Conditions: Acute Myeloid Leukemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
This Phase Ib study is designed to evaluate the safety and pharmacokinetics of atezolizumab when given in combination with Hu5F9-G4 to patients with relapsed or refractory (R/R) acute myeloid leukemia (AML).

Detailed description:

Arms:
arm 1: An initial safety evaluation will be performed in participants with relapsed AML. If atezolizumab in combination with Hu5F9-G4 is initially safe and tolerable in participants an additional cohort with R/R AML will be evaluated to further test the safety and anti-tumor activity. If dose-limiting toxicities (DLT) are observed in \>=33% of participants in this initial cohort, a dose de-escalation cohort will be enrolled. If less than 33% of enrolled and dosed participants in any given cohort experience a DLT, an expansion cohort of 15 participants will be enrolled at the highest tolerated dose for this combination. If a dose de-escalation cohort is needed, an expansion cohort will be enrolled at the lower tolerated dose for this combination.

Interventions: intervention 1: Atezolizumab intervention 2: Hu5F9-G4
Intervention descriptions: intervention 1: Atezolizumab will be administered to participants by IV infusion at a fixed dose starting on Day 22 of Cycle 1. In subsequent cycles (Cycles 2 and beyond), IV atezolizumab will be given every 2 weeks (Q2W) on Days 8 and 22 of each 28-day cycle. intervention 2: Two priming doses of 1 mg/kg of Hu5F9-G4 will be administered to participants by continuous IV infusion on Days 1 and 4 of Cycle 1, followed by loading doses of 15 mg/kg IV on Day 8 and 30 mg/kg IV on Day 11. Starting on Day 15 of Cycle 1, Hu5F9-G4 maintenance will be given by IV infusion at a dose of 30 mg/kg once a week (QW) of each 28-day cycle. Dosing for de-escalation, if needed: Hu5F9-G4 will be given as two priming doses of 1 mg/kg IV on Days 1 and 4, followed by loading doses of 10 mg/kg IV on Day 8 and 15 mg/kg on Day 11. Starting on Day 15, maintenance treatment with Hu5F9-G4 will be given by IV infusion at a dose of 15 mg/kg once a week (QW).

Protocol document:
Prot_SAP_000.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.
Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol GO40828, Version 3 
PROTOCOL
TITLE:
A PHASE Ib, OPEN-LABEL STUDY EVALUATING 
THE SAFETY AND PHARMACOKINETICS OF 
ATEZOLIZUMAB (ANTI–PD-L1 ANTIBODY) 
ADMINISTERED IN COMBINATION WITH 
Hu5F9-G4 TO PATIENTS WITH RELAPSED 
AND/OR REFRACTORY ACUTE MYELOID 
LEUKEMIA
PROTOCOL NUMBER:
GO40828
VERSION NUMBER:
3
EUDRACT NUMBER:
Not applicable
IND NUMBER:
147530
NCT NUMBER:
NCT03922477
TEST PRODUCTS:
Atezolizumab (RO5541267) and Hu5F9-G4
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below.
 
05-Aug-2020 23:24:57
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol GO40828, Version 3 
PROTOCOL HISTORY
Protocol
Version
Date Final
2
5 February 2020
1
13 December 2018


Atezolizumab—F. Hoffmann-La Roche Ltd
3/Protocol GO40828, Version 3 
PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Protocol GO40828 has been amended in response to feedback from the U.S. Food and 
Drug Administration (FDA) Division of Hematologic Malignancies 1 (DHM1). Changes to 
the protocol are summarized below:

Rules for dose modification and changes in dose scheduling following dose-limiting 
toxicity (DLT) have been amended for clarity and consistency with the study design 
(Sections 3.1.1 and 3.1.2.2).

Language has been added regarding suggested testing for the determination of the 
underlying etiology and appropriate attribution for DLTs (Section 3.1.2.3).

DLT definitions have been modified to address specific concerns outlined by the 
FDA (Section 3.1.2.3).

A stopping rule for excess toxicity for the expansion phase has been added,
including clinical assumptions and description of the statistical methodology used to 
calculate the early stopping bounds (Section 3.1.2.4, Table 1).

The projected enrollment period and length of study have been updated 
(Section 3.2).

Language has been added to provide additional rationale for the atezolizumab 
starting dose and schedule in this population (Section 3.3.1).

The inclusion criteria have been revised to include only patients with relapsed 
and/or refractory acute myeloid leukemia who have experienced treatment failure 
with all therapies of known benefit (Section 4.1.1).

Management guidelines for infusion-related reactions have been revised to 
incorporate observation periods between atezolizumab and Hu5F9-G4 infusions on 
days when both drugs are administered (Section 4.3.2 1, Table 2 and Appendix 1).

The IND number has been replaced throughout the protocol with a new IND number 
assigned by the DHM1.
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.


Atezolizumab—F. Hoffmann-La Roche Ltd
4/Protocol GO40828, Version 3 
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 25
1.1
Background on Acute Myeloid Leukemia............................... 25
1.2
Background on Atezolizumab................................................ 26
1.2.1
Atezolizumab Nonclinical Studies.......................................... 27
1.2.2
Atezolizumab Clinical Pharmacokinetics and 
Immunogenicity ..................................................................... 27
1.2.3
Atezolizumab Clinical Studies................................................ 28
1.2.4
Atezolizumab Clinical Safety ................................................. 28
1.3
Background on Hu5F9-G4..................................................... 29
1.3.1
Hu5F9-G4 Nonclinical Studies............................................... 31
1.4
Study Rationale and BenefitRisk Assessment..................... 32
2.
OBJECTIVES AND ENDPOINTS ............................................................... 33
2.1
Safety Objective .................................................................... 33
2.2
Pharmacokinetic Objectives .................................................. 33
2.3
Efficacy Objectives ................................................................ 34
2.3.1
Primary Efficacy Objective..................................................... 34
2.3.2
Secondary Efficacy Objective................................................ 34
2.4
Immunogenicity Objective...................................................... 35
2.5
Exploratory Biomarker Objective ........................................... 35
3.
STUDY DESIGN......................................................................................... 35
3.1
Description of the Study......................................................... 35
3.1.1
Overview of Study Design ..................................................... 36
3.1.2
Safety Evaluation Phase........................................................ 38
3.1.2.1
Dose-Limiting Toxicity Assessment....................................... 38
3.1.2.2
Rules for Dose Modification and Changes in 
Dose Scheduling following Dose-Limiting Toxicity................. 38
3.1.2.3
Definition of Dose-Limiting Toxicity........................................ 39
3.1.2.4
Stopping Rule for Excess Toxicity for Expansion 
Phase .................................................................................... 40


Atezolizumab—F. Hoffmann-La Roche Ltd
5/Protocol GO40828, Version 3 
3.2
End of Study and Length of Study......................................... 41
3.3
Rationale for Study Design.................................................... 41
3.3.1
Rationale for Atezolizumab Dose and Schedule.................... 41
3.3.2
Rationale for Patient Population ............................................ 42
3.3.3
Rationale for Relapsed and/or Refractory AML ..................... 43
3.3.4
Rationale for Hu5F9-G4 Dose ............................................... 43
3.3.5
Rationale for Pharmacokinetic Evaluation 
Schedule................................................................................ 44
3.3.6
Rationale for Biomarker Assessments................................... 44
3.3.7
Rationale for Atezolizumab Treatment beyond 
Progression ........................................................................... 44
4.
MATERIALS AND METHODS .................................................................... 45
4.1
Patients.................................................................................. 45
4.1.1
Inclusion Criteria.................................................................... 45
4.1.2
Exclusion Criteria................................................................... 48
4.2
Method of Treatment Assignment.......................................... 50
4.3
Study Treatment.................................................................... 51
4.3.1
Study Treatment Formulation, Packaging, 
and Handling ......................................................................... 51
4.3.1.1
Atezolizumab......................................................................... 51
4.3.1.2
Hu5F9-G4.............................................................................. 51
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 52
4.3.2.1
Atezolizumab......................................................................... 52
4.3.2.2
Hu5F9-G4.............................................................................. 53
4.3.3
Investigational Medicinal Product Accountability ................... 54
4.3.4
Post-Study Access to Atezolizumab 
and Hu5F9-G4....................................................................... 54
4.4
Concomitant Therapy and Additional Restrictions................. 55
4.4.1
Permitted Therapy................................................................. 55
4.4.2
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 57
4.4.2.1
Corticosteroids and Tumor Necrosis Factor
Inhibitors................................................................................ 57
4.4.2.2
Herbal Therapies................................................................... 57


Atezolizumab—F. Hoffmann-La Roche Ltd
6/Protocol GO40828, Version 3 
4.4.3
Prohibited Therapy ................................................................ 57
4.5
Study Assessments ............................................................... 58
4.5.1
Informed Consent Forms and Screening Log........................ 59
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 59
4.5.3
Physical Examinations........................................................... 59
4.5.4
Vital Signs.............................................................................. 60
4.5.5
ECOG Performance Status ................................................... 60
4.5.6
AML and Response Evaluations............................................ 60
4.5.7
Laboratory, Biomarker, and Other 
Biological Samples ................................................................ 61
4.5.7.1
Local Laboratory Assessments.............................................. 61
4.5.7.2
Central Laboratory Assessments........................................... 62
4.5.8
Electrocardiograms................................................................ 64
4.5.9
Evaluation of Left Ventricular Ejection Fraction ..................... 65
4.5.10
Anti-Drug Antibody Testing.................................................... 65
4.5.11
Optional Samples for Research Biosample 
Repository ............................................................................. 65
4.5.11.1
Overview of the Research Biosample Repository.................. 65
4.5.11.2
Approval by the Institutional Review Board ........................... 66
4.5.11.3
Sample Collection.................................................................. 66
4.5.11.4
Confidentiality........................................................................ 67
4.5.11.5
Consent to Participate in the Research 
Biosample Repository............................................................ 67
4.5.11.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 68
4.5.11.7
Monitoring and Oversight....................................................... 68
4.6
Treatment, Patient, Study, and 
Site Discontinuation............................................................... 68
4.6.1
Study Treatment Discontinuation........................................... 68
4.6.2
Patient Discontinuation from Study........................................ 69
4.6.3
Study Discontinuation............................................................ 69
4.6.4
Site Discontinuation............................................................... 70


Atezolizumab—F. Hoffmann-La Roche Ltd
7/Protocol GO40828, Version 3 
5.
ASSESSMENT OF SAFETY....................................................................... 70
5.1
Safety Plan ............................................................................ 70
5.1.1
Risks Associated with Atezolizumab ..................................... 70
5.1.2
Risks Associated with Hu5F9-G4 .......................................... 71
5.1.3
Risks Associated with Combination Use of 
Atezolizumab and Hu5F9-G4 ................................................ 71
5.1.4
Dose Modifications for Hu5F9-G4 and 
Atezolizumab......................................................................... 71
5.2
Safety Parameters and Definitions ........................................ 71
5.2.1
Adverse Events ..................................................................... 72
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 72
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 73
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 74
5.3.1
Adverse Event Reporting Period ........................................... 74
5.3.2
Eliciting Adverse Event Information....................................... 75
5.3.3
Assessment of Severity of Adverse Events ........................... 75
5.3.4
Assessment of Causality of Adverse Events ......................... 76
5.3.5
Procedures for Recording Adverse Events............................ 76
5.3.5.1
Infusion-Related Reactions.................................................... 77
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 77
5.3.5.3
Adverse Events That Are Secondary to 
Other Events.......................................................................... 77
5.3.5.4
Persistent or Recurrent Adverse Events................................ 78
5.3.5.5
Abnormal Laboratory Values ................................................. 78
5.3.5.6
Abnormal Vital Sign Values ................................................... 79
5.3.5.7
Abnormal Liver Function Tests.............................................. 79
5.3.5.8
Deaths ................................................................................... 80
5.3.5.9
Preexisting Medical Conditions.............................................. 80
5.3.5.10
Lack of Efficacy or Worsening of Acute Myeloid 
Leukemia............................................................................... 80
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 81


Atezolizumab—F. Hoffmann-La Roche Ltd
8/Protocol GO40828, Version 3 
5.3.5.12
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 81
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 83
5.4.1
Emergency Medical Contacts................................................ 83
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 84
5.4.2.1
Events That Occur prior to Study 
Treatment Initiation................................................................ 84
5.4.2.2
Events That Occur after Study Treatment 
Initiation ................................................................................. 84
5.4.3
Reporting Requirements for Pregnancies.............................. 84
5.4.3.1
Pregnancies in Female Patients............................................ 84
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 85
5.4.3.3
Abortions ............................................................................... 85
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 86
5.5
Follow-Up of Patients after Adverse Events .......................... 86
5.5.1
Investigator Follow-Up........................................................... 86
5.5.2
Sponsor Follow-Up ................................................................ 86
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 86
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 87
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 87
6.1
Determination of Sample Size ............................................... 87
6.2
Summaries of Conduct of Study............................................ 88
6.3
Demographic and Baseline Characteristics........................... 88
6.4
Safety Analyses..................................................................... 88
6.5
Pharmacokinetic Analyses..................................................... 88
6.6
Efficacy Analyses .................................................................. 89
6.6.1
Primary Efficacy Endpoint...................................................... 89
6.6.2
Secondary Efficacy Endpoints............................................... 90
6.7
Immunogenicity Analyses...................................................... 90
6.8
Biomarker Analyses............................................................... 91


Atezolizumab—F. Hoffmann-La Roche Ltd
9/Protocol GO40828, Version 3 
7.
DATA COLLECTION AND MANAGEMENT ............................................... 91
7.1
Data Quality Assurance......................................................... 91
7.2
Electronic Case Report Forms............................................... 91
7.3
Source Data Documentation.................................................. 92
7.4
Use of Computerized Systems .............................................. 92
7.5
Retention of Records............................................................. 92
8.
ETHICAL CONSIDERATIONS.................................................................... 93
8.1
Compliance with Laws and Regulations ................................ 93
8.2
Informed Consent.................................................................. 93
8.3
Institutional Review Board ..................................................... 94
8.4
Confidentiality........................................................................ 95
8.5
Financial Disclosure .............................................................. 95
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION............................................................................. 96
9.1
Study Documentation ............................................................ 96
9.2
Protocol Deviations................................................................ 96
9.3
Site Inspections ..................................................................... 96
9.4
Administrative Structure......................................................... 96
9.5
Dissemination of Data and Protection of 
Trade Secrets........................................................................ 96
9.6
Protocol Amendments ........................................................... 97
10. REFERENCES ........................................................................................... 98
LIST OF TABLES
Table 1
Early Stopping Boundaries for Expansion Cohort....................... 41
Table 2
Administration of First and Subsequent Atezolizumab and  
Hu5F9-G4 Infusions.................................................................... 53
Table 3
Timing for Vital Sign Measurements for First and 
Subsequent Infusions ................................................................. 60
Table 4
Proposed Exploratory Biomarkers .............................................. 64
Table 5
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in the NCI CTCAE ......................................... 75
Table 6
Causal Attribution Guidance ....................................................... 76
Table 7
Probability of Safety-Signal Detection with a Cohort of 21 
Patients....................................................................................... 88


Atezolizumab—F. Hoffmann-La Roche Ltd
10/Protocol GO40828, Version 3 
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 36
Figure 2
Hu5F9-G4 Achieves Target PK Levels at Clinically Feasible 
Doses.......................................................................................... 43
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 101
Appendix 2
Schedule of Pharmacokinetic and Immunogenicity Samples.... 107
Appendix 3
Schedule of Biomarker Samples............................................... 110
Appendix 4
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 111
Appendix 5
Response Evaluation Criteria.................................................... 112
Appendix 6
Preexisting Autoimmune Diseases and Immune Deficiencies .. 115
Appendix 7
Anaphylaxis Precautions........................................................... 116
Appendix 8
Overall Guidelines for Management of Patients Who 
Experience Adverse Events...................................................... 117
Appendix 9
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 123


Atezolizumab—F. Hoffmann-La Roche Ltd
11/Protocol GO40828, Version 3 
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE Ib, OPEN-LABEL STUDY EVALUATING 
THE SAFETY AND PHARMACOKINETIC OF 
ATEZOLIZUMAB (ANTI–PD-L1 ANTIBODY) 
ADMINISTERED IN COMBINATION WITH Hu5F9-G4 
TO PATIENTS WITH RELAPSED AND/OR 
REFRACTORY ACUTE MYELOID LEUKEMIA
PROTOCOL NUMBER:
GO40828
VERSION NUMBER:
3
EUDRACT NUMBER:
Not applicable
IND NUMBER:
147530
NCT NUMBER:
NCT03922477
TEST PRODUCT:
Atezolizumab (RO5541267) and Hu5F9-G4
MEDICAL MONITOR:
, M.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 return a copy of this signed original of this form as instructed by your local 
monitor and retain a signed copy for your study files.


Atezolizumab—F. Hoffmann-La Roche Ltd
12/Protocol GO40828, Version 3 
PROTOCOL SYNOPSIS
TITLE:
A PHASE Ib, OPEN-LABEL STUDY EVALUATING THE SAFETY 
AND PHARMACOKINETICS OF ATEZOLIZUMAB (ANTI–PD-L1 
ANTIBODY) ADMINISTERED IN COMBINATION WITH Hu5F9-G4 
TO PATIENTS WITH RELAPSED AND/OR REFRACTORY ACUTE 
MYELOID LEUKEMIA
PROTOCOL NUMBER:
GO40828
VERSION NUMBER:
3
EUDRACT NUMBER:
Not applicable
IND NUMBER:
147530
NCT NUMBER:
NCT03922477
TEST PRODUCTS:
Atezolizumab (RO5541267) and Hu5F9-G4
PHASE:
Ib
INDICATION:
Acute myeloid leukemia
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This Phase Ib study is designed to evaluate the safety and pharmacokinetics of atezolizumab 
when given in combination with Hu5F9-G4 to patients with relapsed or refractory (R/R) acute 
myeloid leukemia (AML).  Specific objectives and corresponding endpoints for the study are 
outlined below.
In this protocol, "study treatment" refers to the combination of treatments assigned to patients 
as part of this study (i.e., atezolizumab and Hu5F9-G4).
Safety Objective
The primary safety objective for this study is to characterize the safety and tolerability of 
atezolizumab administered in combination with Hu5F9-G4 to patients with R/R AML on the 
basis of the following endpoints:

Incidence of adverse events, with severity determined through use of the National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results

Change from baseline in physical examination findings
Pharmacokinetic Objectives
The pharmacokinetic (PK) objective for this study is to characterize the pharmacokinetics of 
atezolizumab and Hu5F9-G4 when administered in combination to patients with R/R AML on 
the basis of the following endpoints:

Serum concentrations of atezolizumab 

Serum concentrations of Hu5F9-G4 at specified timepoints


Atezolizumab—F. Hoffmann-La Roche Ltd
13/Protocol GO40828, Version 3 
The exploratory PK objective for this study is to assess potential PK interactions between 
atezolizumab and Hu5F9-G4 on the basis of the following endpoints:

Serum concentrations of atezolizumab given in combination with Hu5F9-G4 compared with 
atezolizumab given alone (based on historical data)

Serum concentrations of Hu5F9-G4 given in combination with atezolizumab compared with 
Hu5F9-G4 given alone (based on historical data)
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab 
administered in combination with Hu5F9-G4 to patients with R/R AML on the basis of the 
following endpoints:

Complete remission (CR), CR with incomplete platelet recovery (CRp), CR with incomplete 
hematologic recovery (CRi), and CR with partial hematologic recovery (CRh) rate after up to 
6 cycles of combination therapy, as determined by the investigator, according to the 
International Working Group (IWG) 2003 and European LeukemiaNet (ELN) 2010 criteria 

Duration of response (DOR), defined as the time from the initial response (CR, CRp, CRi, 
CRh, or partial remission [PR]) to the time of disease progression or death, whichever 
occurs first
Secondary Efficacy Objective
The secondary efficacy objective for this study is to make a preliminary assessment of the 
anti-neoplastic activity of atezolizumab administered in combination with Hu5F9-G4 to patients 
with R/R AML on the basis of the following endpoints: 

Objective response rate achieved in the study, defined as the percentage of patients with a 
PR or better (i.e., CRCRp CRiCRhPR)

Event-free survival, defined as the time from study entry to the date of induction treatment 
failure or relapse from CR, CRp, CRh, CRi, or death from any cause

Leukemia-free survival, defined (only for patients achieving a CR, CRp, CRh, or CRi) as the 
time from the date of achievement of remission (CR, CRp, or CRi) until the date of relapse 
from CR, CRp, CRh, CRi, or death from any cause

Overall survival, defined as time from study entry to the date of death from any cause

Progression-free survival, defined as the time from the first day of study treatment to 
disease progression or death, whichever occurs first

Rate of transfusion independence, defined as the percentage of patients who achieve 
transfusion independence (i.e., achieving any continuous 56-day window without requiring 
platelet or RBC transfusions) at any time during study treatment

Duration of transfusion independence, defined as the number of consecutive days of 
transfusion independence, measured from 1 day after the last transfusion to disease 
progression or subsequent transfusion 
Immunogenicity Objective
The immunogenicity objective for this study is to evaluate the immune response to atezolizumab 
and Hu5F9-G4 on the basis of the following endpoints:

Incidence of anti-drug antibodies (ADAs) against atezolizumab during the study relative to 
the prevalence of ADAs at baseline

Incidence of ADAs against Hu5F9-G4 during the study relative to the prevalence of ADAs at 
baseline


Atezolizumab—F. Hoffmann-La Roche Ltd
14/Protocol GO40828, Version 3 
Exploratory Biomarker Objective
The exploratory biomarker objective for this study is to identify biomarkers that are predictive of 
response to atezolizumab in combination with Hu5F9-G4 (i.e., predictive biomarkers), are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), are 
associated with acquired resistance to atezolizumab and/or Hu5F9-G4, are associated with 
susceptibility to developing adverse events, can provide evidence of atezolizumab and/or 
Hu5F9-G4 activity, or can increase the knowledge and understanding of disease biology on the 
basis of the following endpoints:

Relationship between biomarkers in blood and bone marrow (including somatic mutations) 
and efficacy, safety, PK, immunogenicity, expression profiles, bone marrow aspirate stromal 
factors, or other biomarker endpoints

To determine the effect of single agent Hu5F9-G4 on T-cell activation and bone marrow
infiltration in patients with R/R AML
Study Design
Description of Study
This is a Phase Ib, open-label, multicenter, non-randomized study of atezolizumab, evaluating 
the safety and pharmacokinetics of atezolizumab (an antiPD-L1 monoclonal antibody) given in 
combination with Hu5F9-G4 (an anti-CD47 monoclonal antibody) for the treatment of patients 
with R/R AML (excluding promyelocytic leukemia). 
An initial safety evaluation will be performed in 6 patients with relapsed AML.  If atezolizumab in 
combination with Hu5F9-G4 is found to be initially safe and tolerable in patients with R/R AML, 
an additional cohort of 15 patients with R/R AML will be evaluated to further test the safety and 
anti-tumor activity of atezolizumab in combination with Hu5F9-G4.
If dose-limiting toxicities (DLTs) are observed in 33% of patients (2 or more of 6 patients) in 
this initial safety cohort, a dose de-escalation cohort of 6 patients will be enrolled.  If 33% of 
the enrolled (1 patient or no patients) and dosed patients in any given cohort experience a DLT, 
an expansion cohort of 15 patients will be enrolled at the higher tolerated dose for this 
combination.  If a dose de-escalation cohort is needed (n 12 for safety cohorts), an expansion 
cohort of 9 patients will be enrolled at the lower tolerated dose for this combination.
The maximum number of patients enrolled in this study will be 21 patients (this number will 
include patients assessed for DLT plus those potentially removed prior to DLT assessment).
The proposed treatment regimen during Cycle 1 is a biomarker-driven treatment plan designed 
to assess the effect of single-agent Hu5F9-G4 on markers of immune activation in AML.  This 
safety cohort is designed to assess the safety, tolerability, and clinical activity of Hu5F9-G4 in 
combination with atezolizumab based on the following schedule:

Atezolizumab:  Atezolizumab will be administered to patients by IV infusion at a fixed dose 
of 840 mg, starting on Day 22 of Cycle 1.  In subsequent cycles (Cycles 2 and beyond), 
840 mg of IV atezolizumab will be given every 2 weeks (Q2W) on Days 8 and 22 of each 
28-day cycle. 

