16 and CD56).
x Perform at the same time as tumor assessments at 12 and 18 months after initiation of induction treatment.
y Requires separate patient consent for RCR participation.  Not applicable for a site that has not been granted approval for RCR sampling.
z Availability of adequate archival or freshly biopsied tumor tissue samples should be confirmed at screening (see Section 4.5.7 for details).
aa A tumor biopsy sample will be collected prior to the start of Cycle 2 and at the time of progression unless no adequate tumor site is accessible.
bb Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to the screening period until the EOI or EOM visit, whichever occurs later.
cc After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 35 days after the last dose of study 
treatment.  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 up to 2 years after the last dose of study treatment; and for SPM (related and unrelated), which should be reported as serious 
adverse events until up to 3 years after the last dose of lenalidomide.The investigator should follow each adverse event until the event has 
resolved to baseline grade or better, until the event is assessed as stable by the investigator, until the patient is lost to follow-up, or until the 
patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to any of the study 
treatment components or trial-related procedures until a final outcome can be reported.
dd The screening PET-CT scan must be performed within 35 days prior to Day 1 of Cycle 1.
ee Perform only for patients who have received at least two cycles of induction treatment.
ff If PET-CT scan is positive at EOI, perform at 12 months after initiation of induction treatment, within 14 days prior to treatment administration.


Appendix 1
Schedule of Assessments (cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
145/Protocol BO29562, Version 8
gg Includes CT scan of the neck (if clinically indicated), chest, abdomen, and pelvis.  If contrast is medically contraindicated (e.g., patients with 
contrast allergy or impaired renal clearance), MRI scans of the chest, abdomen, and pelvis (and neck, if clinically indicated) and a non-contrast 
CT scan of the chest may be performed.  Combined PET/CT scanners may be used to collect diagnostic CT scans, but only according to the 
technical guidelines in the imaging manual.  The screening CT scan must be performed within 35 days prior to Day 1 of Cycle 1.
hh Perform at the end of Cycle 2 (within 7 days prior to Day 1 of Cycle 3) and at 12, 18, and 24 months after initiation of induction treatment, within 
14 days prior to treatment administration. Patients with radiographic evidence of progression at the end of Cycle 2 who continue to receive study 
treatment per criteria defined in Section 3.1.1 should have a CT scan repeated 48 weeks later.
ii Perform only if not done within the previous 3 months.
jj Perform every 6 months.
kk Bone marrow biopsy and aspirate must be performed within approximately 3 months prior to Day 1 of Cycle 1.
ll For patients with bone marrow involvement at screening, a repeat assessment will be performed at EOI if there is radiologic evidence of a 
complete response, and during maintenance or at EOM if there is radiologic evidence of a complete response or if clinically indicated 
(e.g., if there is clinical suspicion of progressive disease in the bone marrow with no radiologic evidence of progression).
mm Refer to Sections 4.3.2.4 and 4.3.2.5 for details on dosing and schedule.  At each cycle, each patient will be supplied with only enough 
lenalidomide for that cycle.  During maintenance treatment, lenalidomide will be administered for a maximum of 12 months.
nn Patient may be assessed every 2 months if atezolizumab has been discontinued and maintenance treatment is continued with obinutuzumab 
single agent 






Appendix 2
Pharmacokinetic and Immunogenicity Sampling Schedule for Obinutuzumab, Atezolizumab, and 
Lenalidomide (cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
148/Protocol BO29562, Version 8
Study Visit
Serum Obinutuzumab 
PK Sample a,b, c
Serum Atezolizumab 
PK Sample a
Serum Obinutuzumab 
HAHA Sample a
Serum Atezolizumab 
Anti-Therapeutic 
Antibody Sample a
Plasma Lenalidomide 
PK Sample a, d
120 days (30 days) 
after the last dose of 
obinutuzumab and the 
last dose of 
atezolizumab 
(as appropriate for the 
sample)
x
x
x
x