Hu5F9-G4:  Two priming doses of 1 mg/kg of Hu5F9-G4 will be administered to patients by 
continuous IV infusion on Days 1 and 4 of Cycle 1, followed by loading doses of 15 mg/kg 
IV on Day 8 and 30 mg/kg IV on Day 11.  Starting on Day 15 of Cycle 1, Hu5F9-G4 
maintenance will be given by IV infusion at a dose of 30 mg/kg once a week (QW) of each 
28-day cycle.  On days when both atezolizumab and Hu5F9-G4 are administered (Day 22 
of Cycle 1 and Days 8 and 22 of subsequent cycles), Hu5F9-G4 should be administered 
first and the interval between Hu5F9-G4 and atezolizumab infusions should follow 
guidelines as outlined in the protocol. 
If DLTs are observed in 33% of patients (i.e., 2 or more of 6 patients) in this initial safety 
cohort, a dose de-escalation cohort of 6 patients will be enrolled.  The dosing schedules for this 
de-escalation cohort will be as follows: 

Atezolizumab will be administered to patients by IV infusion at a fixed dose of 840 mg, 
starting on Day 22 of Cycle 1.  In subsequent cycles, 840 mg of atezolizumab administered 
by IV infusion will be given Q2W on Days 8 and 22 of each 28-day cycle.


Atezolizumab—F. Hoffmann-La Roche Ltd
15/Protocol GO40828, Version 3 

Hu5F9-G4 will be given as two priming doses of 1 mg/kg IV on Days 1 and 4, followed by 
loading doses of 10 mg/kg IV on Day 8 and 15 mg/kg on Day 11.  Starting on Day 15, 
maintenance treatment with Hu5F9-G4 will be given by IV infusion at a dose of 15 mg/kg QW.

If 33% (i.e., 1 or fewer of 6 patients) patients in the de-escalation cohort experience a 
DLT, an expansion cohort of 9 patients will be enrolled to further test the safety and 
anti-tumor activity of atezolizumab in combination with Hu5F9-G4, using the same 
dosing regimen.
If DLTs are observed in 33% of patients (i.e., 1 or fewer of 6 patients) in the initial safety 
cohort, an expansion cohort of 15 patients will be enrolled to further test the safety and 
anti-tumor activity of atezolizumab in combination with Hu5F9-G4 using the same dosing 
regimen.
Study treatment will be administered until unacceptable toxicity or loss of clinical benefit, as 
determined by the investigator, after local biopsy results (if available) and clinical status 
(e.g., symptomatic deterioration such as pain secondary to disease) are assessed. 
Safety Evaluation Phase
Dose-Limiting Toxicity Assessment 
The first 6 patients enrolled in the safety cohort will be eligible for DLT assessment.  The DLT 
assessment window for the safety cohort is 56 days from the first dose of Hu5F9-G4. 
All patients who experience a DLT during the DLT assessment window will be considered 
evaluable for safety evaluation decisions. 
Patients who withdraw from study treatment (atezolizumab plus Hu5F9-G4) for any reason
other than a DLT during this assessment window will not be considered evaluable for safety 
evaluation decisions and will be replaced.  The total number of enrolled patients in this study will 
be capped at 21 patients.  If patients are replaced prior to DLT assessment, discontinued 
patients will be counted toward the total limit of 21 patients. 
During the DLT evaluation window, patients will not be allowed to make up missed doses; 
patients will resume dosing at their next scheduled dose.  Patients who are unable to receive 
the next scheduled dose of Hu5F9-G4 or atezolizumab as a result of study treatmentrelated 
adverse events will be considered to have met the DLT criteria. 
Rules for Dose Modification and Changes in Dose Scheduling following Dose-Limiting Toxicity
Dose modification following the DLT window will occur in accordance with the following rules: 

The safety cohort will enroll up to 6 patients.  

If DLTs are observed in 33% of patients (i.e., 2 or more of 6 patients) in this initial 
safety cohort, a dose de-escalation cohort of 6 patients will be enrolled.  The dosing 
schedules for this de-escalation cohort will be as follows:
–
Atezolizumab will be administered to patients by IV infusion at a fixed dose of 
840 mg, starting on Day 22 of Cycle 1. In subsequent cycles, 840 mg of atezolizumab 
administered by IV infusion will be given Q2W on Days 8 and 22 of each 
28-day cycle.
–
Hu5F9-G4 will be given as two priming doses of 1 mg/kg IV on Days 1 and 4, 
followed by loading doses of 10 mg/kg IV on Day 8 and 15 mg/kg on Day 11.  
Starting on Day 15, maintenance treatment with Hu5F9-G4 will be given by IV 
infusion at a dose of 15 mg/kg QW.
–
If a DLT is observed in 33% of patients (i.e., 2 or more of 6 dose de-escalation 
patients), the dose and schedule will be considered intolerable and the MTD will have 
been exceeded.
–
The dose level(s) and schedule at which 33% of patients (i.e., 1 or fewer of 6 dose 
de-escalation patients) experience a DLT will be declared the optimal dose 
and schedule and an expansion cohort of 9 patients will be enrolled using the same 
dosing regimen.


Atezolizumab—F. Hoffmann-La Roche Ltd
16/Protocol GO40828, Version 3 

If DLTs are observed in 33% of patients (i.e., 1 or fewer of 6 patients) in the initial 
safety cohort, an expansion cohort of 15 patients will be enrolled to further test the safety 
and anti-tumor activity of atezolizumab in combination with Hu5F9-G4, using the same 
dosing regimen.. 
Definition of Dose-Limiting Toxicity 
A DLT is defined as any of the following adverse events that are causally related to study 
treatment that occur during the DLT assessment window and are considered by the investigator 
to be related to atezolizumab, Hu5F9-G4, or the combination of atezolizumab with Hu5F9-G4.  
For potential overlapping toxicities, investigators are encouraged to perform additional testing, 
such as tissue biopsy, imaging, peripheral blood smears, immunological assays, and other 
laboratory studies to determine the underlying etiology and appropriate attribution (whether the 
event is related to atezolizumab, Hu5F9-G4, or the combination of atezolizumab and Hu5F9-
G4.  Testing is to be determined by the investigator, according to local medical standards, and 
if needed, in consultation with the Medical Monitor, based on an individual patient’s clinical 
presentations.  Testing may elucidate whether the event is an immune-mediated adverse event 
caused by atezolizumab, including those events that should be reported to the Sponsor 
immediately (i.e., within 24 hours). 
Any of the following adverse events that occur during Cycles 1 or 2 will be considered a DLT (if 
causality is determined to be yes according to Table 5) for atezolizumab alone or in combination 
with Hu5F9-G4: 

Any adverse event (regardless of NCI CTCAE v5.0 grade) that leads to dose reduction or 
withdrawal

Any infusion-related toxicity Grade 3 (e.g., allergic reaction/hypersensitivity, fever, pain, 
bronchospasm, wheezing, or hypoxia) 

Hypocellular (5% cellularity) or aplastic bone marrow 3 without evidence of 
myeolodysplastic syndrome, leukemia, or infectious etiology that lasts for 35 days from the 
first occurrence 

Grade 3 liver enzyme (ALT or AST) and Grade 3 creatinine elevations

Grade 3 thrombocytopenia associated with clinically significant bleeding that requires 
transfusion of red cells and platelets 

Grade 3 non-hematologic adverse events (with certain Grade 3 exceptions discussed 
below) 

Grade 4 neutropenia and thrombocytopenia lasting past Cycle 2 Day 28 in the absence 
of disease (defined as the presence of 5% bone marrow blasts)
The following Grade 3 events will not be considered DLTs: 

Grade 3 nausea, vomiting, or diarrhea that resolves to Grade 1 or better within 7 days of 
supportive therapy and does not require total parenteral nutrition, tube feeding, or 
prolonged hospitalization

Grade 3 asymptomatic or mildly symptomatic rash that can be adequately managed with 
supportive care or resolves to become asymptomatic and/or Grade 2 within 7 days of 
supportive therapy 

Grade 3 fatigue, asthenia, or fever that resolves to Grade 2 within 7 days 

Grade 3 arthralgia that can be adequately managed with supportive therapy or that resolves 
to Grade 2 within 7 days 

Asymptomatic Grade 3 laboratory abnormalities (other than liver enzyme and creatinine 
elevations) that resolve to Grade 2 within 72 hours
All DLTs will be reported on an electronic Case Report Form (eCRF), the standard Adverse 
Event eCRF in the Sponsor’s electronic data capture system within 24 hours.  All DLTs will be 
considered adverse events of special interest for this protocol and will be reported to the 
Sponsor in an expedited manner.  Dose modification decisions will be made by the Sponsor in 
consultation with investigators after review of available relevant data. 


Atezolizumab—F. Hoffmann-La Roche Ltd
17/Protocol GO40828, Version 3 
Stopping Rule for Excess Toxicity for Expansion Phase
Early stopping boundaries for the expansion cohort are based on the Pearson-Klopper 
confidence intervals of the observed toxicity rate, and a target toxicity rate of no more than 
20%.  The stopping boundary for a given number of enrolled patients is the minimum number 
of patients with excess toxicity that would lead to a toxicity rate with its lower 95% 
confidence boundary higher than 20%. During the expansion phase, an episode of excess 
toxicity will be defined as any adverse event meeting criteria for a DLT as outlined in the 
protocol.
Number of Patients
A total of 21 patients will be enrolled in this study at approximately 610 sites globally.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at the time of signing Informed Consent Form

Life expectancy of at least 12 weeks

Eastern Cooperative Oncology Group Performance Status 02 

Ability to comply with the study protocol, in the investigator’s judgment

Documented and confirmed R/R AML per WHO classification, except acute promyelocytic 
leukemia, and lack of response to all therapies of known benefit
Refractory AML is defined as failure to attain a CR following exposure to at least two 
courses of intensive induction regimens, six cycles of single-agent hypomethylating 
agent (HMA), or at least two cycles of venetoclax-containing regimens (combined to low-
dose cytarabine or HMAs).
Relapsed AML is defined as the morphological detection of 5% bone marrow blasts, 
reappearance of leukemic blasts in the blood, or development of extramedullary disease.  
For patients previously found to be in CR and minimal residual disease (MRD) negative 
(by flow cytometry), reappearance of a leukemic population by MRD testing can be 
classified as being relapsed AML (conversion from CR MRD negative to CR MRD 
positive). 

Adequate end-organ function, defined using the following laboratory parameters obtained 
within 28 days prior to the first dose of study drug:

AST, ALT, and ALP 2.5 upper limit of normal (ULN)

Serum bilirubin 2 ULN, with the following exception: 
Patients with known Gilbert disease or clear evidence of transfusion-related 
hemolysis who have serum bilirubin 3 ULN may be enrolled.  Cases of 
transfusion-related hemolysis must be discussed and approved by the 
Medical Monitor.

Serum creatinine 2 ULN

Negative HIV test at screening

Negative hepatitis B surface antigen (HBsAg) test at screening

Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb 
test followed by quantitative hepatitis B virus (HBV) DNA 500 IU/mL at screening
The HBV DNA test will be performed only for patients who have a positive total HBcAb 
test.

Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test.


Atezolizumab—F. Hoffmann-La Roche Ltd
18/Protocol GO40828, Version 3 

WBC count 20 103/L prior to the first dose of study treatment and prior to each 
Hu5F9-G4 dose for Cycle 1
Patients with WBC 20 103/L can be treated with hydroxyurea throughout the trial to 
reduce the WBC to 20 103/L.

Willingness and ability to provide pretreatment bone marrow aspirate and biopsy and 
agreement to provide subsequent bone marrow aspirates and biopsies during 
study treatment

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, and agreement to refrain from 
donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 5 months after the final dose of 
atezolizumab and/or Hu5F9-G4, whichever is longer.  Women must refrain from 
donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(tubal ligation, removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, established proper use of hormonal contraceptives that 
inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study 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.

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, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
1%per year during the treatment period and for at least 120 days after the final dose of 
atezolizumab and/or Hu5F9-G4.  Men must refrain from donating sperm during this 
same period.
With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for at least 60 days after the final dose of atezolizumab and/or 
Hu5F9-G4 to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study 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.

For women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) 
or surgically sterile:  requirement for a negative serum pregnancy test result within 14 days 
prior to initiation of study treatment
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Previous allogeneic hematopoietic stem cell transplant within 6 months prior to enrollment, 
active graft versus host disease, or requiring transplant-related immunosuppression 

Prior solid organ transplant

Evidence of active central nervous system (CNS) involvement by leukemia 
Patients with a history of leukemic CNS involvement that has been treated may have to 
undergo lumbar puncture and/or magnetic resonance imaging assessment prior to study 
entry at the discretion of the Medical Monitor.


Atezolizumab—F. Hoffmann-La Roche Ltd
19/Protocol GO40828, Version 3 

Pregnancy or lactation or intention to become pregnant during the study or within 5 months 
after the final dose of atezolizumab and/or Hu5F9-G4, whichever is longer
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study drug.

History of idiopathic pulmonary fibrosis, organizing pneumonitis (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis

History of autoimmune disease

Patients with a history of autoimmune-related hypothyroidism who are on a stable 
dose of thyroid replacement may be eligible for this study.

Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen 
may be eligible for this study.

Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of the following conditions are met:

Rash must cover 10% of body surface area.

Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids.

No occurrence of acute exacerbations of the underlying condition that require psoralen 
plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin 
inhibitors, or high-potency or oral corticosteroids within the previous 12 months.

Treatment with investigational therapy within 14 days prior to initiation of study drug

Any approved AML-related therapy within 14 days prior to enrollment
Granulocyte colony-stimulating factor to treat neutropenic fever and/or infection is 
permitted.
Hydroxyurea may be used throughout the trial to control peripheral blood blast counts in 
response to the first dose of study treatment.

Immunosuppressive therapy (including, but not limited to, azathioprine, mycophenolate 
mofetil, cyclosporine, tacrolimus, methotrexate, and antinecrosis factor agents) within 
6 weeks of Day 1 of Cycle 1

Daily requirement for corticosteroids (10 mg/day prednisone or equivalent, except for 
inhalation corticosteroids) within 2 weeks prior to Day 1 of Cycle 1

Prior treatment with immune checkpoint blockade therapies (antiCTLA-4, 
antiPD-1, or antiPD-L1) or immune agonists (anti-CD137, anti-CD40, and anti-OX40) or 
immune antagonists (anti-CD47)

Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon-and interleukin-2) within 4 weeks or 5 half-lives of the drug, whichever is longer, 
prior to Day 1 of Cycle 1

Treatment with denosumab (or other RANKL inhibitor) 4 weeks before the first dose and for 
10 weeks after the final dose of atezolizumab
Patients receiving denosumab therapy must be willing to be treated with a 
bisphosphonate while receiving study treatment.

Administration of a live, attenuated vaccine within 4 weeks of Day 1 of Cycle 1 or 
anticipation that such a live, attenuated vaccine will be required during the study or within 
5 months after the final dose of atezolizumab
Influenza vaccination should be given during influenza season only (approximately 
October through May in the northern hemisphere and approximately April through 
September in the southern hemisphere).  Patients must agree not to receive live, 
attenuated vaccines (e.g., FluMist®) within 28 days prior to enrollment, during treatment, 
or within 5 months following the final dose of atezolizumab.

Planned major surgery during the study

Illicit drug or alcohol abuse within 12 months prior to screening, in the 
investigator’s judgment


Atezolizumab—F. Hoffmann-La Roche Ltd
20/Protocol GO40828, Version 3 

Poor peripheral venous access, unless prior central venous catheter placement has 
been performed

Active infection
Patients being treated for non-serious infectious complications (e.g., oral candidiasis or 
uncomplicated urinary tract infection) with oral or topical antimicrobials may be eligible 
for study treatment (antimicrobial treatment must be completed prior to Day 1 of Cycle 1 
and cases must be discussed and approved by the Medical Monitor).

Severe infection requiring hospitalization or IV antibiotics within 14 days prior to enrollment
Patients receiving prophylactic antibiotics, antifungals, and antivirals as a result of 
prolonged neutropenia in the absence of active documented infection are eligible.
Patients receiving IV antibiotics and hospitalization for febrile neutropenia may be 
eligible, where initial diagnosis of neutropenic fever was not due to any infectious 
etiology and the patient has been afebrile for 72 hours.

Any serious medical condition or abnormality in clinical laboratory test results that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of the 
study

History or presence of an abnormal ECG finding that is clinically significant in the 
investigator’s opinion, including complete left bundle branch block, second- or third-degree 
heart block, and evidence of prior myocardial infarction

History of other malignancy within 2 years prior to screening, with the exception of those 
with a negligible risk of metastasis or death (e.g., 5-year overall survival of 90%), such as 
adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized 
prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer

Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary 
cells or any component of the atezolizumab, azacytidine, or Hu5F9-G4 formulation

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known allergy or hypersensitivity to any component of the atezolizumab and/or 
Hu5F9-G4 formulation
End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs. 
Length of Study
The last patient is expected to be enrolled 22 months after the first patient is enrolled, and the 
LPLV is expected to occur approximately 15 months after the last patient is enrolled.  The total 
study duration is therefore expected to take approximately 37 months. 
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are atezolizumab and Hu5F9-G4.
Test Products (Investigational Drugs)
Atezolizumab
The dose level of atezolizumab in this study is 840 mg administered to patients by IV infusion 
on Days 8 and 22 of each 28-day cycle (Q2W) for patients enrolled in the safety cohort and in 
the expansion cohort.  During the first cycle of treatment (Cycle 1), patients will receive 840 mg 
IV atezolizumab only on Day 22 in order to collect bone marrow and blood samples for 
biomarker assessment after steady state has been reached for Hu5F9-G4. 
Hu5F9-G4
The initial priming dose will be administered as a continuous IV infusion in 250 mL of normal 
saline over 180 minutes to reduce the risk of acute hemagglutination.  All other infusions for 
doses 1 mg/kg will be administered in 500 mL over 120 minutes.  If more than 4 weeks have 
elapsed since the last dose of Hu5F9-G4 and the patient is to resume treatment, patients must 
undergo intra-patient dose escalation again of Hu5F9-G4 based on their original dosing regimen 
(e.g., 1 mg/kg of priming dose on Days 1 and 4, 15 mg/kg on Day 8, and 30 mg/kg on Days 11, 
15, and 22). 


Atezolizumab—F. Hoffmann-La Roche Ltd
21/Protocol GO40828, Version 3 
The dose level of Hu5F9-G4 administered to patients by IV infusion in this study varies 
according to the week of treatment.  Initially, two priming doses of 1 mg/kg will be given on 
Days 1 and 4 of Cycle 1.  This will be followed by loading doses of 15 mg/kg on Day 8, followed 
by 30 mg/kg on Day 11 of Cycle 1.  Starting on Day 15, Hu5F9-G4 maintenance will be given at 
a dose of 30 mg/kg QW.  
Non-Investigational Medicinal Products
Premedication is required before administration of the first four doses of Hu5F9-G4 with 
6501000 mg of oral acetaminophen and 2550 mg of oral or IV diphenhydramine or 
comparable regimen.  
Statistical Methods
Primary Analysis
The safety analyses will include all patients who receive any amount of either study drug, with 
patients grouped as a whole.
Safety will be assessed through summaries of adverse events, change from baseline in 
targeted vital signs, laboratory test results, and physical examination findings.
All collected adverse event data will be listed by assigned dose level and patient number. 
All adverse events occurring on or after treatment on Day 1 of Cycle 1 will be summarized by 
mapped term, appropriate thesaurus levels, and NCI CTCAE v5.0 toxicity grade.  In addition, all 
serious adverse events, including deaths, will be listed separately and summarized.  DLTs and 
adverse events leading to treatment discontinuation will also be listed separately.
Determination of Sample Size  
Design considerations covering all cohorts were not made with regard to explicit power and 
type I error considerations but to obtain preliminary safety, efficacy, PK, and pharmacodynamic 
information on atezolizumab in combination with Hu5F9-G4.  The planned enrollment for this 
study is 21 patients, depending on the safety profile observed during the safety evaluation 
phase.  The study will enroll approximately 6 patients in the safety cohort and approximately 
15 patients in the expansion cohort.  The sample size may increase as a result of dose findings.  
The probabilities of observing adverse events in at least 1 patient, given the varying actual 
adverse event rates, are listed in the following table. 
Probability of Safety-Signal Detection with a Cohort of 21 Patients
True Underlying Probability 
of an Adverse Event
Probability of Observing at Least One 
Adverse Event in 21 Patients (%)
0.01
19.0
0.025
41.2
0.05
65.9
0.075
80.5
0.1
89.0
Interim Analysis
Interim looks may be performed during the study. Response data will be compared with the 
comparable historical data using statistical methodology such as a predictive and/or posterior 
probability design, with the modification that the uncertainty in the historical control data is fully 
taken into account by utilizing a distribution on the control response rate to enable internal 
decision-making for future development. The possible data sources to be used as historical 
controls may be publications, real-world data sources, and other reliable information on efficacy 
from other studies in similar patient groups that will be available by the time of the interim 
analysis.


Atezolizumab—F. Hoffmann-La Roche Ltd
22/Protocol GO40828, Version 3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
allo-HSCT
allogeneic hematopoietic stem cell transplant
AML
acute myeloid leukemia
antiCTLA-4
anticytotoxic T lymphocyteassociated protein 4 
CDC
complement-dependent cytotoxicity
Cmax
maximum concentration
Cmin
minimum concentration
CMV 
cytomegalovirus 
CR
complete remission
CRh
complete remission with partial hematologic recovery 
CRi
complete remission with incomplete hematologic 
recovery
CRp
complete remission with incomplete platelet recovery
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose-limiting toxicity
DOR
duration of response
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EFS
event-free survival
ELN
European LeukemiaNet
EMA
European Medicines Agency
Fc
fragment crystallizable
FDA
(U.S.) Food and Drug Administration
FISH
fluorescence in situ hybridization
G-CSF
granulocyte colony-stimulating factor
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
HMA
hypomethylating agent
IAP
integrin-associated protein
ICH
International Council for Harmonisation
IDH1 (2)
isocitrate dehydrogenase 1 (2)


Atezolizumab—F. Hoffmann-La Roche Ltd
23/Protocol GO40828, Version 3 
Abbreviation
Definition
IFN-
interferon-
IL-2
interleukin-2
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IRF
independent review facility
IRR
infusion-related reaction
IWG
International Working Group
IxRS
interactive voice or web-based response system
LDAC
low-dose cytarabine
LFS
leukemia-free survival
LPLV
last patient, last visit
LVEF
left ventricular ejection fraction
MDS
myelodysplastic syndrome
MLFS
morphologic leukemia-free state
MRD
minimal residual disease
MTD
maximum tolerated dose
NCI CTCAE v5.0
National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamic
PFS
progression-free survival
PK
pharmacokinetic
PO
by mouth; orally
PR
partial remission
Q2W
every 2 weeks
Q3W
every 3 weeks
QTcF
QT interval corrected through use of 
Fridericia's formula
QW
once a week
RBR
Research Biosample Repository
Rh
Rhesus (factor)
R/R
relapsed and/or refractory (acute myeloid leukemia)
QTcF
QT interval corrected through use of 
Fridericia's formula


Atezolizumab—F. Hoffmann-La Roche Ltd
24/Protocol GO40828, Version 3 
Abbreviation
Definition
SIRP
signal regulatory protein
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing


Atezolizumab—F. Hoffmann-La Roche Ltd
25/Protocol GO40828, Version 3 
1.
BACKGROUND
1.1
BACKGROUND ON ACUTE MYELOID LEUKEMIA
Acute myeloid leukemia (AML) is a hematopoietic neoplasm that is characterized by 
rapid proliferation, clonal heterogeneity, and abnormal differentiation. Until recently, the 
general management strategy for patients with AML had not changed significantly over 
the last three decades. 
The initial assessment of patients with AML is to determine whether a patient is a 
candidate for intensive induction chemotherapy. If a complete remission (CR) is 
achieved with a cytarabine and an anthracycline-containing regimen (i.e., 73
fractionated gemtuzumab ozogamicin, 73midostaurin for FLT3-mutated AML, or 
liposomal daunorubicin plus cytarabine for higher-risk AML), then post-remission 
chemotherapy (i.e., consolidation) is administered. Depending on cytogenetic and/or 
molecular prognostic markers, allogeneic hematopoietic stem cell transplantation
(allo-HSCT) may be recommended after achieving the first CR, provided a donor source 
is available and the patient remains in good health.
Treatment with high-dose chemotherapy regimens can cure 35%40% of adults who 
are 60 years old (Döhner et al. 2010). However, the cure rate is much lower (5%15%) 
in patients who are 60 years or older. Outcomes are even worse in older patients who 
are unable to receive induction chemotherapy or allo-HSCT, with a median survival of 
just 510 months. Such patients are often treated palliatively with hypomethylating 
agents (HMAs) (azacitidine, decitabine) or low-dose cytarabine (LDAC). 
A Phase III study of decitabine versus a conventional-care regimen (LDAC was the most 
common choice) determined that treatment with decitabine was associated with a 
survival advantage (7.7 vs. 5 months) but did not meet the predefined threshold for 
statistical significance (Kantarjian et al. 2012). Nevertheless, the European Medicines 
Agency (EMA), but not the U.S. Food and Drug Administration (FDA), has approved the 
use of both decitabine and azacitidine in older patients with AML. The Phase III
AML-001 study of azacitidine versus a conventional-care regimen also showed
increased survival with azacitidine (10.4 vs. 6.5 months); this difference was not
statistically significant but can be viewed as clinically meaningful (Dombret et al. 2015).
More recently, the combination of venetoclax plus HMA therapy has shown to be a novel, 
well-tolerated regimen with clinically promising activity in patients with AML. Approval by 
the U.S. FDA is anticipated by the fourth quarter of 2018.


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Response to treatment during relapse from remission depends on the length of
remission and other prognostic factors, with longer duration of remission and lack of 
poor prognostic factors (e.g., prior allo-HSCT, complex cytogenetics, and older age) 
associated with better responses to salvage chemotherapy and prolonged survival 
(Breems et al. 2005). There is no consensus standard of care in this setting. In fit 
patients, the goal is to treat with an intensive salvage chemotherapy regimen, followed
by an allo-HSCT if a CR is achieved.
One of the most challenging situations in AML management remains for patients who do 
not respond to initial chemotherapy (10%40% of patients) (Thol et al. 2015). Here, the
data are very limited, but the approach is the same as in the relapsed setting:
high-intensity salvage chemotherapy followed by allo-HSCT. Over the past 12 months, 
three new small molecule inhibitors have shown promising clinical activity in patients 
with relapsed and/or refractory (R/R) AML. Inhibitors of the isocitrate dehydrogenase 1 
and 2 enzymes (IDH1 and IDH2 inhibitors) have shown promising single-agent activity in 
IDH1-and IDH2-mutated AML, respectively. Enasidenib (an IDH2 inhibitor) was recently 
approved by the U.S. FDA for the treatment of R/R IDH2-mutated AML, as was
ivosidenib (an IDH1 inhibitor). For patients with FLT3-mutated AML, the QuANTUM-R 
trial recently demonstrated improved responses and overall survival (OS) in patients 
randomized to receive quizartinib; the drug has received fast-track designation for filing 
to the FDA. Despite recent improvements, all phases of AML treatment remain areas of 
high unmet medical need; however, the need is most pressing in the R/R and older, 
treatment-naive, chemotherapy unfit populations.
1.2
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding
to fragment crystallizable (Fc) receptors, thus eliminating detectable Fc-effector function
and associated antibody-mediated clearance of activated effector T cells.
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy.
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, and triple-negative breast cancer.


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Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies.
1.2.1
Atezolizumab Nonclinical Studies 
The nonclinical strategy of the atezolizumab program was to assess the in vitro and
in vivo activity to determine in vivo pharmacokinetic (PK) behavior, to evaluate the safety 
profile, and to identify a Phase I starting dose. Comprehensive pharmacology, PK, and 
toxicology evaluations were performed with atezolizumab. The safety, pharmacokinetics, 
and toxicokinetics of atezolizumab were investigated in mice and cynomolgus monkeys 
to support IV administration and to aid in projecting the appropriate starting dose in 
humans. Given the similar binding of atezolizumab to 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; 
heightened immune responses and the potential to increase immune-associated
inflammatory lesions were identified as possible safety risks for patients.
Refer to the latest version of the Atezolizumab Investigator’s Brochure for details with
regard to the nonclinical studies.
1.2.2
Atezolizumab Clinical Pharmacokinetics and Immunogenicity
Exposure to atezolizumab increased proportionally over the dose range of 120 mg/kg,
which included the fixed dose of 1200 mg administered every 3 weeks (Q3W). On the
basis of a population-PK analysis that included 472 patients in the dose range of
120 mg/kg, the typical population clearance was 0.20 L/day, the volume of distribution
at steady state was 6.9 L, and the terminal half-life was 27 days. The population-PK 
analysis suggested that steady state was obtained after 69 weeks (two to three cycles) 
of repeated dosing. The systemic accumulation in area under the concentrationtime 
curve, maximum concentration, and trough concentration was 1.91-, 1.46-, and 2.75-fold, 
respectively. Subsequent PK studies support the use of 840 mg of atezolizumab every 
2 weeks and 1640 mg of atezolizumab every 4 weeks.
The development of anti-therapeutic antibodies (ADAs) to atezolizumab has been
observed in patients in all dose cohorts and has been associated with changes in
pharmacokinetics for some patients in the lower dose cohorts (0.3, 1, and 3 mg/kg). 
The development of detectable ADAs has not had a significant impact on atezolizumab
pharmacokinetics for doses from 10 to 20 mg/kg. Patients receiving the 10-, 15-, and 
20-mg/kg dose levels have maintained the expected target trough concentrations of drug 


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despite the detection of ADAs. To date, no clear relationship between detection of ADAs 
and adverse events or infusion reactions has been observed.
See the Atezolizumab Investigator’s Brochure for additional details on clinical 
pharmacokinetics and immunogenicity.
1.2.3
Atezolizumab Clinical Studies 
For details of additional ongoing studies, refer to the latest version of the Atezolizumab
Investigator’s Brochure.
1.2.4
Atezolizumab Clinical Safety
As of 17 May 2018, an estimated 16,000 or more patients with solid tumor and 
hematologic malignancies had received atezolizumab in clinical trials as a single agent
or in combination with cytotoxic chemotherapy and/or targeted therapy. Safety findings 
of single-agent atezolizumab across multiple tumor types in the clinical development 
program are consistent with the known mechanism of action of atezolizumab and the 
underlying disease. Overall, treatment with atezolizumab is well tolerated, with a 
manageable adverse event profile. Currently, no maximum tolerated dose (MTD), no
dose-limiting toxicities (DLTs), and no clear dose-related trends in the incidence of 
adverse events have been determined.
For updated single-agent efficacy and adverse event profile, please refer to 
Atezolizumab Investigator's Brochure. The adverse events observed with atezolizumab 
in combination with chemotherapy and/or targeted therapies are consistent with the 
known risks of each study treatment.
The percentage of patients who discontinued atezolizumab because of any adverse
event is consistent when given as a single agent or in combination with chemotherapy
(e.g., 5.4% in Study PCD4989g and 5.8% in Study GP28328, respectively). The
percentage of patients with any Grade 5 adverse event was similar when atezolizumab 
was given as a single agent or in combination with chemotherapy (e.g., 1.6% in 
Study PCD4989g and 1.0% in Study GP28328).
Immune-mediated adverse events are consistent with the role of the PD-L1/PD-1 
pathway in regulating peripheral tolerance. Given the mechanism of action of 
atezolizumab, events associated with inflammation and/or immune-mediated adverse 
events are 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 and/or myasthenia 
gravis, meningoencephalitis, and myocarditis, hypophysitis, nephritis, and myositis.
Overall, most of the immune-mediated adverse events observed with atezolizumab have
been mild and self-limiting. Immune-mediated adverse events should be recognized 


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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.
More recently, atezolizumab has been tested in patients with advanced myeloid 
malignancies (i.e., myelodysplastic syndrome [MDS] and AML) as a single agent and in 
combination with HMAs (both in the front-line and the R/R settings). In MDS, the 
single-agent adverse event profile did not demonstrate any unexpected toxicities. 
However, an increased rate of fatal adverse events was observed in patients receiving 
atezolizumab in combination with azacitidine given as front-line therapy compared with 
published rates for all deaths with azacytidine monotherapy in the first 3 months (28.6% 
vs. 11%, respectively) (Gerds et al. 2017). In addition, the overall safety profile (Grade 3
and 4 serious adverse events and adverse events leading to discontinuation) of 
atezolizumab plus azacitidine is worse than azacitidine monotherapy. The overall rate of 
infections appears to be higher for the combination than what is reported in the literature 
for azacitidine monotherapy in the front-line treatment setting for MDS and best 
supportive care in R/R MDS, which was not expected based on the mechanism of action
and single-agent data.
In AML, the single-agent adverse event profile did not demonstrate any unexpected 
toxicities, but no evidence of clinical benefit was noted. The combination study of 
guadecitabine plus atezolizumab was stopped early based on the increased early death 
rate observed in previously untreated patients with MDS treated with azacitidine plus 
atezolizumab.
Refer to the Atezolizumab Investigator’s Brochure for details on adverse events
observed in patients treated with atezolizumab monotherapy or in combination with other
agents and for details on immune-mediated adverse events that were observed in 
patients treated with atezolizumab. Guidelines for the management of immune-
mediated adverse events can be found in the Atezolizumab Investigator’s Brochure.
1.3
BACKGROUND ON Hu5F9-G4
Hu5F9-G4 is a recombinant humanized anti-CD47 monoclonal antibody of the IgG4 
isotype containing a Ser-Pro substitution in the hinge region (position 228) of the 
heavy chain to reduce Fab arm exchange. Hu5F9-G4 is a first-in-class anti-cancer 
therapeutic agent targeting the CD47/SIRPaxis.  
Hu5F9-G4 is secreted by a genetically engineered CHOK1SVcell line as a 
disulfide-linked glycosylated tetramer, consisting of two identical 444 amino acid heavy 
chains and two identical 219 amino acid light chains.  The molecular formula for 
Hu5F9-G4 is C6462H9960N1718O2027S48, and the predicted molecular weight is 
145687.6 daltons based on the amino acid sequence and excluding contributions from 
N-linked glycosylation.


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Binding of Hu5F9-G4 to human CD47 on target malignant cells blocks the “don’t eat me” 
signal to macrophages and enhances tumor cell phagocytosis. In addition, Hu5F9-G4 
elicits an anti-tumor T-cell response by means of phagocyte-mediated 
cross-presentation of tumor antigens to T cells (Tseng et al. 2013). CD47 is a 50-kD cell 
surface glycoprotein that is widely expressed on cancer cells and in normal tissues 
(Brown and Franzier 2001). CD47 consists of an extracellular Ig superfamily domain 
linked to five transmembrane spanning regions and a short intracellular cytoplasmic 
domain (Brown and Franzier 2001). It binds to a variety of integrins and 
thrombospondin-1; however, its interaction with SIRPis thought to be the major 
mediator of its function as a negative checkpoint regulator of phagocytosis.
CD47 binding to the receptor SIRPon the surface of cells of the innate immune system, 
such as macrophages and dendritic cells, initiates a signal transduction cascade that 
blocks phagocytosis.  In this way, CD47 functions as an inhibitor of phagocytosis by 
delivering a dominant inhibitory signal to phagocytic cells (Blazar et al. 2001; Okazawa 
et al. 2005).  However, the complex process of phagocytosis depends on the relative 
balance of pro-phagocytic and anti-phagocytic inputs.  Most normal cells, apart from 
aging RBCs (Oldenborg et al. 2000; Okazawa et al. 2005), lack expression of 
pro-phagocytic signals (Jaiswal et al. 2009; Majeti et al. 2009; Chao et al. 2012) and are 
unaffected by CD47 blockade.  In contrast, most cancer cells express pro-phagocytic 
signals on their cell surface, many of which are not yet molecularly characterized 
(Chao et al. 2012).  As a consequence, effective phagocytosis requires two events:  
silencing of the CD47/SIRPinhibition pathway and interaction of the pro-phagocytic 
signal with its receptor.  Cancer cells uniformly exhibit increased expression of CD47, 
presumably to prevent phagocytic elimination by innate immune cells (Jaiswal et al. 
2010).  When CD47 is blocked from interacting with SIRP(e.g., using an antibody to 
CD47), pro-phagocytic signals dominate, enabling phagocytosis of the cancer cells, 
which results in inhibition of tumor growth and metastasis.
Hu5F9-G4 is an anti-human CD47 monoclonal antibody that blocks the interaction of 
CD47 with its receptor and enables phagocytosis of human cancer cells (Liu et al. 2015).
The activity of Hu5F9-G4 is primarily dependent on blocking CD47 binding to SIRPand 
not on the recruitment of Fc-dependent effector functions, although the presence of the 
IgG4 Fc domain is required for its full activity. For this reason, Hu5F9-G4 was 
engineered with a human IgG4 isotype that is relatively inefficient at recruiting 
Fc-dependent effector functions that might enhance toxic effects on normal 
CD47-expressing cells (Liu et al. 2015). Preclinical studies using xenograft cancer 
models provide compelling evidence that Hu5F9-G4 triggers phagocytosis and 
elimination of cancer cells from human solid tumors and hematologic malignancies. 
Based on the mechanism of action and its potent preclinical activity, Hu5F9-G4 is being
developed as a novel therapeutic candidate for solid tumors and hematologic
malignancies.


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Data from several studies indicate that the mechanism of action of Hu5F9-G4 does not 
involve Fc-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) or 
complement-dependent cytotoxicity (CDC) effector functions. In order to reduce the 
potential for cytotoxicity against normal CD47-expressing cells, Hu5F9-G4 was 
constructed on a human IgG4 isotype scaffold to minimize the recruitment of 
Fc-dependent effector functions such as ADCC and CDC. Several cell-based studies 
were subsequently performed to assess the ability of Hu5F9-G4 to stimulate ADCC or 
CDC activity, in which Fc-mediated ADCC or CDC effector functions were not observed.
1.3.1
Hu5F9-G4 Nonclinical Studies
Nonclinical safety assessment of Hu5F9-G4 was performed in non-human primates 
(i.e., cynomolgus and rhesus monkeys).  Binding affinity studies demonstrated that 
Hu5F9-G4 binds to human CD47 and cynomolgus monkey CD47 with high affinity 
(dissociation constant8.0 pM and 10 pM, respectively).  In contrast, Hu5F9-G4 (and its 
parent 5F9) does not bind to mouse CD47.
The therapeutic effect of Hu5F9-G4 on human AML was evaluated in human patient 
AML xenograft tumor models in vivo with two independent primary patient samples 
(SU028 and SU048).  Six weeks after xenotransplantation, therapy was initiated with 
daily intraperitoneal injections of either control mouse IgG or 100 μg of Hu5F9-G4 
(5 mice per treatment cohort for each patient AML xenograft model).  Daily doses of 
100 g of Hu5F9-G4 over 2 weeks cleared AML in the bone marrow of all mice at the 
end of treatment with recovery of normal hematopoiesis in the bone marrow, leading to a 
major survival benefit compared with control cohorts.  Serum levels of 50150 g/mL of 
Hu5F9-G4 were achieved after 2 weeks of treatment.
In studies designed to explore the dose-dependent therapeutic efficacy of Hu5F9-G4 on 
human AML in a human patient AML xenograft tumor model in vivo, daily doses of 
100 g of Hu5F9-G4 or twice weekly doses of 500 g of Hu5F9-G4 eradicated AML after 
2 weeks of treatment in the majority of mice.  In addition, 3 of 16 mice (2 in the 100-g 
Hu5F9-G4 treatment group and 1 in the 500-g Hu5F9-G4 treatment group) were not 
cured after the first treatment course.  Re-treatment resulted in a significant reduction of 
AML burden in the bone marrow and long-term remission.  However, 2 mice relapsed 
again after 5 months and therefore received a third and fourth treatment course with 
Hu5F9-G4, but the mice either did not respond or relapsed again after a 2-month 
remission.
In xenografted mice with very high circulating leukocytes (50% of total WBC count) and 
marrow infiltration with AML (80%), Hu5F9-G4 treatment caused death within 1 hour of 
administration of the first dose. In all cases in which mice were xenografted with primary 
human solid tumors, the mice did not have a high level of circulating tumor burden. 
For full details on Hu5F9-G4 nonclinical studies, please refer to the Hu59-G4 
Investigator's Brochure.  


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1.4
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
The PD-L1 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) (see Atezolizumab Investigator's Brochure for 
details).
Clinical data emerging in the field of tumor immunotherapy have demonstrated that 
therapies focused on enhancing T-cell responses against cancer can result in a 
significant survival benefit in patients with advanced malignancies (Hodi et al. 2010; 
Kantoff et al. 2010; Chen et al. 2012). However, clinical trials of patients with myeloid 
malignancies have shown disappointing results. 
Similarly, the ongoing Phase I clinical trial (SCI-CD47-002), testing single-agent 
Hu5F9-G4 (an anti-CD47 monoclonal antibody), has not demonstrated significant activity 
in patients with R/R AML. Reduction in bone marrow blast count and prolonged stable 
disease have been observed.
Single-agent atezolizumab has been generally well tolerated in patients with advanced 
myeloid malignancies (see Atezolizumab Investigator's Brochure for detailed safety 
results).  In advanced myeloid malignancies, the percentage of patients discontinuing 
single-agent atezolizumab because of adverse events was low (10%).  Similarly, no 
safety concerns have been identified in patients with AML who have been treated with 
single-agent Hu5F9-G4.  To date, no DLTs were documented and no study
treatmentrelated deaths have been observed.  No MTD has been defined for this agent 
(for details, see the Hu5F9-G4 Investigator's Brochure for detailed safety results).
As of the clinical cutoff date (1 March 2017), no DLTs had occurred in the 13 patients 
treated in Study SCI-CD47-002.  A DLT of Grade 3 anemia, which was assessed as 
related to Hu5F9-G4, was reported for the first patient treated.  Because this patient had 
baseline Grade 3 anemia prior to treatment and given that Grade 3 anemia is common 
at baseline in patients with R/R AML, Grade 3 anemia was subsequently removed as a 
DLT.  No additional DLTs have been reported since that first patient.
As of the clinical cutoff date, a total of 27 serious adverse events had been reported.
Of these events, 25 events were assessed by the investigator to be unrelated to study 
treatment and two events were assessed as related to study treatment (two events of 
anemia and one event of blood and lymphatic system disorders reported for 1 patient 
and one event of pyrexia). All events have resolved.
Despite limited single-agent activity reported with both investigational agents when used 
as single agents, preclinical data have demonstrated that Hu5F9-G4 elicits an anti-tumor 


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T-cell response (see the Hu5F9-G4 Investigator's Brochure for full details).  In addition, 
pharmacodynamic (PD) assessment of bone marrow biopsies from patients with AML 
demonstrated a significant increase in the bone marrow infiltrate of T cells with 
Hu5F9-G4 treatment. CD47 blockade leads to tumor cell phagocytosis by macrophages 
and subsequent cross-presentation of tumor antigens by macrophages and other 
antigen-presenting cells to CD8 T-cells, eliciting an adaptive immune cell response 
(Tseng et al. 2013). AntiPD-1)/PD-L1 antibodies enable enhanced T-cell activity 
through blockade of T-cell checkpoint inhibition and reversal of T-cell exhaustion. 
Thus, the combination of Hu5F9-G4 with an antiPD-1/PD-L1 antibody can lead to 
an enhanced T-cell anti-tumor response through these complementary mechanisms 
of action.
This study will enroll patients with R/R AML.  Given the relatively poor prognosis and 
limited treatment options for these patients, this population is considered appropriate for 
clinical trials of novel therapeutic candidates.  The benefitrisk ratio for atezolizumab in 
combination with Hu5F9-G4 is expected to be acceptable in this setting.
2.
OBJECTIVES AND ENDPOINTS
This Phase Ib study is designed to evaluate the safety and pharmacokinetics of 
atezolizumab when given in combination with Hu5F9-G4 to patients with R/R AML.  
Specific objectives and corresponding endpoints for the study are outlined below.
In this protocol, "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e., atezolizumab and Hu5F9-G4).
2.1
SAFETY OBJECTIVE
The primary safety objective for this study is to characterize the safety and tolerability of 
atezolizumab administered in combination with Hu5F9-G4 to patients with R/R AML on 
the basis of the following endpoints:

Incidence of adverse events, with severity determined through use of the National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 
(NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results

Change from baseline in physical examination findings
2.2
PHARMACOKINETIC OBJECTIVES
The PK objective for this study is to characterize the pharmacokinetics of atezolizumab
and Hu5F9-G4 when administered in combination to patients with R/R AML on the basis 
of the following endpoints:

Serum concentrations of atezolizumab 

Serum concentrations of Hu5F9-G4 at specified timepoints


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The exploratory PK objective for this study is to assess potential PK interactions 
between atezolizumab and Hu5F9-G4 on the basis of the following endpoints:

Serum concentrations of atezolizumab given in combination with Hu5F9-G4 
compared with atezolizumab given alone (based on historical data)

Serum concentrations of Hu5F9-G4 given in combination with atezolizumab
compared with Hu5F9-G4 given alone (based on historical data)
2.3
EFFICACY OBJECTIVES
2.3.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab 
administered in combination with Hu5F9-G4 to patients with R/R AML on the basis of the 
following endpoints:

CR, CR with incomplete platelet recovery (CRp), CR with incomplete hematologic 
recovery (CRi), and CR with partial hematologic recovery (CRh) rate after up to 
6 cycles of combination therapy, as determined by the investigator, according to the 
International Working Group (IWG) 2003 and European LeukemiaNet (ELN) 2010 
criteria (Döhner et al. 2017)

Duration of response (DOR), defined as the time from the initial response (CR, CRp, 
CRi, CRh, or partial remission [PR]) to the time of disease progression or death, 
whichever occurs first
2.3.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to make a preliminary assessment of 
the anti-neoplastic activity of atezolizumab administered in combination with Hu5F9-G4 
to patients with R/R AML on the basis of the following endpoints:

Objective response rate (ORR) achieved in the study, defined as the percentage of 
patients with a PR or better (i.e., CRCRpCRiCRhPR)

Event-free survival (EFS), defined as the time from study entry to the date of 
induction treatment failure or relapse from CR, CRp, CRh, CRi, or death from 
any cause

Leukemia-free survival (LFS), defined (only for patients achieving a CR, CRp, CRh,
or CRi) as the time from the date of achievement of remission (CR, CRp, or CRi) 
until the date of relapse from CR, CRp, CRh, CRi, or death from any cause