1 year after the last 
dose
x
x
x
x

HAHAhuman anti-human antibody; PKpharmacokinetic.
a For induction and maintenance, sample collection timing is relative to specified drug.
b For induction and maintenance, following analysis of the serum PK sample for obinutuzumab quantitation, the remaining sample may be used for 
HAHA analysis (if HAHA analysis is not already planned at that timepoint) at the discretion of the clinical pharmacologist and/or the clinical 
scientist, should there be any unusual results in the obinutuzumab concentrations. 
c For discontinuation and follow-up, following analysis of the serum pharmacokinetic sample for obinutuzumab quantitation, the remaining sample 
may be used for HAHA analysis (if HAHA analysis is not already planned at that timepoint) at the discretion of the clinical pharmacologist and/or 
the clinical scientist, should there be any unusual results in the obinutuzumab concentrations.
d On lenalidomide PK sampling visits, lenalidomide dose will be taken in the clinic.
e An “x” entry indicates that the PK sample is to be taken at any time during the visit.
f
If the Cycle 1 Day 1 dose of obinutuzumab is split over two days, take the 30-minute, post-end-of-infusion obinutuzumab PK sample relative to 
the end of the infusion on Day 2, and ensure that the date and time of the PK collection are accurately recorded.


Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
149/Protocol BO29562, Version 8
Appendix 3
Lugano Response Criteria for Malignant Lymphoma
(Cheson et al. 2014)
In this study, a PET-CTbased complete response requires normal bone marrow by 
morphology for patients with bone marrow involvement at baseline.  If indeterminate by 
morphology, immunohistochemistry should be negative. Additionally, the designation of 
PET-CTbased PR requires that CT-based response criteria for a CR or PR be met in 
addition to the PET-CTbased response criteria for a PR.
Revised Criteria for Response Assessment
Response and Site
PET-CTBased Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all of the 
following)
Lymph nodes and 
extralymphatic 
sites
Score 1, 2, or 3 a with or without a 
residual mass on 5PS b
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic 
uptake or with activation within spleen 
or marrow (e.g., with chemotherapy or 
myeloid colony-stimulating factors), 
uptake may be greater than normal 
mediastinum and/or liver.  In this 
circumstance, complete metabolic 
response may be inferred if uptake at 
sites of initial involvement is no greater 
than surrounding normal tissue even if 
the tissue has high physiologic uptake.
Target nodes/nodal masses must 
regress to 1.5 cm in LDi
No extralymphatic sites of disease
Non-measured 
lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in 
marrow
Normal by morphology; if indeterminate, 
IHC negative


Appendix 3
Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) (cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
150/Protocol BO29562, Version 8
Revised Criteria for Response Assessment
Response and Site
PET-CTBased Response
CT-Based Response
Partial
Partial metabolic response
Partial remission (all of the following)
Lymph nodes and 
extralymphatic 
sites
Score 4 or 5 b with reduced uptake 
compared with baseline and residual 
mass(es) of any size
50% decrease in SPD of up to six
target measurable nodes and 
extranodal sites
At interim, these findings suggest 
responding disease
When a lesion is too small to measure on 
CT, assign 5 mm5 mm as the 
default value
At end of treatment, these findings 
indicate residual disease
When no longer visible, 00 mm
For a node 5 mm 5 mm, but smaller 
than normal, use actual measurement 
for calculation
Non-measured 
lesion
Not applicable
Absent/normal, regressed, but no 
increase
Organ enlargement
Not applicable
Spleen must have regressed by 50% in 
length beyond normal
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake 
compatible with reactive changes from 
chemotherapy allowed).  If there are 
persistent focal changes in the 
marrow in the context of a nodal 
response, consideration should be 
given to further evaluation with MRI or 
biopsy or an interval scan.
Not applicable
No response or stable 
disease 
No metabolic response
Stable disease
Target nodes/nodal 
masses, 
extranodal 
lesions
Score 4 or 5 b with no significant change 
in FDG uptake from baseline at 
interim or end of treatment
50% decrease from baseline in SPD of 
up to six dominant, measurable nodes 
and extranodal sites; no criteria for 
progressive disease are met
Non-measured 
lesion
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable


Appendix 3
Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) (cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
151/Protocol BO29562, Version 8
Revised Criteria for Response Assessment
Response and Site
PET-CTBased Response
CT-Based Response
Progressive disease
Progressive metabolic disease
Progressive disease requires at least 
one of the following 
Individual target 
nodes/nodal 
masses
Score 4 or 5 b with an increase in 
intensity of uptake from baseline 
and/or
PPD progression:
Extranodal lesions
New FDG-avid foci consistent with 
lymphoma at interim or 
end-of-treatment assessment
An individual node/lesion must be 
abnormal with:
LDi 1.5 cm and
Increase by 50% from PPD nadir and
An increase in LDi or SDi from nadir
0.5 cm for lesions 2 cm
1.0 cm for lesions 2 cm
In the setting of splenomegaly, the 
splenic length must increase by 50% 
of the extent of its prior increase 
beyond baseline (e.g., a 15-cm 
spleen must increase to 16 cm).  
If no prior splenomegaly, must 
increase by at least 2 cm from 
baseline.
New or recurrent splenomegaly 
New or clear progression of preexisting 
non-measured lesions


Appendix 3
Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) (cont.)
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Revised Criteria for Response Assessment
Response and Site
PET-CTBased Response
CT-Based Response
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another 
etiology (e.g., infection, inflammation); 
if uncertain regarding etiology of new 
lesions, biopsy or interval scan may 
be considered
Regrowth of previously resolved lesions
A new node1.5 cm in any axis
A new extranodal site 1.0 cm in any 
axis; if 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
5PS5-point scale; CTcomputed tomography; FDGfluorodeoxyglucose; GIgastrointestinal; 
IHCimmunohistochemistry; LDilongest transverse diameter of a lesion; MRImagnetic resonance 
imaging; PETpositron emission tomography; PPDcross product of the LDi and perpendicular diameter; 
SDishortest axis perpendicular to the LDi; SPDsum of the product of the perpendicular diameters for 
multiple lesions.
a
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time 
of an interim scan.  However, in trials involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate response (to avoid undertreatment).  Measured 
dominant lesions:  Up to six of the largest dominant nodes, nodal masses, and extranodal lesions 
selected to be clearly measurable in two diameters.  Nodes should preferably be from disparate regions 
of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal 
lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous 
lesions, or those noted on palpation.  Non-measured lesions:  Any disease not selected as measured; 
dominant disease and truly assessable disease should be considered not measured.  These sites 
include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that 
do not meet the requirements for measurability but are still considered abnormal, as well as truly 
assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal 
masses, and other lesions that cannot be confirmed and followed by imaging.  In Waldeyer’s ring or in 
extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum 
with complete metabolic response, but should be no higher than surrounding normal physiologic uptake 
(e.g., with marrow activation as a result of chemotherapy or myeloid growth factors).
b
PET 5PS:  1no uptake above background; 2uptake mediastinum; 3uptake mediastinum 
but liver; 4uptake moderately liver; 5uptake markedly higher than liver and/or new lesions; 
Xnew areas of uptake unlikely to be related to lymphoma.


Appendix 3
Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) (cont.)
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REFERENCE
Cheson B, Fisher R, Barrington S, et al. Recommendations for initial evaluation, staging 
and response assessment of Hodgkin and nonHodgkin lymphoma: The Lugano 
Classification. J Clin Oncol 2014;32:305969.


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Appendix 4
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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Appendix 5
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 (38C), 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.