OS, defined as time from study entry to the date of death from any cause

Progression-free survival (PFS), defined as the time from the first day of study 
treatment to disease progression or death, whichever occurs first

Rate of transfusion independence, defined as the percentage of patients who 
achieve transfusion independence (i.e., achieving any continuous 56-day window 
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
Duration of transfusion independence, defined as the number of consecutive days of 
transfusion independence, measured from 1 day after the last transfusion to disease 
progression or subsequent transfusion 
2.4
IMMUNOGENICITY OBJECTIVE
The immunogenicity objective for this study is to evaluate the immune response to 
atezolizumab and Hu5F9-G4 on the basis of the following endpoints:

Incidence of ADAs against atezolizumab during the study relative to the prevalence 
of ADAs at baseline

Incidence of ADAs against Hu5F9-G4 during the study relative to the prevalence of 
ADAs at baseline
2.5
EXPLORATORY BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify biomarkers that are 
predictive of response to atezolizumab in combination with Hu5F9-G4 (i.e., predictive 
biomarkers), are associated with progression to a more severe disease state 
(i.e., prognostic biomarkers), are associated with acquired resistance to atezolizumab 
and/or Hu5F9-G4, are associated with susceptibility to developing adverse events, can 
provide evidence of atezolizumab and/or Hu5F9-G4 activity, or can increase the 
knowledge and understanding of disease biology on the basis of the following endpoints:

Relationship between biomarkers in blood and bone marrow (including somatic 
mutations) (listed in Section 4.5.7.2) and efficacy, safety, PK, immunogenicity, 
expression profiles, bone marrow aspirate stromal factors, or other biomarker 
endpoints

To determine the effect of single agent Hu5F9-G4 on T-cell activation and bone 
marrow infiltration in patients with R/R AML
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase Ib, open-label, multicenter, non-randomized study of atezolizumab, 
evaluating the safety and pharmacokinetics of atezolizumab (an antiPD-L1 monoclonal 
antibody) given in combination with Hu5F9-G4 (an anti-CD47 monoclonal antibody) for
the treatment of patients with R/R AML (excluding promyelocytic leukemia). 
An initial safety evaluation will be performed in 6 patients with relapsed AML. If 
atezolizumab in combination with Hu5F9-G4 is found to be initially safe and tolerable in 
patients with R/R AML, an additional cohort of 15 patients with R/R AML will be 
evaluated to further test the safety and anti-tumor activity of atezolizumab in combination 
with Hu5F9-G4.
If DLTs are observed in 33% of patients (i.e., 2 or more of 6 patients) in this initial 
safety cohort, a dose de-escalation cohort of 6 patients will be enrolled. If 33% of the 
enrolled (1 patient or no patients) and dosed patients in any given cohort experience a 


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DLT, an expansion cohort of 15 patients will be enrolled at the higher tolerated dose for 
this combination. If a dose de-escalation cohort is needed (n12 for safety cohorts), an 
expansion cohort of 9 patients will be enrolled at the lower tolerated dose for this 
combination.  The maximum number of patients enrolled in this study will be 21 patients 
(this number will include patients assessed for DLT plus those potentially removed prior 
to DLT assessment).
3.1.1
Overview of Study Design
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1.
Figure 1
Study Schema
Atezoatezolizumab; DLTdose-limiting toxicity; Q2W every 2 weeks; QW once a week.
Note:  On days when both atezolizumab and Hu5F9-G4 are administered (Day 22 of Cycle 1 and 
Days 8 and 22 of subsequent cycles), Hu5F9-G4 should be administered first and the interval 
between Hu5F9-G4 and atezolizumab infusions should follow guidelines as outlined in Table 2.
Safety Cohort (n6) 
Atezolizumab:   
840 IV Q2W, starting on Day 22 of Cycle 1 (Days 8 and 22 of 
Cycle 2 and beyond)
Hu-5F9-G4:  
Week 1:  1 mg/kg  IV on Days 1 and 4  
Week 2:  15 mg/kg IV on Day 8 and 30 mg/kg on Day 11
Week 3 and beyond:  30 mg/kg IV QW, starting on Day 15
2 or more patients with DLTs  
(33% of patients)
DLT Evaluation
Dose De-Escalation Cohort (n6) 
Atezolizumab:   
840 IV Q2W, starting on Day 22 of Cycle 1 (Days 8 and 22 of Cycle 2 and
beyond) 
Hu-5F9-G4:  
Two priming doses:  1 mg/kg  IV on Days 1 and 4 of Week 1
Two loading doses: 10 mg/kg IV on Day 8 and 15 mg/kg on Day 11
Maintenance dose:  15 mg/kg IV QW, starting on Day 15
Expansion Cohort (n9) 
Atezolizumab: 
840 IV Q2W, starting on Day 22 of Cycle 1 (Days 8 and 22 of 
Cycle 2 and beyond)
Hu-5F9-G4:  highest tolerated dose for combination
Combination Safe  
and Tolerable 
Expansion Cohort (n15) 
Atezolizumab:   
840 IV Q2W, starting on Day 22 of Cycle 1 (Days 8 and 22 of 
Cycle 2 and beyond)
Hu-5F9-G4:  
Week 1:  1 mg/kg  IV on Days 1 and 4  
Week 2:  15 mg/kg IV on Day 8 and 30 mg/kg on Day 11
Week 3 and beyond:  30 mg/kg IV QW, starting on on Day 15


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The proposed treatment regimen during Cycle 1 is a biomarker-driven treatment plan
designed to assess the effect of single-agent Hu5F9-G4 on markers of immune 
activation in AML. This safety cohort is designed to assess the safety, tolerability, and 
clinical activity of Hu5F9-G4 in combination with atezolizumab based on the 
following schedule:

Atezolizumab:  Atezolizumab will be administered to patients by IV infusion at a 
fixed dose of 840 mg, starting on Day 22 of Cycle 1. In subsequent cycles (Cycles 2 
and beyond), 840 mg of IV atezolizumab will be given every 2 weeks (Q2W) on 
Days 8 and 22 of each 28-day cycle. 

Hu5F9-G4:  Two priming doses of 1 mg/kg of Hu5F9-G4 will be administered to 
patients by continuous IV infusion on Days 1 and 4 of Cycle 1, followed by loading 
doses of 15 mg/kg IV on Day 8 and 30 mg/kg IV on Day 11. Starting on Day 15 of 
Cycle 1, Hu5F9-G4 maintenance will be given by IV infusion at a dose of 30 mg/kg 
once a week (QW) of each 28-day cycle. On days when both atezolizumab and 
Hu5F9-G4 are administered (Day 22 of Cycle 1 and Days 8 and 22 of subsequent 
cycles), Hu5F9-G4 should be administered first and the interval between Hu5F9-G4 
and atezolizumab infusions should follow guidelines as outlined in Table 2. 
If DLTs are observed in 33% of patients (i.e., 2 or more of 6 patients) in this initial 
safety cohort, a dose de-escalation cohort of 6 patients will be enrolled.  The dosing 
schedules for this de-escalation cohort will be as follows:

Atezolizumab will be administered to patients by IV infusion at a fixed dose of 
840 mg, starting on Day 22 of Cycle 1.  In subsequent cycles, 840 mg of 
atezolizumab administered by IV infusion will be given Q2W on Days 8 and 22 of 
each 28-day cycle.

Hu5F9-G4 will be given as two priming doses of 1 mg/kg IV on Days 1 and 4, 
followed by loading doses of 10 mg/kg IV on Day 8 and 15 mg/kg on Day 11. 
Starting on Day 15, maintenance treatment with Hu5F9-G4 will be given by IV 
infusion at a dose of 15 mg/kg QW.  

If 33% (i.e., 1 or fewer of 6 patients) patients in the de-escalation cohort 
experience a DLT, an expansion cohort of 9 patients will be enrolled to further test 
the safety and anti-tumor activity of atezolizumab in combination with Hu5F9-G4,
using the same dosing regimen
If DLTs are observed in33% of patients (i.e., 1 or fewer of 6 patients) in the initial 
safety cohort, an expansion cohort of 15 patients will be enrolled to further test the safety 
and anti-tumor activity of atezolizumab in combination with Hu5F9-G4, using the same 
dosing regimen.
Study treatment will be administered until unacceptable toxicity or loss of clinical benefit,
as determined by the investigator, after local biopsy results (if available) and clinical 
status (e.g., symptomatic deterioration such as pain secondary to disease) are assessed.  


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3.1.2
Safety Evaluation Phase
3.1.2.1
Dose-Limiting Toxicity Assessment 
The first 6 patients enrolled in the safety cohort will be eligible for DLT assessment. 
The DLT assessment window for the safety cohort is 56 days from the first dose of 
Hu5F9-G4. 
All patients who experience a DLT during the DLT assessment window will be 
considered evaluable for safety evaluation decisions. 
Patients who withdraw from study treatment (atezolizumab plus Hu5F9-G4) for any 
reason other than a DLT during this assessment window will not be considered 
evaluable for safety evaluation decisions and will be replaced. The total number of 
enrolled patients in this study will be capped at 21 patients. If patients are replaced prior 
to DLT assessment, discontinued patients will be counted toward the total limit of 
21 patients. 
During the DLT evaluation window, patients will not be allowed to make up missed 
doses; patients will resume dosing at their next scheduled dose. Patients who are 
unable to receive the next scheduled dose of Hu5F9-G4 or atezolizumab as a result of 
study treatmentrelated adverse events will be considered to have met the DLT criteria. 
3.1.2.2
Rules for Dose Modification and Changes in Dose Scheduling 
following Dose-Limiting Toxicity
Dose modification following the DLT window will occur in accordance with the following 
rules:

The safety cohort will enroll up to 6 patients.  

If DLTs are observed in 33% of patients (i.e., 2 or more of 6 patients) in this 
initial safety cohort, a dose de-escalation cohort of 6 patients will be enrolled.  The 
dosing schedules for this de-escalation cohort will be as follows:
–
Atezolizumab will be administered to patients by IV infusion at a fixed dose of 
840 mg, starting on Day 22 of Cycle 1.  In subsequent cycles, 840 mg of 
atezolizumab administered by IV infusion will be given Q2W on Days 8 and 
22 of each 28-day cycle.
–
Hu5F9-G4 will be given as two priming doses of 1 mg/kg IV on Days 1 and 4, 
followed by loading doses of 10 mg/kg IV on Day 8 and 15 mg/kg on Day 11.  
Starting on Day 15, maintenance treatment with Hu5F9-G4 will be given by 
IV infusion at a dose of 15 mg/kg QW.
–
If a DLT is observed in 33% of patients (i.e., 2 or more of 6 dose 
de-escalation patients), the dose and schedule will be considered intolerable 
and the MTD will have been exceeded.


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–
The dose level(s) and schedule at which 33% of patients (i.e., 1 or fewer of 
6 dose de-escalation patients) experience a DLT will be declared the optimal 
dose and schedule and an expansion cohort of 9 patients will be enrolled 
using the same dosing regimen.

If DLTs are observed in 33% of patients (i.e., 1 or fewer of 6 patients) in the 
initial safety cohort, an expansion cohort of 15 patients will be enrolled to further 
test the safety and anti-tumor activity of atezolizumab in combination with 
Hu5F9-G4, using the same dosing regimen. 
3.1.2.3
Definition of Dose-Limiting Toxicity 
A DLT is defined as any of the following adverse events that are causally related to 
study treatment that occur during the DLT assessment window and are considered by 
the investigator to be related to atezolizumab, Hu5F9-G4, or the combination of 
atezolizumab with Hu5F9-G4 (see Section 5.3.4, Table 5, for guidance on causal
attribution). For potential overlapping toxicities, investigators are encouraged to perform 
additional testing, such as tissue biopsy, imaging, peripheral blood smears, 
immunological assays, and other laboratory studies to determine the underlying etiology 
and appropriate attribution (whether the event is related to atezolizumab, Hu5F9-G4, or 
the combination of atezolizumab and Hu5F9-G4.  Testing is to be determined by the 
investigator, according to local medical standards, and if needed, in consultation with 
the Medical Monitor, based on an individual patient’s clinical presentations.  Testing 
may elucidate whether the event is an immune-mediated adverse event caused by 
atezolizumab, including those events listed in Section 5.2.3 that should be reported to 
the Sponsor immediately (i.e., within 24 hours). 
Any of the following adverse events that occur during Cycles 1 or 2 will be considered a 
DLT (if causality is determined to be yes according to Table 5) for atezolizumab alone or 
in combination with Hu5F9-G4: 

Any adverse event (regardless of NCI CTCAE v5.0 grade) that leads to dose 
reduction or withdrawal 

Any infusion-related toxicity Grade 3 (e.g., allergic reaction/hypersensitivity, fever, 
pain, bronchospasm, wheezing, or hypoxia) 

Hypocellular (5% cellularity) or aplastic bone marrow 3 without evidence of MDS, 
leukemia, or infectious etiology that lasts for 35 days from the first occurrence 

Grade 3 liver enzyme (ALT or AST) and Grade 3 creatinine elevations

Grade 3 thrombocytopenia associated with clinically significant bleeding that 
requires transfusion of red cells and platelets 

Grade 3 non-hematologic adverse events (with certain Grade 3 exceptions 
discussed below) 

Grade 4 neutropenia and thrombocytopenia lasting past Cycle 2 Day 28 in the 
absence of disease (defined as the presence of 5% bone marrow blasts)


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The following Grade 3 events will not be considered DLTs: 

Grade 3 nausea, vomiting, or diarrhea that resolves to Grade 1 or better within 
7 days of supportive therapy and does not require total parenteral nutrition, tube 
feeding, or prolonged hospitalization

Grade 3 asymptomatic or mildly symptomatic rash that can be adequately managed 
with supportive care (for further details see the Atezolizumab Investigator’s 
Brochure) or resolves to become asymptomatic and/or Grade 2 within 7 days of 
supportive therapy 

Grade3 fatigue, asthenia, or fever that resolves to Grade2 within 7 days 

Grade 3 arthralgia that can be adequately managed with supportive therapy or that 
resolves to Grade 2 within 7 days 

Asymptomatic Grade 3 laboratory abnormalities (other than liver enzyme and 
creatinine elevations) that resolve to Grade 2 within 72 hours 
All DLTs will be reported on an electronic Case Report Form (eCRF), the standard 
Adverse Event eCRF in the Sponsor’s electronic data capture (EDC) system within 
24 hours (see Section 5.3.5). All DLTs will be considered adverse events of special 
interest for this protocol and will be reported to the Sponsor in an expedited manner, as 
indicated in Section 5.2.3. Dose modification decisions will be made by the Sponsor in 
consultation with investigators after review of available relevant data. 
3.1.2.4
Stopping Rule for Excess Toxicity for Expansion Phase
Early stopping boundaries for the expansion cohort are based on the Pearson-Klopper 
confidence intervals of the observed toxicity rate, and a target toxicity rate of no more 
than 20%. The stopping boundary for a given number of enrolled patients is the 
minimum number of patients with excess toxicity that would lead to a toxicity rate 
with its lower 95% confidence boundary higher than 20% (see Table 1.  During the 
expansion phase, an episode of excess toxicity will be defined as any adverse event 
meeting criteria for a DLT as outlined in Section 3.1.2.3.


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Table 1
Early Stopping Boundaries for Expansion Cohort
Number of 
Patients Enrolled
Stopping 
Boundary (Number 
of Patients Who 
Experience Excess 
Toxicity)
Observed Toxicity 
Rate a
95% Confidence 
Interval
3
3
100%
(29%, 100%)
4
4
100%
(40%, 100%)
5
4
80%
(28%, 99%)
6
4
78%
(22%, 96%)
7
5
71%
(29%, 96%))
8
5
62.5%
(24%, 91%)
9
5
56%
(21%, 86%)
10
6
60%
(26%, 88%)
11
6
55%
(23%, 83%)
12
6
50%
(21%, 79%)
13
7
54%
(25%, 81%)
14
7
50%
(23%, 77%)
15
7
47%
(21%, 73%)
a The confidence interval for the observed toxicity rate calculated based on the 
Pearson-Klopper method.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs. 
The last patient is expected to be enrolled 22 months after the first patient is enrolled,
and the LPLV is expected to occur approximately 15 months after the last patient is 
enrolled. The total study duration is therefore expected to take approximately 37 months. 
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Atezolizumab Dose and Schedule
Atezolizumab will be administered at a fixed dose of 840 mg IV Q2W (840 mg on Days 8 
and 22 of each 28-day cycle).  The exception will occur at Cycle 1, when only 1 cycle 
dose of atezolizumab will be administered at a fixed dose of 840 mg IV on Day 22 
(biomarker-driven treatment schedule).  The starting dose and schedule of atezolizumab 
840 mg IV Q2W is currently approved in the United States in several indications, 
including urothelial carcinoma, nonsmall cell lung cancer, triple-negative breast 
cancer, and small cell lung cancer (Tecentriq® U.S. Package Insert). Based on the 
mechanism of action of the drug, pathophysiology of disease, and study population 
characteristics, it is not expected that the safety profile would be different for the AML 
population.  Thus, atezolizumab 840 mg Q2W could be considered a safe starting dose 
and schedule. The dosing schedule used in this protocol is similar to the atezolizumab 


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dosing schedule tested in previous clinical studies in patients with myeloid 
malignancies, such as relapsed/refractory and previously untreated AML and 
relapsed/refractory and previously untreated myelodysplastic syndrome 
(ClinicalTrials.gov Identifier: NCT02935361 and NCT02508870).
3.3.2
Rationale for Patient Population
Although the single-agent clinical activity of both atezolizumab and Hu5F9-G4 is limited 
in patients with advanced myeloid malignancies (ORR of 10%), preclinical exposure to 
Hu5F9-G4 is known to elicit a robust anti-tumor T-cell response. As such, in a sarcoma 
model, the combination of anti-CD47 (pro-phagocytic) and anticytotoxic T 
lymphocyteassociated protein 4 (antiCTLA-4) (increased T-cell activation) antibodies 
results in decreased tumor growth and tumor regression compared with each used alone 
(refer to the Hu5F9-G4 Investigator's Brochure). In addition, PD assessment of bone 
marrow biopsies from patients with AML treated with Hu5F9-G4 demonstrated a 
significant increase in the bone marrow infiltrate of T cells, suggesting that sequential 
inhibition of CD47 signaling followed by blockade of PD-L1 may lead to clinical activity in 
patients with advanced myeloid malignancies.
The median T-cell population in bone marrow aspirates of patients with AML is 8%–25% 
(Daver et al. 2016).  T cells make up a significantly larger proportion of the 
CD45-positive population (non-leukemic cells) in bone marrow aspirates from patients 
with AML compared with healthy donors (Daver et al. 2018).  T cells in patients with AML 
exhibit distinct phenotypic and genotypic differences from T cells of healthy donors.  The 
T cells in the bone marrow of patients with AML express activation markers (such as 
CD25, CD69, OX40) at a significantly higher rate than seen in healthy donors, indicating 
that the AML bone marrow is an inflamed microenvironment (Vidriales et al. 1993;
Van den Hove et al. 1998).  There is an increased overall expression of inhibitory 
surface molecules associated with T-cell exhaustion of CD4 and CD8 T cells in 
patients with AML compared with controls (Snorfeil et al. 2013; Daver et al. 2016; 
Tan et al. 2016).  In addition, compared with healthy controls, patients with relapsed 
and newly diagnosed AML had a higher percentage of exhausted T-cell phenotype 
(PD-1  TIM3  and PD-1  LAG3  CD8 T cells) in the bone marrow (Williams et al. 
2017).  PD-1 expression on the T cells in bone marrow was higher in 
multiple-relapsed AML compared with first-salvage AML, newly diagnosed AML, or 
healthy donors (PD-1 on T cells in patients with multiple relapsed AML, which were 
greater than in patients receiving first salvage therapy and greater than in newly 
diagnosed patients, which were greater than in healthy donors), suggesting 
progressive T-cell exhaustion with more advanced-stage AML (Daver et al. 2016).
There are no approved treatments for patients with AML who are unable to achieve an 
initial CR or patients who relapse after initial response, with poor survival among this 
group of patients.  Therefore, there is a high unmet medical need for new therapies for 
patients with R/R AML. 


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On the basis of these data, there is a strong preclinical and PD rationale for exploring 
the use of atezolizumab in combination with Hu5F9-G4 in patients with R/R AML. Finally, 
it is unclear why the PD-L1positive immune-cell infiltrate present in the bone marrow of 
patients with AML and MDS is unresponsive to checkpoint modulation.  Therefore, an 
unselected patient population will be enrolled in order to obtain samples for exploratory 
biomarkers of checkpoint resistance.
3.3.3
Rationale for Relapsed and/or Refractory AML
Between 10% and 40% of newly diagnosed patients with AML do not achieve CR with 
intensive induction therapy and are therefore categorized as having disease that is 
primary refractory or resistant. In addition, between 30% and 80% of patients who
achieve a CR will subsequently relapse. Few of these patients can be cured with 
conventional salvage therapy (Thol et al. 2015). Most patients with R/R AML should be 
enrolled in clinical trials, given that highly effective and standardized treatments for AML
are lacking and clinical trial enrollment is encouraged in this population.
3.3.4
Rationale for Hu5F9-G4 Dose
The dosing schedule chosen for Hu5F9-G4 was established during the Phase I clinical 
trial, during which no MTD was identified at doses of up to 30 mg/kg twice a week.  In 
addition, PD assessments, conducted during the same Phase I clinical trial 
demonstrated that a priming dose for the first week, followed by escalating doses during 
the second week, and subsequently by weekly doses of the anti-CD47 monoclonal 
antibody, was not associated with early deaths, was safe and well tolerated in AML 
patients, resulted in a linear PK profile (see Figure 2), and optimal CD47 antigen binding 
in bone marrow at steady state (see Figure 2). 
Figure 2
Hu5F9-G4 Achieves Target PK Levels at Clinically Feasible Doses
5F9Hu5F9-G4; PKpharmacokinetic.
Source:  Agoram et al. 2018.


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3.3.5
Rationale for Pharmacokinetic Evaluation Schedule 
The proposed sampling scheme for atezolizumab and Hu5F9-G4 concentration 
assessments will contribute to the characterization of study drug PK profiles in AML. 
Atezolizumab concentration results may be compared with single-agent data or available 
data from other atezolizumab clinical studies to assess whether there is any alteration in 
atezolizumab pharmacokinetics when co-administered with Hu5F9-G4 to patients with 
AML and to correlate any clinical activity and safety events. 
The PK profile of Hu5F9-G4 will be characterized and may be compared with historical
data to assess whether there is any alteration in PK properties when co-administered 
with atezolizumab.  Based on the elimination pathways of the two molecules, PK 
interaction is not expected.  
3.3.6
Rationale for Biomarker Assessments 
Changes in immune-related biomarkers in blood and bone marrow may provide 
evidence for biologic activity of atezolizumab treatment combinations in humans and 
may allow for the development of a blood-based biomarker to help predict which patients 
may benefit from treatment with atezolizumab. In addition, these assessments may also 
highlight unique properties associated with resistance to checkpoint inhibitors in 
advanced myeloid malignancies. An exploratory objective of this study is to make a 
preliminary assessment of potential biomarkers associated with disease biology, 
mechanism(s) of action, potential mechanism(s) of resistance, pharmacodynamics, 
prognosis, and improvement of diagnostic assays.
Development of a predictive diagnostic assay that enables prospective identification of 
patients who are likely to respond to treatment with atezolizumab, alone or in 
combination with Hu5F9-G4, may allow for preselection of patients who are likely to 
benefit from treatment with these agents in future clinical studies. 
Published results suggest that expression of PD-L1 in tumors (Herbst et al. 2014) and 
tumor immune cell infiltrates (Powles et al. 2014) correlate with response to antiPD-1 
therapy. In this study, AML specimens from patients who meet the eligibility criteria (see 
Sections 4.1.1 and 4.1.2) will be tested for PD-L1 expression (see Section 4.5.7.2 for 
sample requirements). 
Other exploratory biomarkers, including potential predictive and prognostic markers that 
are related to response or clinical benefit of atezolizumab, tumor immunobiology, and 
tumor-type markers, may also be analyzed.
3.3.7
Rationale for Atezolizumab Treatment beyond Progression
Cancer immunotherapies may result in early apparent radiographic progression 
(pseudoprogression or tumor immune infiltration), including the appearance of new 
lesions followed by delayed response (Wolchok et al. 2009). Additionally, responding 
tumors may appear to increase in size because of the influx of immune cells (Hoos et al. 


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2010; Pennock et al. 2012). Unconventional response patterns have been described in 
patients treated with antiCTLA-4 (Wolchok et al. 2009) and have been observed in the 
preliminary experience with atezolizumab in Study PCD4989g. 
This has led to the use of modified Response Evaluation Criteria in Solid Tumors 
(RECIST) to account for potential pseudoprogression in clinical studies of atezolizumab 
in solid tumors.  Tumor flare in patients with lymphoma and patients with chronic 
lymphocytic leukemia has been described in patients treated with lenalidomide (Eve and 
Rule 2010; Chanan-Khan et al. 2011).  The clinical response has been studied in vitro 
and is believed to be a result of inhibition of B cellreceptor signaling and integrin 41 
adhesion of malignant cells to fibronectin and vascular cell adhesion protein 1.  Although 
a similar tumor flare syndrome has not been described in the treatment of patients with 
AML or MDS, it is possible that such a phenomenon could occur.  This could manifest 
itself as a decline in blood counts as a result of systemic or local cytokine release as a 
PD effect of treatment or T-cell infiltration of the bone marrow, leading not only to tumor 
killing but also to a bystander effect on normal bone marrow cells.  Current response 
criteria for AML do not consider such observations, which is a phenomenon somewhat 
similar to the pseudoprogression described above in patients with solid tumors.
The decision to continue treatment beyond progression should be made between the 
patient and the investigator and should take into consideration the patient’s wishes, 
clinical status, side effects experienced with study treatment, prognosis, and availability 
of other approved or experimental therapies. Treatment beyond progression also 
requires approval from the Medical Monitor. Patients who elect to receive treatment 
beyond progression will be required to sign a second copy of the original Consent Form 
and an Informed Consent Form for treatment beyond progression, depending on an 
institution’s specific Institutional Review Board (IRB) requirements.
4.
MATERIALS AND METHODS
4.1
PATIENTS
A maximum of 21 patients with R/R AML will be enrolled in this study. The planned 
enrollment for dose safety is between 6 and 12 patients, depending on the DLTs
observed.  Enrollment of the expansion cohort will range between 9 and 15 patients.  
The overall enrollment of this study will remain constant at 21 patients. 
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at the time of signing Informed Consent Form

Life expectancy of at least 12 weeks

Eastern Cooperative Oncology Group (ECOG) Performance Status 02
(see Appendix 4)


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
Ability to comply with the study protocol, in the investigator’s judgment

Documented and confirmed R/R AML per WHO classification, except acute 
promyelocytic leukemia, and lack of response to all therapies of known benefit
Refractory AML is defined as failure to attain a CR following exposure to at least 
two courses of intensive induction regimens, six cycles of single-agent HMA, or 
at least two cycles of venetoclax-containing regimens (combined to LDAC or 
HMAs).
Relapsed AML is defined as the morphological detection of 5% bone marrow 
blasts, reappearance of leukemic blasts in the blood, or development of 
extramedullary disease. For patients previously found to be in CR and minimal 
residual disease (MRD) negative (by flow cytometry), reappearance of a 
leukemic population by MRD testing can be classified as being relapsed AML 
(conversion from CR MRD negative to CR MRD positive).

Adequate end-organ function, defined using the following laboratory parameters 
obtained within 28 days prior to the first dose of study drug:
–
AST, ALT, and ALP 2.5upper limit of normal (ULN)
–
Serum bilirubin 2ULN, with the following exception:
Patients with known Gilbert disease or clear evidence of transfusion-related 
hemolysis who have serum bilirubin 3ULN may be enrolled.  Cases of 
transfusion-related hemolysis must be discussed and approved by the 
Medical Monitor.
–
Serum creatinine 2ULN

Negative HIV test at screening

Negative hepatitis B surface antigen (HBsAg) test at screening

Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total 
HBcAb test followed by quantitative hepatitis B virus (HBV) DNA 500 IU/mL at 
screening
The HBV DNA test will be performed only for patients who have a positive total 
HBcAb test.

Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV 
antibody test followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test.

WBC count20103/L prior to the first dose of study treatment and prior to each
Hu5F9-G4 dose for Cycle 1
Patients with WBC 20103/L can be treated with hydroxyurea throughout the 
trial to reduce the WBC to 20103/L.

Willingness and ability to provide pretreatment bone marrow aspirate and biopsy 
and agreement to provide subsequent bone marrow aspirates and biopsies during 
study treatment


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
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, and agreement to refrain 
from donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 5 months after the final dose of 
atezolizumab and/or Hu5F9-G4, whichever is longer. Women must refrain from 
donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical 
sterilization (tubal ligation, removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical study 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.

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, men must remain abstinent or use 
a condom plus an additional contraceptive method that together result in a failure 
rate of 1%per year during the treatment period and for at least 120 days after 
the final dose of atezolizumab and/or Hu5F9-G4.  Men must refrain from 
donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 60 days after the final dose of 
atezolizumab and/or Hu5F9-G4 to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical study 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.

For women who are not postmenopausal (12 months of nontherapy-induced 
amenorrhea) or surgically sterile: requirement for a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment


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4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Previous allo-HSCT within 6 months prior to enrollment, active graft versus host 
disease, or requiring transplant-related immunosuppression

Prior solid organ transplant

Evidence of active CNS involvement by leukemia 
Patients with a history of leukemic CNS involvement that has been treated may 
have to undergo lumbar puncture and/or magnetic resonance imaging
assessment prior to study entry at the discretion of the Medical Monitor.

Pregnancy or lactation or intention to become pregnant during the study or within 
5 months after the final dose of atezolizumab and/or Hu5F9-G4, whichever is longer
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study drug.

History of idiopathic pulmonary fibrosis, organizing pneumonitis (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis

History of autoimmune disease
Patients with a history of autoimmune-related hypothyroidism who are on a 
stable dose of thyroid replacement may be eligible for this study.
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin 
regimen may be eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of the following conditions 
are met:
– Rash must cover 10% of body surface area.
– Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids.
– No occurrence of acute exacerbations of the underlying condition that require 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors, or high-potency or oral corticosteroids within the 
previous 12 months.

Treatment with investigational therapy within 14 days prior to initiation of study drug

Any approved AML-related therapy within 14 days prior to enrollment
Granulocyte colony-stimulating factor (G-CSF) to treat neutropenic fever and/or 
infection is permitted.
Hydroxyurea may be used throughout the trial to control peripheral blood blast 
counts in response to the first dose of study treatment.


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
Immunosuppressive therapy (including, but not limited to, azathioprine, 
mycophenolate mofetil, cyclosporine, tacrolimus, methotrexate, and antinecrosis 
factor [anti-TNF] factor agents) within 6 weeks of Day 1 of Cycle 1

Daily requirement for corticosteroids (10 mg/day prednisone or equivalent, except 
for inhalation corticosteroids) within 2 weeks prior to Day 1 of Cycle 1

Prior treatment with immune checkpoint blockade therapies (antiCTLA-4, 
antiPD-1 or antiPD-L1) or immune agonists (anti-CD137, anti-CD40, and 
anti-OX40) or immune antagonists (anti-CD47)

Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon [IFN]-and interleukin [IL]-2) within 4 weeks or 5 half-lives of the drug, 
whichever is longer, prior to Day 1 of Cycle 1

Treatment with denosumab (or other RANKL inhibitor) 4 weeks before the first dose 
and for 10 weeks after the final dose of atezolizumab
Patients receiving denosumab therapy must be willing to be treated with a 
bisphosphonate while receiving study treatment.

Administration of a live, attenuated vaccine within 4 weeks of Day 1 of Cycle 1 or 
anticipation that such a live, attenuated vaccine will be required during the study or 
within 5 months after the final dose of atezolizumab
Influenza vaccination should be given during influenza season only 
(approximately October through May in the northern hemisphere and 
approximately April through September in the southern hemisphere).  Patients 
must agree not to receive live, attenuated vaccines (e.g., FluMist®) within 28 days 
prior to enrollment, during treatment, or within 5 months following the final dose 
of atezolizumab.

Planned major surgery during the study

Illicit drug or alcohol abuse within 12 months prior to screening, in the 
investigator’s judgment

Poor peripheral venous access, unless prior central venous catheter placement has 
been performed

Active infection
Patients being treated for non-serious infectious complications (e.g., oral 
candidiasis or uncomplicated urinary tract infection) with oral or topical 
antimicrobials may be eligible for study treatment (antimicrobial treatment must 
be completed prior to Day 1 of Cycle 1 and cases must be discussed and 
approved by the Medical Monitor).


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
Severe infection requiring hospitalization or IV antibiotics within 14 days prior 
to enrollment
Patients receiving prophylactic antibiotics, antifungals, and antivirals as a 
result of prolonged neutropenia in the absence of active documented infection 
are eligible.
Patients receiving IV antibiotics and hospitalization for febrile neutropenia may be 
eligible, if initial diagnosis of neutropenic fever was not due to any infectious 
etiology and the patient has been afebrile for 72 hours.

Any serious medical condition or abnormality in clinical laboratory test results that, in 
the investigator’s judgment, precludes the patient’s safe participation in and 
completion of the study

History or presence of an abnormal ECG finding that is clinically significant in the 
investigator’s opinion, including complete left bundle branch block, second- or 
third-degree heart block, and evidence of prior myocardial infarction

History of other malignancy within 2 years prior to screening, with the exception 
of those with a negligible risk of metastasis or death (e.g., 5-year OS of 90%), 
such as adequately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine 
cancer

Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster 
ovary cells or any component of the atezolizumab, azacytidine, or Hu5F9-G4 
formulation

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins

Known allergy or hypersensitivity to any component of the atezolizumab and/or 
Hu5F9-G4 formulation
4.2
METHOD OF TREATMENT ASSIGNMENT
This is an open-label study. 
Enrollment tracking will be performed through the use of the interactive voice or 
web-based response system (IxRS). Prior to initiation of screening, the study site 
personnel should confirm through the appropriate communication channel that the safety 
or expansion cohort is open 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 review 
prior to enrollment of the patient.  Once the Sponsor reviews a patient for enrollment, a 
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 for a particular 
disease cohort.


Atezolizumab—F. Hoffmann-La Roche Ltd
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The first 6 patients with relapsed AML will be assigned to the safety cohort. Once these 
patients are fully assessed and deemed to be safely tolerating the study treatment, an 
additional 15 patients with R/R AML will be enrolled in the expansion cohort as shown in 
Figure 1.
4.3
STUDY TREATMENT
The investigational medicinal products (IMPs) for this study are atezolizumab and 
Hu5F9-G4.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab
Atezolizumab will be supplied by the Sponsor as a sterile liquid in a single-use, 20-mL 
glass vial.  The vial contains approximately 20 mL (1200 mg) of atezolizumab solution.
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure.
4.3.1.2
Hu5F9-G4 
Hu5F9-G4 is a sterile, clear, to slightly opalescent, colorless, preservative-free liquid for 
IV administration. Hu5F9-G4 drug product is supplied by the Sponsor at a concentration 
of 20 mg/mL in 200-mg (10-mL) single-use, type 1 borosilicate glass vials with butyl 
rubber stoppers and aluminum seals. The product is formulated for IV administration in 
0.01% (w/v) polysorbate 20, 5% (w/v) sorbitol, and 10 mM sodium acetate, at pH 5.0, 
and Sterile Water for Injection. Each product vial is intended to deliver 10 mL of drug 
solution (200 mg of Hu5F9-G4). Saline for infusion will be used as the diluent for final 
dosage preparation. 
Hu5F9-G4 is shipped refrigerated and must be stored at 2C8°C (36F46°F) until use, 
with access limited to pharmacy personnel, the Principal Investigator, or a duly 
designated person. A temperature log must be kept to document the refrigerator 
temperature.  If the temperature is not maintained, the Sponsor should be contacted.
Recommended safety measures for preparation and handling of Hu5F9-G4 include 
laboratory coats and gloves.  In addition, Hu5F9-G4 cannot be mixed with any other 
drug in the infusion bag or administration.  Hu5F9-G4 should not be administered as a 
bolus injection.
Hu5F9-G4 should be protected from light. Sufficient protection from light is provided by 
the secondary container. No specific light protection is needed during preparation of the 
dosing solution and infusion.
Hu5F9-G4 is not formulated with a preservative. Therefore, once the sterile vials are
entered, all dose preparations should be performed aseptically. The infusion of the drug
should be completed within 8 hours of preparation of the solution.


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4.3.2
Study Treatment Dosage, Administration, and Compliance
4.3.2.1
Atezolizumab
The dose level of atezolizumab in this study is 840 mg administered to patients by IV 
infusion on Days 8 and 22 of each 28-day cycle (Q2W) for patients enrolled in the safety
cohort and in the expansion cohort. During the first cycle of treatment (Cycle 1), patients 
will receive 840 mg IV atezolizumab only on Day 22 in order to collect bone marrow and 
blood samples for biomarker assessment after steady state has been reached for 
Hu5F9-G4. 
Any overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration eCRF. Adverse events associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF. 
Administration of atezolizumab will be performed in a monitored setting in which there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions. For anaphylaxis precautions, see Appendix 7. 
Atezolizumab and Hu5F9-G4 infusions will be administered per the instructions outlined 
in Table 2. 


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Table 2
Administration of First and Subsequent Atezolizumab and 
Hu5F9-G4 Infusions
First Infusion
Subsequent Infusions

No premedication is permitted prior to the 
atezolizumab infusion.

Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should be 
measured within 60 minutes prior to the 
infusion.

Atezolizumab should be infused over 
60 (15) minutes.

If clinically indicated, vital signs should be 
measured every 15 (5) minutes during the 
infusion and at 30 (10) minutes after the 
infusion.

For the first two doses of atezolizumab 
following Hu5F9-G4, at least 60 minutes 
should be allowed for observation after 
Hu5F-G4 administration and 60 minutes 
for observation after atezolizumab 
administration.

Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.

If the patient experienced an infusion-
related reaction with any previous 
infusion, premedication with 
antihistamines, anti-pyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator.

Vital signs should be measured within 
60 minutes prior to the infusion.

Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion.

If the patient experienced an infusion-
related reaction with the previous infusion 
or if clinically indicated, vital signs should 
be measured every 15 (5) minutes 
during the infusion and at 
30 (10) minutes after the infusion.

If no infusion-associated adverse events 
are observed during the initial two 
combination treatment sessions, a 
30-minute observation period between 
Hu5F9-G4 and atezolizumab infusion 
and a 30-minute observation period after 
atezolizumab infusion could be 
considered for subsequent 
administrations.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Guidelines for medical management of IRRs are provided in the Appendix 8.
4.3.2.2
Hu5F9-G4 
The initial priming dose will be administered as a continuous IV infusion in 250 mL of 
normal saline over 180 minutes to reduce the risk of acute hemagglutination.  All other 
infusions for doses 1 mg/kg will be administered in 500 mL over 120 minutes.  If more 
than 4 weeks have elapsed since the last dose of Hu5F9-G4 and the patient is to 
resume treatment, patients must undergo intra-patient dose escalation again of 
Hu5F9-G4 based on their original dosing regimen (e.g., 1 mg/kg of priming dose on 
Days 1 and 4, 15 mg/kg on Day 8, and 30 mg/kg on Days 11, 15, and 22). 


Atezolizumab—F. Hoffmann-La Roche Ltd
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The dose level of Hu5F9-G4 administered to patients by IV infusion in this study varies
according to the week of treatment.  Initially, two priming doses of 1 mg/kg will be given 
on Days 1 and 4 of Cycle 1. This will be followed by loading doses of 15 mg/kg on 
Day 8, followed by 30 mg/kg on Day 11 of Cycle 1. Starting on Day 15, Hu5F9-G4
maintenance will be given at a dose of 30 mg/kg QW.  
Premedication is required before administration of the first four doses of Hu5F9-G4 with 
6501000 mg of oral acetaminophen and 2550 mg of oral or IV diphenhydramine or 
comparable regimen.  
Recommended safety measures for preparation and handling of Hu5F9-G4 include 
laboratory coats and gloves.  In addition, Hu5F9-G4 cannot be mixed with any other 
drug in the infusion bag or administration.  Hu5F9-G4 should not be administered as a 
bolus injection.
There have been no late-onset hypersensitivity reactions. Thus, recommendations 
for potential infusion reactions should follow recommendations from Table 2
(see Section 4.3.2.1).  Guidelines for medical management of infusion-related reactions 
(IRRs) are provided in the Appendix 8.
4.3.3
Investigational Medicinal Product Accountability
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 (if supplied by the Sponsor)
with the appropriate documentation. The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor. The site must obtain written authorization from 
the Sponsor before any 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-Study Access to Atezolizumab and Hu5F9-G4
Currently, Sponsor does not have any plans to provide Roche IMPs (atezolizumab and 
Hu5F9-G4) or any other study treatments or interventions to patients who have 
completed the study.  The Sponsor may evaluate whether to continue providing 
atezolizumab and Hu5F9-G4 in accordance with the Roche Global Policy on Continued 
Access to Investigational Medicinal Product, available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf


Atezolizumab—F. Hoffmann-La Roche Ltd
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4.4
CONCOMITANT THERAPY AND ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, vaccines,
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 14 days prior to screening 
to the study completion or treatment discontinuation visit.  All such medications should 
be reported to the investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin)

Inactivated influenza vaccinations

Megestrol acetate administered as an appetite stimulant 

Mineralocorticoids (e.g., fludrocortisone)

Prophylactic use of oral antibiotics, anti-viral medications, and anti-fungal 
medications for prolonged neutropenia according to the following guidelines:
– Mandated use of anti-microbial prophylaxis (fluoroquinolone) for all patients
enrolled in the study until 4 weeks following documentation of CR (CR or CRi) 
is documented:
Oral levofloxacin (500 mg daily)
Oral ciprofloxacin (500 mg orally [PO] twice daily)
A third generation cephalosporins (e.g., cefotaxime, cefixime, ceftazidime, 
cefpodoxime, ceftriaxone, cefdinir, cefoperazone, ceftibuten, moxalactam, 
ceftizoxime)
Other recommended antibiotic prophylaxis routinely preferred by the 
investigator or based on institutional guidelines
– Mandated use of anti-fungal prophylaxis for patients with ANC 500/L at any 
time during the study and until 4 weeks following documentation of a CR
(CR or CRi):
Posaconazole: oral suspension 200 mg (5 mL) PO three times daily or tablet
300 mg PO twice daily on Day 1, followed by 300 mg PO daily
Voriconazole: 200 mg PO twice daily
Isavuconazonium sulfate (Cresemba): 180 mg PO (two capsules every 
8 hours for six doses followed by two capsules once daily)
Other recommended anti-fungal prophylaxis routinely preferred by the 
investigator or based on institutional guidelines


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– Mandated use of anti-viral prophylaxis for patients with ANC 500/L at any time 
during the study and until 4 weeks following documentation of CR (CR or CRi):  
Acyclovir: 400 mg once daily or 200 mg twice daily
Valacyclovir: 500 mg or 1,000 mg orally every 8 hours
Other recommended anti-viral prophylaxis routinely preferred by the 
investigator or based on institutional guidelines

The use of G-CSF to treat a documented or suspected infection associated with 
febrile neutropenia 

Anti-emetic therapy, in accordance with institutional guidelines, is allowed for 
supportive-care purposes. 

Systemic corticosteroids, tocilizumab, and TNF-inhibitors 
In the event of severe systemic IRRs or systemic inflammatory activation, the 
Medical Monitor should be notified as soon as possible after the patient has been 
treated. Systemic corticosteroids, tocilizumab, and TNF-inhibitors may 
attenuate potential beneficial immunological effects of treatment with 
atezolizumab but may be administered for moderate immune-mediated adverse 
events at the discretion of the treating physician. If feasible, alternatives to 
corticosteroids should be considered. 

For males and females of reproductive potential, highly effective means of 
contraception (see Section 4.1.1)
Premedication with antihistamines, anti-pyretic medicines, and/or analgesics may be 
administered for the second and subsequent atezolizumab infusions only, at the 
discretion of the investigator.
In general, investigators should manage a patient's care (including preexisting conditions) 
with supportive therapies other than those defined as cautionary or prohibited therapies 
(see Sections 4.4.2 and 4.4.3) as clinically indicated, per local standard practice. For 
patients achieving a CR (CR, CRi, CRp, or CRh), prophylactic anti-infective therapy, 
including antibiotic, anti-viral, and anti-fungal therapy can be discontinued, at the 
discretion of the investigator, no earlier than 30 days from documentation of CR. 
Patients who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists 
(e.g., famotidine, cimetidine), or equivalent medications per local standard practice.  
Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists; see Appendix 7).


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4.4.2
Cautionary Therapy for Atezolizumab-Treated Patients
4.4.2.1
Corticosteroids and Tumor Necrosis FactorInhibitors
Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations in which 
systemic corticosteroids or TNF-inhibitors would be routinely administered, alternatives, 
including antihistamines, should be considered.  If the alternatives are not feasible, 
systemic corticosteroids and TNF-inhibitors may be administered at the discretion of 
the investigator.
Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events when associated with atezolizumab therapy (refer 
to Appendix 9 for details).
4.4.2.2
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer (see 
Section 4.4.3) may be used during the study at the discretion of the investigator.
4.4.3
Prohibited Therapy
Any concomitant therapy intended for the treatment of cancer, whether health authority
approved or experimental, is prohibited. This includes, but is not limited to, the following: 

Erythropoietin-stimulating agents within 2 weeks of Day 1 of Cycle 1

G-CSF solely to maintain ANC and not associated with the treatment of a
documented or suspected infection in the setting of febrile neutropenia 

Concomitant therapy intended for the treatment of cancer whether health 
authorityapproved or experimental, is prohibited for various time periods prior to 
starting study treatment, depending on the agent (see Section 4.1.2), and during 
study treatment, until disease progression is documented and the patient has 
discontinued study treatment.
Traditional herbal medicines should not be administered because the ingredients 
of many herbal medicines are not fully studied, and their use may result in 
unanticipated drugdrug interactions that may cause or confound assessment 
of toxicity. 

Investigational therapy is prohibited within 14 days prior to initiation of study 
treatment and during study treatment.

Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs 
because of its potential for causing agranulocytosis.


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58/Protocol GO40828, Version 3 
The following therapies are excluded while patients are receiving atezolizumab and for 
10 weeks after the final dose of atezolizumab: 

Patients who are receiving a RANKL inhibitor (denosumab) prior to enrollment must 
be willing and eligible to receive a bisphosphonate instead; denosumab could 
potentially alter the activity and the safety of atezolizumab. 

Patients are not allowed to receive immunostimulatory agents, including but not 
limited to interferon-(IFN-), IFN-, or interleukin-2 (IL-2). These 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.

Systemic immunostimulatory agents (including, but not limited to, IFNs and IL-2) are 
prohibited within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to 
initiation of study treatment and during study treatment because these agents could 
potentially increase the risk for autoimmune conditions when given in combination 
with atezolizumab.