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Appendix 6
Follicular Lymphoma International Prognostic Index
Table 1
Follicular Lymphoma International Prognostic Index
FLIPI Risk Factor
Ann Arbor Stage III or IV
Age 60 years
Serum LDH 1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 6
Follicular Lymphoma International Prognostic Index (cont.)
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Table 2
Follicular Lymphoma International Prognostic Index 2
FLIPI2 Risk Factor
Bone marrow involvement
Age 60 years
2 microglobulin 1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; FLIPI2Follicular Lymphoma International Prognostic Index 2; 
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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Appendix 7
Anaphylaxis Precautions
EQUIPMENT NEEDED

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice 

Antihistamines

Corticosteroids

IV 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:

Stop the study treatment infusion.

Maintain an adequate airway.

Administer glucocorticoids, antihistamines, epinephrine, or other medications as 
required by patient status and directed by the physician in charge.

Continue to observe the patient and document observations.


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Appendix 8
Preexisting Autoimmune Diseases
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below will be excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, patients with transient autoimmune 
manifestations of an acute infectious disease that resolved upon treatment of the 
infectious agent are not excluded (e.g., acute Lyme arthritis).  Please contact the 
Medical Monitor regarding any uncertainty over autoimmune exclusions.
Acute disseminated
encephalomyelitis
Addison’s disease
Ankylosing spondylitis
Antiphospholipid antibody
syndrome
Aplastic anemia
Autoimmune hemolytic anemia
Autoimmune hepatitis
Autoimmune 
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune 
thrombocytopenic purpura
Behcet’s disease
Bullous pemphigold
Chronic inflammatory
demyelinating
polyneuropathy
Chung-Strauss syndrome
Crohn’s disease
Dermatomyositis
Diabetes mellitus type 1
Dysautonomia
Epidermolysis bullosa acquista
Gestational pemphigoid
Giant cell arteritis
Goodpasture’s syndrome
Graves’ disease
Guillain-Barré syndrome
Hashimoto’s disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki’s disease
Lambert-Eaton myasthenia
syndrome
Lupus erythematosus
Lyme diseasechronic
Meniere’s syndrome
Mooren’s ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus 
syndrome
Optic neuritis
Ord’s thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodusa
Polyarthritis
Polyglandular autoimmune 
syndrome
Primary biliary cirrhosis
Psoriasis
Reiter’s syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Stiff-Person syndrome
Takayasu’s arteritis
Ulcerative colitis
Vitiligo
Vogt-Kovanagi-Harada 
disease
Wegener’s granulomatosis


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Appendix 9
Calculation of Creatinine Clearance Using 
the Cockcroft-Gault Formula
Creatinine clearance (men) (140Age)Lean body weight (kg)
Serum Creatinine (mg/dL) 72
Creatinine clearance (women)0.85 (140Age)Lean body weight (kg)
Serum Creatinine (mg/dL) 72
Adapted from:  Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from 
adjusted serum creatinine [editorial]. Nephron 1992;62:24956.


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Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of 
atezolizumab may not have an immediate therapeutic effect, and in severe cases, 
immune-mediated toxicities may require acute management with topical corticosteroids, 
systemic corticosteroids, or other immunosuppressive agents. 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have 
met the criteria for permanent discontinuation, resumption of atezolizumab may 
be considered if the patient is deriving benefit and has fully recovered from the 
immune-mediated event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor. 
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will have computed 
tomography (CT) scans of the chest performed at every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, 
pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or 
pulmonary hypertension.  Management guidelines for pulmonary events are provided 
in Table 1.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
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Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary 
event, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Bronchoscopy or BAL is recommended.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BAL bronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
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HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored 
throughout study treatment.  Management guidelines for hepatic events are provided in 
Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits or 
to baseline values. 
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
LFT liver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
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Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
LFT liver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
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165/Protocol BO29562, Version 8
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea 
or Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate 
treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Diarrhea or 
colitis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
GI gastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
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166/Protocol BO29562, Version 8
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea 
or Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist for evaluation and confirmation 
biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
GI gastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Section 5.1.5.1 Table 11.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine 
whether thyroid abnormalities are present.  Pituitary hormone levels and function tests 
(e.g., TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, 
testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH 
stimulation test) and magnetic resonance imaging (MRI) of the brain (with detailed 