Patients should not receive immunosuppressive medications, including, but not 
limited to, cyclophosphamide, azathioprine, and methotrexate. These agents could 
potentially alter the activity and the safety of atezolizumab. Systemic corticosteroids 
and antiTNF-agents may attenuate potential beneficial immunologic effects of 
treatment with atezolizumab but may be administered at the discretion of the 
treating physician. If feasible, alternatives to these agents should be considered. 

Patients must not receive live, attenuated vaccines (e.g., FluMist®) within 4 weeks 
prior to Day 1 of Cycle 1, at any time during the study, or within 5 months following 
the final dose of atezolizumab. Inactivated vaccines are allowed. 
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1. 
The schedule for PK and immunogenicity sample collection is presented in Appendix 2, 
and the biomarker sample collection is provided in Appendix 3.  All activities must be 
performed and documented for each patient. 
Patients will be closely monitored for safety and tolerability throughout the study. 
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. 
If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend 
that precludes the visit, the visit should be scheduled on the nearest following feasible 
date, with subsequent visits rescheduled accordingly.


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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 (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history
will be recorded at baseline.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 7 days prior to initiation of study treatment will 
be recorded.  At the time of each follow-up physical examination, an interval medical 
history should be obtained and any changes in medications and allergies should be 
recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, and 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF. A complete 
physical examination is required during screening, on Day 1 of every cycle of treatment 
beyond Cycle 1 and at the end of treatment, and every 3 months during follow-up prior to 
progression (see Appendix 1).
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  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.
Height and weight should be recorded at specified timepoints (height to be measured
only at screening).


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4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressures while the patient is in a seated position, and temperature. 
Vital signs (including resting, blood oxygen saturation measured by pulse oximetry) will 
be recorded during screening. Vital signs (not including pulse oximetry) will be 
measured prior to every injection of Hu5F9-G4. After Hu5F9-G4 administration, vital 
sign monitoring is not required unless clinically indicated. The patient’s vital signs 
should be recorded up to 60 minutes prior to each atezolizumab infusion (see Table 3). 
Vital signs should also be recorded during or after the atezolizumab infusion if clinically 
indicated. Additional vital sign measurements should be obtained per the specified 
timepoints in Appendix 1.
Blood oxygen saturation by pulse oximetry (while the patient is resting) should also be 
determined within 60 minutes before the first dose of atezolizumab.
Table 3
Timing for Vital Sign Measurements for First and 
Subsequent Infusions
Study Drug
Timing for Vital Sign Measurements
First Infusion
Subsequent Infusions
Hu5F9-G4

Measure within 60 minutes prior to 
the atezolizumab infusion.

Record patient's vital signs during or 
after the infusion if clinically 
indicated.

Measure within 60 minutes prior 
to the atezolizumab infusion.

Record patient's vital signs 
during or after the infusion if 
clinically indicated.
Atezolizumab 
See Table 2 for guidelines.

See Table 2 for guidelines.
4.5.5
ECOG Performance Status
Performance status will be assessed using the ECOG Performance Status Scale and 
recorded on the eCRF (see Appendix 4).
4.5.6
AML and Response Evaluations
Any evaluable or measurable disease must be documented at screening and 
re-assessed at each subsequent cancer evaluation. Patients should have AML
evaluation and classification based on the 2010 ELN and 2017 ELN criteria (see 
Appendix 5). Disease prognosis should also be classified at screening using the 
modified ELN risk classification (see Appendix 5). Responses will be assessed by the 
investigator through use of the ELN recommendations (see Appendix 5). 
Bone marrow examinations must include aspirate and biopsy (whenever possible) for 
morphology, flow cytometry, and routine cytogenetic and are required at screening.  
If fluorescence in situ hybridization (FISH) is performed at screening, FISH must be 


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performed during subsequent assessments.  Refer to Section 4.5.7.2 for timepoints and 
requirements regarding collection of required bone marrow samples (aspirates and 
trephine/core biopsies) for exploratory biomarker studies.  Bone marrow aspirates and 
biopsies are to be performed on Day 22 of Cycle 1 and subsequently after 3 and 
6 months of study treatment (i.e., Day 1 of Cycles 4 and 7; see Appendix 1).  Beyond 
6 months of study treatment, bone marrow aspirates are required within 7 days prior to 
study drug administration on Day 1 of every 3 months (i.e., Day 1 of Cycles 10, 13, 16, 
etc.) (for determination of response), at the time of relapse or progressive disease, and 
at the end of treatment. For patients in follow-up who discontinue study treatment prior 
to disease progression, bone marrow aspirates and biopsy should be collected every 
4 months (see Appendix 1). All bone marrow examinations should be assessed locally 
(see Section 4.5.3).  Local institutional policies should be followed at any other time 
during the study when a bone marrow examination is deemed necessary by the 
investigator. 
In addition, information on transfusion requirements prior to and during study treatment 
will also be collected (see Appendix 1).
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Samples for hematology, serum chemistry panel, virology, coagulation, and pregnancy 
will be analyzed at the study site’s local laboratory. Central laboratories will coordinate 
the collection of fresh bone marrow and blood samples for the assessment of 
atezolizumab and Hu5F9-G4 pharmacokinetics and biomarkers, ADA assays, and 
autoantibody testing. Instruction manuals and supply kits will be provided for all central 
laboratory assessments. 
4.5.7.1
Local Laboratory Assessments
Local laboratory assessments will include the following: 

Hematology:  CBC, including RBC count, hemoglobin, hematocrit, WBC with 
differential count (i.e., neutrophils [bands are optional], lymphocytes, eosinophils, 
basophils, and monocytes), reticulocytes, platelet count, and circulating peripheral 
blasts

Serum chemistry panel:  glucose (while patient is fasting at baseline), BUN or urea, 
creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total carbon 
dioxide (if considered standard of care for the region), calcium, phosphorus, albumin, 
total bilirubin, direct bilirubin, ALT, AST, ALP, LDH, creatine kinase, uric acid, and 
total protein

Bone marrow aspirate and trephine biopsy for response assessment (morphology, 
flow cytometry, cytogenetics, and FISH [if applicable]) 

Coagulation:  aPTT or PTT and INR

Thyroid-function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) 
(or total T3 for sites where free T3 is not performed), and free thyroxine (also known 
as T4)


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
HBV serology:  HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb 
test is positive) HBV DNA
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection.

HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection.

Epstein-Barr viral serology (IgG and IgM) 

HIV serology: All patients will be tested for HIV prior to inclusion into the study, and 
patients who are HIV positive will be excluded from the study. 

Pregnancy test
All women of childbearing potential (including those who have had a tubal 
ligation) will have a serum pregnancy test at screening.  Urine pregnancy tests 
will be performed at subsequent visits if clinically indicated.  If a urine 
pregnancy test result is positive, dosing will be delayed until the patient’s status 
is determined by a serum pregnancy test.
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).

Urinalysis:  pH, specific gravity, glucose, protein, ketones, and blood; dipstick 
permitted
4.5.7.2
Central Laboratory Assessments
The following assessments will be performed at a central laboratory or by the Sponsor: 

Serum PK samples
Samples will be assayed for the presence of ADAs to atezolizumab and 
Hu5F9-G4 with the use of validated immunoassays. 

Biomarker assays in blood and bone marrow samples 
Blood samples will be obtained for biomarker evaluation (including, but not limited to,
biomarkers that are related to AML or cancer immune biology) from all eligible patients 
according to the schedule in Appendix 3. Samples will be processed to obtain plasma 
for the determination of changes in blood-based biomarkers. Whole blood samples may 
be processed to obtain peripheral blood mononuclear cells (PBMCs) and their 
derivatives (e.g., RNA and/or DNA). 


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Fresh bone marrow aspirates and trephine biopsies with the associated pathology report
must be collected for biomarker analysis at screening, during treatment, at the end of 
treatment, and at the time of disease relapse, progression, and/or suspected 
progression as outlined in Appendix 3. Leftover tissue from unscheduled bone marrow 
aspirate and biopsies (performed per the investigator's discretion for clinical reasons) 
should also be collected for biomarker analysis.

For bone marrow aspirate samples, up to 10 mL of aspirate should be collected.
Preferably, the same aspirate site used for collection of local bone marrow 
laboratory samples (e.g., flow cytometry, cytogenetics, FISH) should not be used for 
collection of bone marrow aspirate samples for exploratory analyses. For every 
10 mL of bone marrow collected, a separate aspirate site should be selected (all 
aspirate sites can be on the ipsilateral iliac crest), if possible.

Trephine/core biopsy tissue samples preferably should be a minimum of 1.5 cm in 
length and 2 cm is optimal. Newly collected tissue should be shipped to a central 
laboratory for decalcification and processing (preferred). If fresh tissue cannot be 
submitted, tissue blocks or 1520 newly serially sectioned, unstained slides of 
trephine/core biopsy samples should be sent to the appropriate central laboratory 
(see the laboratory manual for further details). 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.11), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and for PK or immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.

Blood, bone marrow aspirate, bone marrow biopsy samples, and their derivatives 
(e.g., DNA, RNA) samples collected for biomarker research will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed.
Data arising from clinical genotyping will be subject to the confidentiality standards 
described in Section 8.4.  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.
Screening blood, tumor tissue, and bone marrow aspirate samples, including those 
collected from patients who do not enroll in the study, may be used for future research 
and/or development of disease-related tests or tools.


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Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in Table 4. Biomarker samples may also be used for additional method 
development, assay validation, and characterization.  Given the complexity and 
exploratory nature of biomarker analyses, results from the analyses will not be shared 
with investigators or study participants, unless required by law.
Table 4
Proposed Exploratory Biomarkers
Sample Type 
Timing 
Proposed Non-Inherited Biomarkers
Plasma
Baseline and subsequent 
timepoints during treatment 

Cytokine levels
RNA/DNA extracted from 
blood
Baseline and subsequent 
timepoints during treatment

Transcriptome profiling and 
gene expression profiling

Mutational profiling

TCR cloning
Peripheral blood
Baseline and subsequent 
timepoints during and after 
treatment 

Frequency of immune cell 
populations and CIT markers
Bone marrow aspirate
Baseline and subsequent 
timepoints during and after 
treatment

Frequency of immune cell 
populations and CIT markers

PD-L1 and CD47 expression

Cytokines
RNA/DNA extracted from 
bone marrow 
aspirate/biopsy
Baseline and subsequent 
timepoints during and after 
treatment (time of 
progression)

Mutational profiling

MRD

Transcriptome profiling and 
gene expression profiling

TCR cloning
Bone marrow biopsy
Baseline and subsequent 
timepoints during and after 
treatment

IHC for immune cells

Gene expression profiling
CIT cancer immunotherapy; IHCimmunochemistry; MRDminimal residual disease; 
TCRT-cell receptor.
Refer to the laboratory manual for additional details on laboratory assessments and 
sampling.
4.5.8
Electrocardiograms
Single 12-lead ECG recordings will be obtained during screening and during the study if 
clinically indicated. 
Lead placement should be as consistent as possible. ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes. 


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All ECGs are to be obtained prior to other procedures scheduled at the same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal. Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation), should be avoided 
during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator or designee must review, sign, and date 
all ECG tracings. Paper copies of ECG tracings will be kept as part of the patient's 
permanent study file at the site. 
If at a particular postdose timepoint, the mean QT interval corrected through use of 
Fridericia's formula (QTcF) is 500 ms and/or 60 ms longer than the baseline value, 
another ECG must be recorded, ideally within the next 5 minutes, and ECG monitoring
should continue until QTcF has stabilized on two successive ECGs. The Medical 
Monitor should be notified. Standard-of-care treatment may be instituted at the 
discretion of the investigator. If a PK sample is not scheduled for that timepoint, an 
unscheduled PK sample should be obtained. A decision on study drug discontinuation 
should be made. The investigator should also evaluate the patient for potential 
concurrent risk factors (e.g., electrolyte abnormalities, concomitant medications known 
to prolong the QT interval, severe bradycardia).
4.5.9
Evaluation of Left Ventricular Ejection Fraction
Left ventricular ejection fraction will be by measurement of ejection fraction using 
echocardiogram or multiple-gated acquisition scan at screening and during the study if 
clinically indicated.
4.5.10
Anti-Drug Antibody Testing
Atezolizumab may elicit an immune response. Patients with signs of any potential 
immune response to atezolizumab will be closely monitored. Validated screening, 
confirmatory, and titer assays will be employed to detect ADAs at multiple timepoints 
before, during, and after treatment with atezolizumab and Hu5F9-G4 (see Appendix 2 for 
the schedule of ADA assessments). ADA response will be correlated with relevant 
clinical endpoints to understand its clinical significance. Additional ADA assays (e.g., 
neutralizing antibody assay) may be employed to further characterize ADA response.
4.5.11
Optional Samples for Research Biosample Repository
4.5.11.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.


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Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be used to achieve the following 
objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

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
4.5.11.2
Approval by the Institutional Review Board 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.6) will 
not be applicable at that site.
4.5.11.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to the investigational agents, 
disease, or drug safety:

Blood sample collected on Day 1 of Cycle 1

Leftover blood, serum, plasma, PBMCs, and tumor tissue samples and any 
derivatives thereof (e.g., DNA, RNA, proteins, peptides), including leftover tissue 
samples from medically indicated procedures (e.g., biopsies for extramedullary sites 
of disease), performed at the investigator's discretion during the study 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods. Genomics is increasingly informing 
researcher's understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events.
Data generated from RBR samples will be analyzed in the context of this study but will 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.


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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples are to be stored no later than 15 years after the final Clinical Study Report 
has been completed.  However, the RBR storage period will be in accordance with the 
IRB-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.11.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples 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.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.11.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent 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 RBR samples.  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 and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.


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4.5.11.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent 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.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator or designee must inform the 
Medical Monitor in writing of the patient's wishes through use of the appropriate RBR 
Subject Withdrawal Form and must enter the date of withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent 
to the testing of his or her RBR samples after closure of the site, the investigator or 
designee 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 this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.11.7
Monitoring and Oversight
RBR samples will be tracked in a manner consistent with Good Clinical Practice 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 samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment (atezolizumab and Hu5F9-G4) if 
they experience any of the following:

Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient's potential response to therapy and severity of the event

Any medical condition that may jeopardize the patient's safety if he or she continues 
study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient


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
Use of another nonprotocol-specified anti-cancer therapy

Pregnancy

Loss of clinical benefit as determined by the investigator after an integrated 
assessment of PBMC and/or bone marrow biopsy data and clinical status (e.g., 
symptomatic deterioration such as worse cytopenias) (see Section 3.1.1 for details)
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.  If a patient requests to be 
withdrawn from the study, this request must be documented in the source documents 
and signed by the investigator.  Patients who withdraw from the study will be replaced.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory

Inaccurate or incomplete data recording 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  


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4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice and country or local regulations.

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 
atezolizumab and Hu5F9-G4 in completed and ongoing studies.  The anticipated 
important safety risks are outlined below (see Sections 5.1.1 and 5.1.2).  
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Administration of atezolizumab and Hu5F9-G4 will be 
performed in a monitored setting in which there is immediate access to trained personnel 
and adequate equipment and medicine to manage potentially serious reactions.  
Guidelines for managing patients who experience anticipated adverse events, including 
criteria for treatment interruption or discontinuation, are provided in Appendix 8 and 
Appendix 9.  Refer to Sections 5.25.6 for details on safety reporting (e.g., adverse 
events, pregnancies) for this study.
Administration of atezolizumab and Hu5F9-G4 will be performed in a setting with 
emergency medical facilities and staff who are trained to monitor for and respond to 
medical emergencies. All adverse events and serious adverse events will be recorded 
during the study and for up to 30 days after the final dose of study treatment or until the 
initiation of another anti-cancer therapy, whichever occurs first. The potential safety 
issues anticipated in this study and measures intended to avoid or minimize such 
toxicities are outlined in the following sections.
5.1.1
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 


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activation syndrome (considered to be potential risks for atezolizumab).  Refer to 
Appendix 9 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure for 
a detailed description of anticipated safety risks for atezolizumab.  
5.1.2
Risks Associated with Hu5F9-G4
Hu5F9-G4 has been associated with risks such as the expected effects of anemia and 
hemagglutination in patients with solid tumors and AML who have been treated with 
Hu5F9-G4 and are consistent with preclinical toxicology studies. Use of a priming and 
maintenance dose appears to mitigate the acute hematological effects of Hu5F9-G4.  
Mostly mild to moderate IRRs (fevers, chills, headache, and other symptoms) have 
occurred generally with the first few doses of Hu5F9-G4 and are well managed with 
premedications. Overall, the majority of Hu5F9-G4associated toxicities observed to 
date have been transient and manageable. Supportive care with frequent RBC and 
platelet transfusions has been safely and successfully administered to patients receiving 
Hu5F9-G4 therapy.  
5.1.3
Risks Associated with Combination Use of Atezolizumab 
and Hu5F9-G4
The following adverse events are potential overlapping toxicities associated with 
combination use of atezolizumab and Hu5F9-G4:  pulmonary, hepatic, gastrointestinal, 
endocrine, ocular, cardiac, dermatologic, neurologic, meningoencephalitis, renal events, 
myositis, hemophagocytic lymphohistiocytosis, and macrophage activation syndrome.  
Both atezolizumab and Hu5F9-G4 are known to cause IRRs and anemia.  It is not 
known the synergistic effects of combination therapy on the known adverse event profile 
of single-agent treatment.
5.1.4
Dose Modifications for Hu5F9-G4 and Atezolizumab 
See Appendix 8 for guidance on dose modification for atezolizumab and Hu5F9-G4.
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 Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9
and 5.3.5.10 for more information)

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 inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study 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)


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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; 
see Section 5.3.3); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study 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 study treatment is suspected.

Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency,
hyperthyroidism, and hypophysitis

Hepatitis, including AST or ALT 10ULN

Systemic lupus erythematosus

Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis

Events suggestive of hypersensitivity, IRRs, cytokine-release syndrome, 
influenza-like illness, and systemic inflammatory response syndrome

Nephritis

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)


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
Myositis

Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis

Autoimmune hemolytic anemia

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
and toxic epidermal necrolysis)
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will 
be recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study 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 30 days after 
the final dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest will continue to be reported until 135 days after the final dose of study treatment
or until initiation of new systemic anti-cancer therapy, whichever occurs first.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.


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5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 5
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in the NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.


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5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to study treatment, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 6):

Temporal relationship of event onset to the initiation of study treatment

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (as
applicable)

Known association of the event with 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
Table 6
Causal Attribution Guidance
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than study treatment
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.


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5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured as a 
diagnosis (e.g., "infusion-related reaction") on the Adverse Event eCRF.  If possible, 
avoid ambiguous terms such as "systemic reaction."  Associated signs and symptoms 
should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient 
experiences both a local and systemic reaction to the same dose of study treatment, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related Reaction 
eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.


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5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as 
adverse events.
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., 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."


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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3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 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).


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5.3.5.8
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 R/R AML should be recorded on the Death 
Attributed to Progressive Disease eCRF.  All other deaths that occur during the adverse 
event reporting period, 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).
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").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Acute Myeloid Leukemia
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 IWG 2003 and 2017 ELN recommendations (Döhner et al. 
2017). 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 because of disease progression, it should be reported as an adverse event.


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5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study treatment
administration or performance of an efficacy measurement for the study)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.


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Special situations are not in themselves adverse events, but may result in adverse
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
atezolizumab and Hu5F9-G4, adverse events associated with special situations should 
be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with atezolizumab and Hu5F9-G4, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event).  Special situations should be recorded as 
described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.


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5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
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 outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information in North America
Medical Monitor/Roche Medical Responsible:
, M.D. (primary)
E-mail: 
Telephone No.:
Mobile Telephone No.:
Alternate Medical Monitor Contact Information for All Sites
Medical Monitor:
, M.D.
Email:
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 


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medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Treatment Initiation
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 30 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first.  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 
EDC system.  A report will be generated and sent to Roche Safety Risk Management by 
the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur after the reporting period are 
provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the final
dose of study treatment.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 


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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 and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
120 days after the final dose of study treatment.  A paper Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  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's IRB, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form when updated information on 
the course and outcome of the pregnancy becomes available.  An investigator who is 
contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus, to support an informed 
decision in cooperation with the treating physician and/or obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.


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5.4.3.4
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.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the reporting period for serious adverse events and adverse events of 
special interest defined as 135 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first), 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 treatment, the event should be reported through 
use of the Adverse Event eCRF.  However, 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.


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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, and applicable health 
authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Atezolizumab Investigator's Brochure

Hu5F9-G4 Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary analysis will be based on patient data collected through study 
discontinuation or the end of study. All analyses will be based on the safety-evaluable 
population, defined as all patients who receive any amount of either study drug. 
6.1
DETERMINATION OF SAMPLE SIZE
Design considerations covering all cohorts were not made with regard to explicit power 
and type I error considerations but to obtain preliminary safety, efficacy, PK, and PD
information on atezolizumab in combination with Hu5F9-G4. The planned enrollment for 
this study is 21 patients, depending on the safety profile observed during the safety 
evaluation phase. The study will enroll approximately 6 patients in the safety cohort and 
approximately 15 patients in the expansion cohort. The sample size may increase as a 
result of dose findings. The probabilities of observing adverse events in at least 
1 patient, given the varying actual adverse event rates, are listed in Table 6.


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Table 7
Probability of Safety-Signal Detection with a Cohort of 21 Patients
True Underlying Probability 
of an Adverse Event
Probability of Observing at Least One 
Adverse Event in 20 Patients (%)
0.01
19.0
0.025
41.2
0.05
65.9
0.075
80.5
0.1
89.1
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, major protocol deviations, and discontinuations from the study will be 
summarized descriptively by the assigned dose, schedule, and cohort.
6.3
DEMOGRAPHIC AND BASELINE CHARACTERISTICS
Demographics and baseline characteristics such as age, sex, weight, duration of 
malignancy, and baseline ECOG Performance Status will be summarized using means, 
standard deviations, medians, and ranges for continuous variables, and proportions for 
categorical variables. All summaries will be presented for the overall cohort. 
Study drug administration data will be listed by dose and schedule and any dose 
modifications will be flagged. Means and standard deviations will be used to summarize 
the total dose of atezolizumab and Hu5F9-G4 received. 
6.4
SAFETY ANALYSES
The safety analyses will include all patients who receive any amount of either study drug, 
with patients grouped as a whole.
Safety will be assessed through summaries of adverse events, change from baseline in 
targeted vital signs, laboratory test results, and physical examination findings.
All collected adverse event data will be listed by assigned dose level and patient number. 
All adverse events occurring on or after treatment on Day 1 of Cycle 1 will be 
summarized by mapped term, appropriate thesaurus levels, and NCI CTCAE v5.0 
toxicity grade. In addition, all serious adverse events, including deaths, will be listed 
separately and summarized. DLTs and adverse events leading to treatment 
discontinuation will also be listed separately.
6.5
PHARMACOKINETIC ANALYSES
The PK analysis population will consist of all subjects with at least one PK value that can 
be reported.  As appropriate, serum concentrations of atezolizumab and Hu5F9-G4 will 
be tabulated, summarized, and plotted after appropriate grouping.  Additional PK and 
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may also be performed as appropriate.  If performed, 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 the study 
treatments administered.  Depending on the results from interim PK analyses, the 
frequency of PK sampling may be reduced later in the study.
6.6
EFFICACY ANALYSES
Response assessment data (ORR, DOR, EFS, LFS, OS, PFS, the rate of transfusion 
independence, and the duration of transfusion independence) will be summarized for all 
patients as a single cohort. Time-to-event data will be summarized using Kaplan-Meier 
methods.
Interim looks may be performed during the study. Response data will be compared with 
the comparable historical data using statistical methodology such as a predictive and/or 
posterior probability design (Lee and Liu 2008), with the modification that the uncertainty 
in the historical control data is fully taken into account by utilizing a distribution on the 
control response rate to enable internal decision-making for future development.  The 
possible data sources to be used as historical controls may be publications, real-world 
data sources, and other reliable information on efficacy from other studies in similar 
patient groups that will be available by the time of the interim analysis.
6.6.1
Primary Efficacy Endpoint
Primary efficacy endpoints include CR rate (CRCRpCRiCRh) and DOR.
The CR rate will be assessed as the percentage of patients who achieve a CR, CRp, 
CRi, or CRh (as defined by the IWG 2003 and ELN 2010 criteria) after up to six cycles of 
combination therapy. The CR rate will be estimated, and the 95% confidence interval 
will be calculated.
DOR will be analyzed for the subset of patients who achieve an objective response as 
defined in Section 2.3.1.  DOR is defined as the time from the initial response to the time 
of disease progression or death (whichever occurs first).  If a patient is alive and has not 
experienced progressive disease before the end of the study, DOR will be censored at 
the day of the last cancer assessment.  If no cancer assessments are performed after 
the date of the first occurrence of an objective response, DOR will be censored at the 
date of the first occurrence of an objective response plus 1 day.