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
167/Protocol BO29562, Version 8
pituitary sections) may help to differentiate primary pituitary insufficiency from 
primary adrenal insufficiency.
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Section 5.1.5.1 Table 11.
IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not 
limited to, laboratory (e.g., B-type natriuretic peptide) or cardiac imaging 
abnormalities, dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, 
or syncope.  Immune-mediated myocarditis needs to be distinguished from myocarditis 
resulting from infection (commonly viral, e.g., in a patient who reports a recent history 
of gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing 
cardiac enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac 
MRI as appropriate per institutional guidelines.  A cardiologist should be consulted.  
An endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Section 5.1.5.1
Table 11.
INFUSION-RELATED REACTIONS
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) with Cycle 1 of 
atezolizumab may receive premedication with antihistamines or antipyretics/analgesics 
(e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in 
treating atezolizumab-associated IRRs because of its potential for causing 
agranulocytosis.
Management guidelines for IRR events are provided in Section 4.3.2.2.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
168/Protocol BO29562, Version 8
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as 
serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Section 5.1.5.1 Table 11.
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases 
of rash were mild in severity and self-limited, with or without pruritus.  A 
dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy 
should be considered unless contraindicated.  Management guidelines for dermatologic 
events are provided in Section 5.1.5.1 Table 11.
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic workup is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Section 5.1.5.1 Table 11.
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-mediated meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, 
motor or sensory dysfunction, and altered or depressed level of consciousness.  
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.  
All patients being considered for meningoencephalitis should be urgently evaluated 
with a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, 
or edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Management guidelines for meningoencephalitis are provided in Section 5.1.5.1
Table 11.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
169/Protocol BO29562, Version 8
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of 
atezolizumab.  Eligible patients must have adequate renal function.  Renal function, 
including serum creatinine, should be monitored throughout study treatment.  Patients 
with abnormal renal function should be evaluated and treated for other more common 
etiologies (including prerenal and postrenal causes, and concomitant medications such 
as non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if 
clinically indicated.  A renal biopsy may be required to enable a definitive diagnosis 
and appropriate treatment.
Management guidelines for nephritis are provided in Section 5.1.5.1 Table 11.
IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among 
the most common disorders.  Initial diagnosis is based on clinical (muscle weakness, 
muscle pain, skin rash in dermatomyositis), biochemical (serum creatine kinase 
increase), and imaging (electromyography/MRI) features, and is confirmed with a 
muscle biopsy.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 4.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
170/Protocol BO29562, Version 8
Table 4
Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-mediated 
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-mediated 
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
171/Protocol BO29562, Version 8
Table 4
Management Guidelines for Immune-Mediated Myositis (cont.)
Immune-mediated 
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
Immune-mediated 
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
172/Protocol BO29562, Version 8
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS).  
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of 
the following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
–
Platelet count 100 109/L (100,000/L)
–
ANC 1.0 109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard 
deviations above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should 
be classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181 109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Obinutuzumab and Atezolizumab—F. Hoffmann-La Roche Ltd
173/Protocol BO29562, Version 8
Patients with suspected HLH or MAS should be treated according to the guidelines in
Table 5.
Table 5
Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue atezolizumab and contact Medical 
Monitor.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.

Consider initiation of IV corticosteroids and/or an 
immunosuppressive agent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLH hemophagocytic lymphohistiocytosis; MAS macrophage activation syndrome.
REFERENCES
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage 
activation syndrome complicating systemic juvenile idiopathic arthritis: a 
European League Against Rheumatism/American College of 
Rheumatology/Paediatric Rheumatology International Trials Organisation 
Collaborative Initiative. Ann Rheum Dis 2016;75:4819.