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6.6.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints include ORR, EFS, LFS, PFS, OS, the rate of 
transfusion independence, and the duration of transfusion independence (see 
Section 2.3.2), which will be analyzed as follows:

ORR will be assessed as the proportion of patients who obtain a CR, CRp, CRi, 
CRh or PR (as defined by the IWG 2003 and ELN 2010) after up to six cycles of 
combination therapy. The proportions will be calculated for categorical variables by 
dividing the number of patients with a positive response by the number of patients. 
Patients with no response assessments (for whatever reason) will be considered 
non-responders. 

For EFS, data from patients not known to have any of the listed events will be
censored on the date they were last examined.  For patients who do not achieve a 
CR, CRp, CRh, or CRi, EFS is defined as the point of progression or death, 
whichever comes first.

For LFS, data from patients not known to have any of these events will be censored 
on the date they were last examined.

For OS, data for patients who did not die will be censored at the date of last study 
visit or the last known date to be alive, whichever is later.  If no postbaseline data 
are available, OS will be censored at the date of first treatment plus 1 day. 

Rate of transfusion independence is defined as the proportion of patients who 
achieve transfusion independence at any time during study treatment. Transfusion 
independence is defined as achieving any continuous 56-day window without 
requiring platelet or RBC transfusions. 

Duration of transfusion independence is defined as the number of consecutive days 
of transfusion independence, measured from 1 day after last transfusion to disease 
progression or subsequent transfusion. 
6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one ADA
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned.
The number and proportion of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (postbaseline incidence) 
will be summarized by treatment group.  When determining postbaseline incidence, 
patients are considered to be ADA positive if they are ADA negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more postbaseline samples is at least 0.60-titer unit greater than the titer of the 
baseline sample (treatment-enhanced ADA response).  Patients are considered to be 
ADA negative if they are ADA negative or have missing data at baseline and all 
postbaseline samples are negative, or if they are ADA positive at baseline but do not 


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have any postbaseline samples with a titer that is at least 0.60-titer unit greater than the 
titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported via descriptive statistics.
6.8
BIOMARKER ANALYSES
The exploratory data generated with the use of fresh cancer tissues and/or blood 
samples (see Section 4.5.7.2) may be listed by patient, dose, cohort, and response 
status. In addition, the relationships between these data and observed safety or clinical 
activity may be assessed.
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.  Other electronic 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 that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.


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7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, 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 into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB 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 or paper patient-reported 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 


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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.
Roche will retain study data for 25 years after the clinical study report has been 
completed or for the length of time required by relevant medical or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC
and General Data Protection Regulation as applicable) 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 Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB submission.  The final IRB-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.


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The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB-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 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 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB by the Principal 
Investigator and reviewed and approved by the IRB before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB.  Investigators are also responsible for 
promptly informing the IRB 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.  Investigators may receive written IND safety reports or 


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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, and 
archived in the site's study file. 
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.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB for each study site, as appropriate.
Study data, which may include data on germline mutations, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted clinical study reports 
and other summary reports will be provided upon request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).


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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 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 in accordance with established IRB 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, 
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 to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 610 sites globally will participate and enroll approximately 21 patients.  
The planned enrollment for dose safety is between 6 and 12 patients, depending on the 
DLTs observed.  Enrollment of the expansion cohort will range between 9 and 
15 patients.  Screening and enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker analyses, and PK analyses), as specified in 
Section 4.5.3. 
9.5
DISSEMINATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 


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


Atezolizumab—F. Hoffmann-La Roche Ltd
98/Protocol GO40828, Version 3 
10.
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2009;15:741220.




Appendix 1
Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
102/Protocol GO40828, Version 3 
Assessment/Procedure
Screening
Treatment Cycles (28-Day Cycles)
Treatment 
Discontinuation a
Survival
Follow-Up
Cycle 1
Maintenance 
Cycles 2 and Beyond
Days –28 
to –1 
Day 1
(3 days)
Day 1
(3 days)
30 Days after 
Final Dose
Hematology i
x j
x k
x
x
Serum chemistry panel l
x j
x k
x
x
Pregnancy test m
x j
x
x
Coagulation:  aPTT or PTT and INR
x j
x
Thyroid-function testing:  TSH, free T3 (or 
total T3), and free T4 n
x j
x n
x
Viral serology
x j, o
x p
x p
x p
Urinalysis q
x j
Perform if clinically indicated. r
Atezolizumab PK sample
See Appendix 2 for sampling schedule.
Hu5F9-G4 PK sample
See Appendix 2 for sampling schedule.
ADA sample
See Appendix 2 for sampling schedule.
x
Plasma and whole blood samples for 
biomarkers
See Appendix 3 for sampling schedule.
Blood sample (for DNA isolation) for RBR 
(optional) s
x


Appendix 1
Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
103/Protocol GO40828, Version 3 
Assessment/Procedure
Screening
Treatment Cycles (28-Day Cycles)
Treatment 
Discontinuation a
Survival
Follow-Up
Cycle 1
Cycles 2 and Beyond
Days –28 
to –1 
Day 1
(3 days)
Day 1
(3 days)
30 Days after 
Final Dose
Bone marrow biopsy and aspirate for 
biomarker assessment 
See Appendix 3 for sampling schedule.
Tumor response assessments
x
x t
Concomitant medications u
x u
x
x
x
Adverse events v
x v
x v
x
x
x u
Hu-5F9-G4 administration w
x w
x w
Atezolizumab administration
x x
x x
Survival follow-up and anti-cancer treatment
x y
ADAanti-drug antibody; ECHO echocardiogram; ECOG Eastern Cooperative Oncology Group; eCRFelectronic Case Report Form; 
ELNEuropean LeukemiaNet; HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; 
HCVhepatitis C virus; MUGAmultiple-gated acquisition (scan); PKpharmacokinetic; Q2W every 2 weeks; QW once a week; 
QTcFQT interval corrected through use of Fridericia's formula; RBRResearch Biosample Repository; T3triiodothyronine; 
T4thyroxine; TSHthyroid-stimulating hormone.
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  
a Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit not more than 30 days after their final 
dose of study treatment.  The visit at which response assessment shows progressive disease may be used as the treatment 
discontinuation visit.
b Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 
28 days before initiation of study treatment.
c A pretreatment bone marrow aspirate and biopsy are required.  
d Vital signs will include measurement of respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a 
seated position, and temperature. Vital signs (including resting, blood oxygen saturation measured by pulse oximetry) will be recorded 
during screening. Vital signs (not including pulse oximetry) will be measured prior to every injection of Hu5F9-G4. After Hu5F9-G4 
administration, vital sign monitoring is not required unless clinically indicated. The patient’s vital signs should be assessed up to 
60 minutes prior to each atezolizumab infusion (see Table 2). Vital signs should also be recorded during or after the atezolizumab 
infusion if clinically indicated. Blood oxygen saturation, as measured by pulse oximetry (while the patient is at rest), should also be 
determined within 60 minutes before the first dose of atezolizumab.


Appendix 1
Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
104/Protocol GO40828, Version 3 
e Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
f
Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.
g Single 12-lead ECG recordings will be obtained during screening and as clinically indicated at other timepoints. Lead placement should 
be as consistent as possible. ECG recordings must be performed after the patient has been resting in a supine position for at least 
10 minutes. All ECGs are to be obtained prior to when other procedures are scheduled at the same time (e.g., vital sign measurements, 
blood draws) and should not be obtained within 3 hours after any meal. Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG resting period and during ECG 
recording. For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. If at a particular post-dose 
timepoint, the mean QTcF is 500 ms and/or 60 ms longer than the baseline value, another ECG must be recorded, ideally within the 
next 5 minutes and ECG monitoring should continue until QTcF has stabilized on two successive ECGs. The Medical Monitor should be 
notified. Standard-of-care treatment may be instituted per the discretion of the investigator. 
h Performed at screening and as clinically indicated.
i
Hematology includes CBC, including RBC count, hemoglobin, hematocrit, WBC with differential count (i.e., neutrophils [bands are 
optional], lymphocytes, eosinophils, basophils, and monocytes), reticulocytes, platelet count, and circulating peripheral blasts.
j
Screening laboratory test results must be obtained within 14 days prior to initiation of study treatment.
k If screening laboratory assessments were performed within 24 hours prior to Day 1 of Cycle 1, they do not have to be repeated.
l
Serum chemistry panel includes glucose (while patient is fasting at baseline), BUN or urea, creatinine, sodium, potassium, magnesium, 
chloride, bicarbonate (or total carbon dioxide (if considered standard of care for the region) calcium, phosphorus, albumin, total bilirubin, 
direct bilirubin, ALT, AST, ALP, LDH, creatine kinase, uric acid, and total protein.
m All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening. Urine 
pregnancy tests will be performed at subsequent visits if clinically indicated.  If a urine pregnancy test result is positive, dosing will be 
delayed until the patient’s status is determined by a serum pregnancy test.
n TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every three 
cycles thereafter (i.e., Cycles 4, 7, 10, etc.).
o At screening, patients will be tested for HIV, HBsAg, total HBcAb, HBV antibody, and HCV antibody.  If a patient has a negative HBsAg 
test and a positive total HBcAb test at screening, an HBV DNA test must also be performed to determine if the patient has an HBV 
infection.  If a patient has a positive HCV antibody test at screening, an HCV RNA test must also be performed to determine if the patient 
has an HCV infection.  Epstein-Barr viral serology (IgG and IgM) will also be performed.
p Patients with a positive quantitative HBV DNA at screening (must be 500 IU/mL per the eligibility criteria) will undergo additional HBV 
DNA tests every 3 months (7 days) during treatment, at treatment discontinuation (7 days), and at 3, 6, 9, and 12 months (14 days at 
each timepoint) after treatment discontinuation.  Study treatment and procedures may proceed while HBV DNA is being processed, but 
results should be reviewed by the investigator as soon as they are available.  If HBV DNA increases to 500 IU/mL, consultation with the 
Medical Monitor is required prior to continuation of study treatment and consultation with a hepatologist or gastroenterologist with 
specialty in hepatitis B is recommended.  


Appendix 1
Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
105/Protocol GO40828, Version 3 
q Urinalysis includes pH, specific gravity, glucose, protein, ketones, and blood); dipstick permitted.
r
Urinalysis should be performed as clinically indicated during study treatment.
s Not applicable for a site that has not been granted approval for RBR sampling.  Perform only for patients at participating sites who have 
provided written informed consent to participate.
t
Bone marrow examinations must include aspirate and biopsy (whenever possible) for morphology, flow cytometry, and routine 
cytogenetic and are required at screening.  If fluorescence in situ hybridization (FISH) is performed at screening, FISH must be 
performed during subsequent assessments.  Refer to Section 4.5.7.2 for timepoints and requirements regarding collection of required 
bone marrow samples (aspirates and trephine/core biopsies) for exploratory biomarker studies.  Bone marrow aspirates and biopsies are 
to be performed on Day 22 of Cycle 1 and subsequently after 3 and 6 months of study treatment (i.e., Day 1 of Cycles 4 and 7).  Beyond 
6 months of study treatment, bone marrow aspirates are required within 7 days prior to study drug administration on Day 1 of every 
3 months (i.e., Day 1 of Cycles 10, 13, 16, etc.) for determination of response, at the time of relapse or progressive disease, and at the 
end of treatment. For patients in follow-up who discontinue study treatment prior to disease progression, bone marrow aspirates and 
biopsy should be collected every 4 months.
u Concomitant therapy consists of any medication (e.g., prescription drugs, vaccines, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) used by a patient in addition to protocol-mandated treatment from 7 days prior to screening to the 
study completion or treatment discontinuation visit.
v 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 30 after the 
final dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first, and serious adverse events 
and adverse events of special interest will continue to be reported until 135 days after the final dose of study treatment or until initiation of 
new systemic anti-cancer therapy, whichever occurs first.  After this period, all deaths, regardless of cause, should be reported.  In 
addition, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to 
prior exposure to study treatment (see Section 5.6).
w Two priming doses of 1 mg/kg of Hu5F9-G4 will be administered to patients by continuous IV infusion on Days 1 and 4 of Cycle 1,
followed by loading doses of 15 mg/kg on Day 8 and 30 mg/kg on Day 11. Starting on Day 15 of Cycle 1, Hu5F9-G4 maintenance will be 
given at a dose of 30 mg/kg QW of each 28-day cycle.  
x Atezolizumab will be administered to patients by IV infusion at a fixed dose of 840 mg, starting on Day 22 of Cycle 1.  In subsequent 
cycles, 840 mg of atezolizumab will be given Q2W on Days 8 and 22 of each 28-day cycle. The initial infusion of atezolizumab will be 
delivered over 60 (15) minutes.  Subsequent infusions will be delivered over 30 (10) minutes if the previous infusion was tolerated 
without infusion-associated adverse events, or 60 (15) minutes if the patient experienced an infusion-associated adverse event with the 
previous infusion.  For the first two doses of atezolizumab following Hu5F9-G4, at least 60 minutes should be allowed for observation 
after Hu5F-G4 administration and 60 minutes for observation after atezolizumab administration.  If no infusion-associated adverse 
events are observed during the initial two combination treatment sessions, a 30-minute observation period between Hu5F9-G4 and 
atezolizumab infusion and a 30-minute observation period after atezolizumab infusion could be considered for subsequent 
administrations.


Appendix 1
Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
106/Protocol GO40828, Version 3 
y After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and 
immunotherapy) will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months (unless 
the patient withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this request 
must be documented in the source documents and signed by the investigator.  If the patient withdraws from the study, the study staff may 
use a public information source (e.g., county records) to obtain information about survival status only.


Atezolizumab—F. Hoffmann-La Roche Ltd
107/Protocol GO40828, Version 3 
Appendix 2
Schedule of Pharmacokinetic and Immunogenicity Samples
Visit
Timepoint(s)
Sample Type
Cycle 1, Day 1
Prior to the first infusion of 
Hu5F9-G4

Hu5F9-G4 PK 
(serum)

Hu5F9-G4 ADA 
(serum)
1 hour (15 minutes) after 
the end of the infusion of 
Hu5F9-G4

Hu5F9-G4 PK 
(serum)
Cycle 1, Day 8
Prior to the first infusion of 
Hu5F9-G4

Hu5F9-G4 PK 
(serum)
1 hour (15 minutes) after 
the end of the infusion of 
Hu5F9-G4

Hu5F9-G4 PK 
(serum)
Cycle 1, Day 11 
Prior to the first infusion

Hu5F9-G4 PK 
(serum)
1 hour (15 minutes) after 
the end of the infusion of 
Hu5F9-G4

Hu5F9-G4 PK 
(serum)
Cycle 1, Day 22
Prior to the first infusion of 
Hu5F9-G4 and 
atezolizumab

Atezolizumab PK 
(serum)

Hu5F9-G4 PK 
(serum)

Atezolizumab ADA 
(serum)
30 (10) minutes after the 
atezolizumab infusion

Atezolizumab PK 
(serum)
1 hour (15 minutes) after 
the end of the infusion of 
Hu5F9-G4

Hu5F9-G4 PK 
(serum)
Cycle 2, Day 1
Prior to the first infusion of 
Hu5F9-G4

Hu5F9-G4 PK 
(serum)

Hu5F9-G4 ADA 
(serum)
1 hour (15 minutes) after 
the end of the infusion of 
Hu5F9-G4

Hu5F9-G4 PK 
(serum)
ADAanti-drug antibody; PKpharmacokinetic.
Note:  Except for Day 1 of Cycle 1, all other study visits and assessments 
during the treatment period should be performed within 3 days of the 
scheduled date.  Study assessments may be delayed or moved ahead of the 
window to accommodate holidays, vacations, and unforeseen delays.


Atezolizumab—F. Hoffmann-La Roche Ltd
108/Protocol GO40828, Version 3 
Appendix 2
Schedule of Pharmacokinetic and Immunogenicity Samples
(cont.)
Visit
Timepoint(s)
Sample Type
Cycle 2, Day 8
Prior to the first infusion

Atezolizumab PK 
(serum)

Hu5F9-G4 PK 
(serum)

Atezolizumab ADA 
(serum)
Cycle 2, Day 22
Prior to the first infusion

Atezolizumab 
(PK serum)

Atezolizumab ADA 
(serum)
Cycle 3, Day 1
Prior to the first infusion

Hu5F9-G4 PK 
(serum)

Hu5F9-G4 ADA 
(serum)
1 hour (15 minutes) after
the end of the infusion of 
Hu5F9-G4

Hu5F9-G4 PK 
(serum)
Cycle 3, Day 22
Prior to the first infusion

Atezolizumab PK 
(serum)

Atezolizumab ADA 
(serum)
Cycle 4, Day 22
Prior to the first infusion

Atezolizumab PK 
(serum)

Atezolizumab ADA 
(serum)
Cycle 5, Day 1
Prior to the first infusion

Hu5F9-G4 PK 
(serum)

Hu5F9-G4 ADA 
(serum)
Cycle 7, Day 1
Prior to the first infusion

Hu5F9-G4 PK 
(serum)
Cycle 8, Day 22
Prior to the first infusion

Atezolizumab PK 
(serum)

Atezolizumab ADA 
(serum)
ADAanti-drug antibody; PKpharmacokinetic.
Note:  Except for Day 1 of Cycle 1, all other study visits and assessments 
during the treatment period should be performed within 3 days of the 
scheduled date.  Study assessments may be delayed or moved ahead of the 
window to accommodate holidays, vacations, and unforeseen delays.


Atezolizumab—F. Hoffmann-La Roche Ltd
109/Protocol GO40828, Version 3 
Appendix 2
Schedule of Pharmacokinetic and Immunogenicity Samples
(cont.)
Visit
Timepoint(s)
Sample Type
Cycle 9, Day 1
Prior to the first infusion

Hu5F9-G4 PK 
(serum)
Cycle 11, Day 1
Prior to the first infusion

Hu5F9-G4 PK 
(serum)

Hu5F9-G4 ADA 
(serum)
Cycle 12, Day 22
Prior to the first infusion

Atezolizumab PK 
(serum)

Atezolizumab ADA 
(serum)
Cycle 13, Day 1
Prior to the first infusion

Hu5F9-G4 PK 
(serum)
Cycle 15, Day 1
Prior to the first infusion

Hu5F9-G4 PK 
(serum)

Hu5F9-G4 ADA 
(serum)
Cycle 16, Day 22
Prior to the first infusion

Atezolizumab PK 
(serum)

Atezolizumab ADA 
(serum)
Cycle 17, Day 1, and 
Day 1 of every 2 
cycles thereafter
Prior to the first infusion

Hu5F9-G4 PK 
(serum)
Treatment 
discontinuation visit 
(30 days after final 
dose)
At visit
Atezolizumab PK 
(serum)
Hu5F9-G4 PK 
(serum)
Atezolizumab ADA 
(serum)
Hu5F9-G4 ADA 
(serum)
12030 days after 
final dose of 
atezolizumab
At visit
Atezolizumab PK 
(serum)
Atezolizumab ADA 
(serum)
ADAanti-drug antibody; PKpharmacokinetic.
Note:  Except for Day 1 of Cycle 1, all other study visits and assessments 
during the treatment period should be performed within 3 days of the 
scheduled date.  Study assessments may be delayed or moved ahead of the 
window to accommodate holidays, vacations, and unforeseen delays.


Atezolizumab—F. Hoffmann-La Roche Ltd
110/Protocol GO40828, Version 3 
Appendix 3
Schedule of Biomarker Samples
Sample Type
Screening
Treatment
At Time of Relapse, PD,
or Suspected PD a, b
Study Tx 
Discon c
Unscheduled
Visit c
Cycle 1
Cycle 2
Cycle 4
Survival
Follow-Up d
Days
28 to 1
Day
1
Day
22
Day 
15
Day 
1
NA
NA
NA
Bone marrow 
aspirate and biopsy
x
x
x
x
x
x
x
Plasma sample
x
x
x
x
x
x
x
Whole-blood sample
x
x
x
x
x
x
x
Discon discontinuation; NAnot applicable; PDprogressive disease; Tx treatment.
a Patients will undergo bone marrow biopsy sample collection, whenever possible, at the time of first evidence of disease progression.  
Biopsies should be performed within 14 days after progression or prior to the next anti-cancer therapy, whichever is sooner.  
b If bone marrow aspirate and/or biopsy are collected to confirm suspected PD, the bone marrow samples and the appropriate blood 
samples should be submitted for biomarker testing.
c If the visit at which a response assessment shows relapse or PD resulting in patient discontinuation is used as the treatment 
discontinuation visit, then an additional sample for study treatment discontinuation does not need to be obtained.
d For patients in follow-up who discontinue study treatment prior to disease progression, bone marrow aspirates and biopsy should be 
collected every 4 months.  All bone marrow examinations should be assessed locally (see Section 4.5.7).


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Appendix 4
Eastern Cooperative Oncology Group Performance Status Scale
Grade
Description
0
Fully active; able to carry on all predisease 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
Response Evaluation Criteria
Category
Definition
Comment
Response
CRMRD−
If studied pretreatment, CR with negativity 
for a genetic marker by RT-qPCR or CR 
with negativity by MFC
CR
Bone marrow blasts 5%, absence of 
circulating blasts and blasts with Auer 
rods, absence of extramedullary disease, 
ANC 1.0109/L (1000/L), and platelet 
count 100109/L (100,000/L)
MRD a or unknown
CRi
All CR criteria except for residual 
neutropenia (1.0 109/L [1000/µL]) or 
thrombocytopenia (100 109/L 
[100,000/µL])
MLFS
Bone marrow blasts 5%, absence of 
blasts with Auer rods, absence of 
extramedullary disease, and no 
hematologic recovery required
Marrow should not 
merely be “aplastic;” 
at least 200 cells 
should be 
enumerated or 
cellularity should be 
at least 10%.
Partial remission 
All hematologic criteria for CR, decrease of 
bone marrow blast percentage to 5% to 
25%, and decrease of pretreatment bone 
marrow blast percentage by at least 50%
Treatment failure
Primary refractory 
disease
No CR or CRi after six courses of 
investigational treatment, excluding 
patients who die as a result of aplasia or 
death because of indeterminate cause
CRcomplete remission; CRicomplete remission with incomplete hematologic recovery; 
CRMRD−complete remission without minimal residual disease; MFCmultiparameter flow 
cytometry; MLFSmorphologic leukemia-free state; MRDminimal residual disease; 
PDprogressive disease; RT-qPCRreal-time quantitative polymerase chain reaction.
a Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a 
differentiation syndrome, that is, a transient increase in the percentage of bone marrow 
blasts and an absolute increase in blood blasts; in the setting of therapy with such 
compounds, an increase in blasts may not necessarily indicate progressive disease.


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Appendix 5
Response Evaluation Criteria (cont.)
Category
Definition
Comment
Treatment failure (cont.)
Death in aplasia
Deaths occurring 7 days following 
completion of initial treatment while 
cytopenic, with aplastic or hypoplastic 
bone marrow obtained within 7 days of 
death, without evidence of persistent 
leukemia
Death from 
indeterminate cause
Deaths occurring before completion of 
therapy or 7 days following its 
completion, or deaths occurring 7 days 
following completion of initial therapy with 
no blasts in the blood, but no bone marrow 
examination available
Response criteria for clinical trials only
Stable disease
Absence of CRMRD−, CR, CRi, PR, MLFS,
and criteria for PD not met
Period of stable 
disease that should 
last for at least 
3 months
Evidence of an increase in percentage of 
bone marrow blasts and/or increase of 
absolute blast counts in the blood:
• >50% increase in marrow blasts over 
baseline (a minimum 15%-point 
increase is required in cases with 30% 
blasts at baseline, or persistent marrow 
blast percentage of 70% over at least 
3 months, without at least a 100% 
improvement in ANC to an absolute 
level (0.5109/L [500/L], and/or 
platelet count to >50 × 109/L [50 000/L] 
non-transfused), or

>50% increase in peripheral blasts 
(WBC% blasts) to 25 109/L 
(25 000/L) (in the absence of 
differentiation syndrome) a or
CRcomplete remission; CRicomplete remission with incomplete hematologic recovery; 
CR MRD−complete remission without minimal residual disease; MFCmultiparameter flow 
cytometry; MLFSmorphologic leukemia-free state; MRDminimal residual disease; 
PDprogressive disease; RT-qPCRreal-time quantitative polymerase chain reaction.
a Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a 
differentiation syndrome, that is, a transient increase in the percentage of bone marrow 
blasts and an absolute increase in blood blasts; in the setting of therapy with such 
compounds, an increase in blasts may not necessarily indicate progressive disease.


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Appendix 5
Response Evaluation Criteria (cont.)
Category
Definition
Comment
Response criteria for clinical trials only (cont.)
Progressive 
disease a
New extramedullary disease
Relapse
Hematologic relapse
(after CRMRD, CR, 
CRi)
Bone marrow blasts 5%, reappearance 
of blasts in the blood, or development of 
extramedullary disease
Molecular relapse 
(after CRMRD) 
If studied pretreatment, recurrence of 
MRD, as assessed using RT-qPCR or by 
MFC
ANCabsolute neutrophil count; CRcomplete remission; CRicomplete remission with 
incomplete hematologic recovery; CRMRDcomplete remission without minimal residual 
disease; MFCmultiparameter flow cytometry; MLFSmorphologic leukemia-free state;
MRDminimal residual disease; PDprogressive disease; RT-qPCRreal-time quantitative 
polymerase chain reaction.
a Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a 
differentiation syndrome, that is, a transient increase in the percentage of bone marrow 
blasts and an absolute increase in blood blasts; in the setting of therapy with such 
compounds, an increase in blasts may not necessarily indicate progressive disease.
REFERENCES
Döhner H, Estey EH, Amadori S, et al. European LeukemiaNet. Diagnosis and
management of acute myeloid leukemia in adults: recommendations from an
international expert panel, on behalf of the European LeukemiaNet. Blood
2010;115:45374.
Döhner H, Estey EH, Grimwade D, et al. Diagnosis and management of AML in adults: 
2017 ELN recommendations from an international expert panel. Blood 
2017;129:42447. 


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Appendix 6
Preexisting Autoimmune Diseases and Immune Deficiencies
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 are 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, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Contact the Medical Monitor regarding any 
uncertainty about autoimmune exclusions.
Autoimmune Diseases and Immune Deficiencies
Acute disseminated
encephalomyelitis
Addison 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
Behçet disease
Bullous pemphigoid
Chronic fatigue syndrome
Chronic inflammatory
demyelinating
polyneuropathy
Churg-Strauss syndrome
Crohn disease 
Dermatomyositis
Diabetes mellitus type 1
Dysautonomia
Epidermolysis bullosa 
acquisita
Gestational pemphigoid
Giant cell arteritis
Goodpasture syndrome
Graves disease
Guillain-Barré syndrome
Hashimoto disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki disease
Lambert-Eaton myasthenia
syndrome
Lupus erythematosus
Lyme disease, chronic
Meniere syndrome
Mooren ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus
syndrome
Optic neuritis
Ord thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodosa
Polyarthritis
Polyglandular autoimmune
syndrome
Primary biliary cirrhosis
Psoriasis
Reiter syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren syndrome
Stiff-Person syndrome
Takayasu arteritis
Ulcerative colitis
Vitiligo
Vogt-Koyanagi-Harada 
disease
Wegener granulomatosis


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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

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Maintain an adequate airway.
3.
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge.
4.
Continue to observe the patient and document observations.


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Appendix 8
Overall Guidelines for Management of Patients Who Experience 
Adverse Events
DOSE MODIFICATIONS
There will be no dose modifications for atezolizumab in this study.  The dose of 
Hu5F9-G4 may be decreased to 20 mg/kg after consultation with the Medical Monitor.
In general, Hu5F9-G4 dose reductions to 20 mg/kg may be considered for 
Hu5F9-G4related toxicities that are Grade 3 or 4; however, the following are generally 
not reasons for dose reduction:

Grade 3 anemia:  Grade 3 hemolytic anemia that is medically significant, requiring 
hospitalization or prolongation of existing hospitalization, disabling or limiting 
self-care activities of daily life, may result in dose reduction

Grade 3 indirect or unconjugated hyperbilirubinemia that resolves to Grade 2 with 
supportive care within 7 days and is not associated with other clinically significant 
sequelae

Grade 3 elevation in ALT, AST, or ALP that resolves to Grade 2 with supportive 
care within 1 week and is not associated with other clinically significant sequelae

Transient Grade 3 nausea, vomiting, diarrhea, local reactions, influenza-like 
symptoms, myalgias, fever, headache, pain during the infusion, or skin toxicity that 
resolves to Grade 2 within 72 hours after medical management (e.g., supportive 
care, including immunosuppressant treatment) has been initiated

Grade 3 fatigue that resolves to Grade 2 within 2 weeks of Day 1 of the next cycle 
of study treatment

Grade 3 Hu5F9-G4related infusion reactions in the absence of an optimal 
pretreatment regimen, which is defined as acetaminophen or a comparable 
non-steroidal anti-inflammatory agent, plus an antihistamine and corticosteroids

Grade 3 tumor lysis syndrome or electrolyte disturbances (hyperkalemia, 
hypophosphatemia, hyperuricemia, etc.) that resolve to Grade 2 or baseline value
within 7 days

Grade 3 or 4 lymphopenia or leukopenia 

Any Grade 3 autoimmune toxicity that clinically resolves to Grade 2 within 7 days 
of initiating therapy

Grade 3 diarrhea or skin toxicity that resolves to Grade 1 or better in 7 days after 
medical management (e.g., immunosuppressant treatment) has been initiated

Other single laboratory values out of normal range that have no clinical correlate 
and resolve to Grade 2 or to baseline within 7 days with adequate medical 
management

Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites


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Appendix 8
Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.)
Patients who are deemed to require further dose reductions 20 mg/kg of Hu5F9-G4 
should be discontinued from study treatment with Hu5F9-G4.
TREATMENT INTERRUPTION
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over 1 month to the equivalent of 10 mg/day oral 
prednisone before atezolizumab can be resumed.  If atezolizumab is withheld for 
12 weeks after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for 12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for 12 weeks if the Medical Monitor agrees that the patient is likely to derive 
clinical benefit.  Atezolizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures) with Medical Monitor approval.  The investigator and 
the Medical Monitor will determine the acceptable length of treatment interruption.
Hu5F9-G4 treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment (see the Dose Modifications section).  If a 
patient misses three or more consecutive doses during the combination treatment period, 
the investigator and Medical Monitor will decide whether the patient should discontinue 
Hu5F9-G4 permanently.  If Hu5F9-G4 is withheld for 28 days because of toxicity, the 
patient should be discontinued from Hu5F9-G4.  However, if the investigator believes the 
patient is likely to derive clinical benefit and the Medical Monitor is in agreement, 
Hu5F9-G4 can be resumed after being withheld for 28 days.  If the time interval 
between Hu5F9-G4 doses is 4 weeks on account of missed doses, a repriming period 
is required prior to restarting weekly doses.  If repriming is necessary, atezolizumab 
should be held during the repriming week and restarted when the 30-mg/kg weekly 
dosing of Hu5F9-G4 begins.
If atezolizumab is discontinued, Hu5F9-G4 should also be discontinued.  If Hu5F9-G4 is 
discontinued, atezolizumab can be continued if the patient is likely to derive clinical 
benefit, as determined by the investigator.
MANAGEMENT GUIDELINES
Guidelines for the management of patients who experience specific adverse events are 
provided in Appendix 9 for atezolizumab-related adverse events and in the Atezolizumab 
Investigator's Brochure.  This section integrates management guidelines for those 
adverse events when both atezolizumab and Hu5F9-G4 have developed guidance.  This 
section also includes generic guidance for management of Hu5F9-G4


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 8
Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.)
when atezolizumab-associated adverse events occur.  This section includes 
management guidelines for Hu5F9-G4associated adverse events.  For cases in which 
management guidelines are not covered in Appendix 9, the Hu5F9-G4 Investigator's 
Brochure, or the protocol, patients should be managed as deemed appropriate by the 
investigator according to best medical judgment.
INFUSION-RELATED REACTIONS AND ANAPHYLAXIS
Management guidelines for patients who experience infusion-related reactions or 
anaphylaxis are presented in Table 1.
Table 1
Guidelines for Management of Patients Who Experience Adverse 
Events Associated with Hu5F9-G4
Event
Action to Be Taken
IRRs and anaphylaxis
IRR, Grade 1
Follow guidelines for atezolizumab in Appendix 9.
For anaphylaxis precautions, see Appendix 7.
IRR, Grade 2 
Follow guidelines for atezolizumab in Appendix 9.
For anaphylaxis precautions, see Appendix 7.
For Hu5F9-G4:

Stop the Hu5F9-G4 infusion, begin an IV infusion of 
normal saline, and treat the patient with diphenhydramine 
50 mg IV or equivalent and/or 500 to 750 mg oral 
paracetamol/acetaminophen.

Remain at bedside and monitor patient until resolution of 
symptoms.

Corticosteroid therapy may also be administered at the 
discretion of the investigator.

If the infusion is interrupted, wait until symptoms resolve, 
then restart the infusion at 50% of the original infusion 
rate when symptoms resolve.

If symptoms recur, then stop infusion and disconnect the 
patient from the infusion apparatus; no further Hu5F9-G4 
will be administered at that visit. The amount of study 
drug infused must be recorded on the electronic Case 
Report Form.

Patients who experience an infusion reaction of Grade 2 
during the 4-hour post-infusion observation period that 
does not resolve during that time should be observed for 
24 hours or until the adverse event resolves, with vital
sign measurements every 4 hours and additional 
evaluations as medically indicated for the management of 
the adverse event.
IRRinfusion-related reaction.


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 8
Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.)
Table 1
Guidelines for Management of Patients Who Experience Adverse 
Events Associated with Hu5F9-G4 (cont.)
Event
Action to Be Taken
IRRs and anaphylaxis (cont.)
IRR, Grade 3 or 4
Follow guidelines for atezolizumab in Appendix 9.
For anaphylaxis precautions, see Appendix 7.
For Hu5F9-G4: 

Stop infusion and permanently discontinue Hu5F9-G4. 

Begin an IV infusion of normal saline, and treat the 
patient as follows: administer bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1000 solution for SC 
administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or 
diphenhydramine 50 mg IV with methylprednisolone 
100 mg IV or equivalent, as needed.

Administer aggressive symptomatic treatment.

All patients will be observed for an additional 24 hours 
or longer until the adverse event resolves, with vital 
sign measurements every 4 hours and additional 
evaluations as medically indicated for the management 
of the adverse event.
Atezolizumab-related toxicities not described above
Grade 1 or 2
Follow guidelines for atezolizumab in Appendix 9.
Continue Hu5F9-G4.
Grade 3
Follow guidelines for atezolizumab in Appendix 9.
Continue Hu5F9-G4.
Grade 4
Follow guidelines for atezolizumab in Appendix 9.
Hu5F9-G4 may be continued at the discretion of the 
investigator per medical judgment.
IRRinfusion-related reaction.
Hu5F9-G4ASSOCIATED ANEMIA 
Anemia, Blood Crosmatching, and Packed RBC Transfusion Procedures
Hu5F9-G4 binds to RBCs and leads to erythrophagocytosis.  This, coupled with anemia 
from other cause in patients with cancers, means that care has to be taken with RBC 
crossmatching and packed RBC transfusions.  There is a possibility that treatment with 
Hu5F9-G4 may obscure assessment of RBC phenotyping, although this has not been 
observed in patients to date.  


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Appendix 8
Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.)
At baseline, prior to initiation of Hu5F9-G4 therapy, blood cell ABO phenotyping for 
minor antigens, type, and screen (ABO blood type and Rhesus [Rh] factor), and direct 
antibody testing (DAT) will be performed to facilitate, together with the prior phenotype, 
allocation of properly crossmatched blood in the event a blood transfusion is warranted.  
For patients after exposure to Hu5F9-G4, ABO, Rh, and DAT may be pan-reactive 
because of Hu5F9-G4 binding to RBCs.  Therefore, if a non-urgent transfusion is 
ordered by the investigator, perform the following procedures:

Front type:  EGA-treated cells (2 maximum) and warm wash 4 (minimum) with 
0.9% saline

Back type:  Perform reverse anti-human globulin for both A and B.

If a valid ABO type cannot be obtained, mark the final report as invalid and notify the 
transfusion service for the site.

Antibody screen
If a pan-agglutinin/warm autoantibody is present in low-ionic-strength solution, repeat the 
antibody screen with polyethylene glycol (PeG).  Perform PeG adsorption studies and 
elution studies.
Blood Components for Transfusion
For all elective red cell transfusions, leukocyte-reduced units matched for the phenotype 
of the patients (as described above) will be used.  Where exact matching for all specified 
blood groups proves impractical (e.g., for MNS), local sites will decide on the 
best-matched donor units to be used.  Cytomegalovirus (CMV) matching (i.e., 
CMV-seronegative units for CMV-seronegative patients) will not be required for this 
study because it will limit the inventory for antigen matching.
If the crossmatch is incompatible, the RBC units that are Coombs crossmatched
incompatible will be selected (e.g., phenotype matched or least incompatible) for issue at 
the discretion of the sites’ transfusion Service Medial Director or equivalent person, 
where available.
Hu5F9-G4 Impact on Red Blood Cell Transfusion Procedures
Hu5F9-G4 binds to red cells and leads to erythrophagocytosis. This, coupled with
anemia from other causes in patients with cancers, means that care has to be taken with 
RBC crossmatching and packed RBC transfusions. There is a possibility that treatment 
with Hu5F9-G4 may obscure assessment of RBC phenotyping, although this has not 
been observed in patients treated to date.


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 8
Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.)
During the screening period prior to initiation of Hu5F9-G4 therapy, blood cell ABO
phenotyping for minor antigens, type and screen (ABO/Rh), and DAT will be performed 
for each patient. This, together with using the prior phenotype, will facilitate allocation of 
properly crossmatched blood in the event a blood transfusion is warranted.
For patients after exposure to Hu5F9-G4:

ABO, Rh, and DAT may be pan-reactive owing to Hu5F9-G4 binding to red cells. 
Therefore, if a non-urgent transfusion is ordered by the investigator, perform the 
following procedures:
–
Front type: EGA-treated cells (approximately 2 maximum) and warm wash 
(approximately 4 minimum) with 0.9% saline.
–
Back type: Perform reverse anti-human globulin for both A and B.
–
If a valid ABO type cannot be obtained, mark the final report as invalid and
notify the transfusion service for the site.

Antibody screen:
If a pan-agglutinin or warm autoantibody is present in low ionic strength solution, 
repeat the antibody screen with polyethylene glycol (PeG). Perform PeG adsorption 
studies and elution studies.
For emergency transfusions, the transfusion laboratory may consider using emergency 
Group O Rh-negative units if the phenotyped units are not available.
Blood plasma therapy will be blood type specific.  Platelets will be blood type compatible 
whenever possible, and if not, will have been tested and found not to have high-titer 
anti-A or anti-B.


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Appendix 9
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. 
MANAGEMENT GUIDELINES
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 also 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.


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
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. 


Atezolizumab—F. Hoffmann-La Roche Ltd
125/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
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. 


Atezolizumab—F. Hoffmann-La Roche Ltd
126/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
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. 


Atezolizumab—F. Hoffmann-La Roche Ltd
127/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
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. 


Atezolizumab—F. Hoffmann-La Roche Ltd
128/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
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 Table 4.
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 pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.


Atezolizumab—F. Hoffmann-La Roche Ltd
129/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:

Continue atezolizumab.

Monitor TSH every 4 weeks.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.

Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated hyperthyroidism.
c
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
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. 


Atezolizumab—F. Hoffmann-La Roche Ltd
130/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform appropriate imaging.

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 and patient is stable on 
replacement therapy, resume atezolizumab. b

If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical 
Monitor. c
Hyperglycemia, 
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.
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

Monitor for glucose control.

Resume atezolizumab when symptoms resolve and glucose 
levels are stable.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
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 or equivalent.  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. 


Atezolizumab—F. Hoffmann-La Roche Ltd
131/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

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.

Initiate hormone replacement if clinically indicated.

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 hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

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.

Initiate hormone replacement if clinically indicated.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
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. 


Atezolizumab—F. Hoffmann-La Roche Ltd
132/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

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
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to ophthalmologist.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.  

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. 


Atezolizumab—F. Hoffmann-La Roche Ltd
133/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
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 Table 6.


Atezolizumab—F. Hoffmann-La Roche Ltd
134/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Table 6
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated
myocarditis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a 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.

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 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
Immune-mediated
myocarditis, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

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.
ECMOextracorporeal membrane oxygenation; VAD ventricular assist device.
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.


Atezolizumab—F. Hoffmann-La Roche Ltd
135/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines,
anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis.
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 7.


Atezolizumab—F. Hoffmann-La Roche Ltd
136/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome
Event
Management
Grade 1 a
Fever b with or 
without 
constitutional 
symptoms

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset.

If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment, c including maintenance of IV 
fluids for hydration.

In case of rapid decline or prolonged CRS (2 days) or in 
patients with significant symptoms and/or comorbidities, consider 
managing as per Grade 2.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics, and monitor closely for IRRs and/or CRS.


Atezolizumab—F. Hoffmann-La Roche Ltd
137/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Grade 2 a
Fever b with 
hypotension not 
requiring 
vasopressors
and/or
Hypoxia requiring 
low-flow oxygen d
by nasal cannula or 
blow-by

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus as needed.

Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate).  Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional 
practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e

Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact Medical Monitor.

If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of atezolizumab may be administered.

For subsequent infusions, consider administration of oral premedication 
with antihistamines, anti-pyretics, and/or analgesics and monitor closely 
for IRRs and/or CRS.

If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact Medical Monitor.


Atezolizumab—F. Hoffmann-La Roche Ltd
138/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Grade 3 a
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin)
and/or
Hypoxia requiring 
high-flow oxygen d
by nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask

Permanently discontinue atezolizumab and contact Medical Monitor. f

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus and vasopressor as needed.

Monitor cardiopulmonary and other organ function closely; monitoring in 
the ICU is recommended.  Administer IV fluids as clinically indicated, 
and manage constitutional symptoms and organ toxicities as per 
institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e

Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.
Grade 4 a
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin)
and/or
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation)

Permanently discontinue atezolizumab and contact Medical Monitor. f

Administer symptomatic treatment. c

Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed.  Monitor other 
organ function closely.  Manage constitutional symptoms and organ 
toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e  For patients who are refractory to anti-
cytokine therapy, experimental treatments g may be considered at the 
discretion of the investigator and in consultation with the Medical 
Monitor.

Hospitalize patient until complete resolution of symptoms.


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Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
ASTCTAmerican Society for Transplantation and Cellular Therapy; BiPAPbi-level positive 
airway pressure; CARchimeric antigen receptor; CPAPcontinuous positive airway pressure; 
CRScytokine-release syndrome; CTCAECommon Terminology Criteria for Adverse Events; 
eCRFelectronic Case Report Form; HLHhemophagocytic lymphohistiocytosis; ICUintensive 
care unit; IRRinfusion-related reaction; MASmacrophage activation syndrome; 
NCCNNational Cancer Comprehensive Network; NCINational Cancer Institute.
Note:  The management guidelines have been adapted from NCCN guidelines for management 
of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for management guidelines is based on ASTCT consensus grading for CRS.  
NCI CTCAE v5.0 should be used when reporting severity of IRRs, CRS, or organ toxicities 
associated with CRS on the Adverse Event eCRF.  Organ toxicities associated with CRS 
should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no 
longer required when subsequently determining event severity (grade).  In this case, the grade 
is driven by the presence of hypotension and/or hypoxia.
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as oxygen 
delivered at 6 L/min.
e There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are 
limited, and the role of such treatment in the setting of antibody-associated CRS has not been 
established.
f
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the 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.  For subsequent infusions, administer oral premedication with antihistamines, 
anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  Premedication with 
corticosteroids and extending the infusion time may also be considered after consulting the 
Medical Monitor and considering the benefitrisk ratio.
g Refer to Riegler et al. (2019) for information on experimental treatments for CRS.


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140/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
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 Table 8.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2
Amylase and/or lipase 1.52.0ULN:

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone.
Asymptomatic with amylase and/or lipase 2.05.0ULN:

Treat as a Grade 3 event.
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider 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, permanently discontinue atezolizumab 
and contact Medical Monitor. c
GIgastrointestinal; ULNupper limit of normal.
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. 


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141/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
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 Table 9.
Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue atezolizumab.

Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue atezolizumab.

Consider patient referral to dermatologist.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist.

Initiate treatment with corticosteroids equivalent to 10 mg/day 
oral prednisone, increasing dose to 12 mg/kg/day if event does 
not improve within 4872 hours.

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
Dermatologic 
event, Grade 4

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. 


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Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
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 Table 10.
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-mediated
neuropathy, 
Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology.

Initiate treatment as per institutional guidelines.

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
Immune-mediated
neuropathy, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c 

Initiate treatment as per institutional guidelines.
Myasthenia gravis 
and Guillain-Barré
syndrome 
(any grade)

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of corticosteroids equivalent to 12 
mg/kg/day oral or IV prednisone.
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. 


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143/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
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.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11.
Table 11 Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact Medical Monitor. a

Refer patient to neurologist.

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.
a 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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Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
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.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12.


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145/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Table 12 Management Guidelines for Renal Events 
Event
Management
Renal event,
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values.
Renal event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to renal specialist.

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
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. 

Refer patient to renal specialist and consider renal biopsy.

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.
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. 


Atezolizumab—F. Hoffmann-La Roche Ltd
146/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
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 13.


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147/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Table 13 Management Guidelines for Immune-Related 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. 


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148/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Table 13
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. 


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149/Protocol GO40828, Version 3 
Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
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), 
which are considered to be potential risks for atezolizumab.  
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)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14.


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Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Table 14 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.
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death-1 antibody: raising awareness among community oncologist. J Oncol 
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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.
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335.
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.