Conditions: Urinary Tract Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1004
Healthy volunteers: no

Brief summary:
This Phase IIIb, multicenter study will assess the safety of atezolizumab as second- to fourth-line treatment for participants with locally advanced or metastatic urothelial or non-urothelial cancer of the urinary tract in addition to evaluate the efficacy of atezolizumab and potential tumor biomarkers associated with atezolizumab.

Detailed description:

Arms:
arm 1: Participants will receive atezolizumab every 3 weeks (Q3W) until investigator assessed loss of clinical benefit, unacceptable toxicity, investigator or participant decision to withdraw from therapy, or death (whichever occurs first).

Interventions: intervention 1: Atezolizumab
Intervention descriptions: intervention 1: Atezolizumab 1200 milligrams (mg) will be administered by intravenous (IV) infusion Q3W.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
 
An Open Label, Single arm, Multicenter, 
Safety Study of Atezolizumab in Locally 
Advanced or Metastatic Urothelial or 
Non-Urothelial Carcinoma of the 
Urinary Tract 
NCT Number: NCT02928406 
Document Dates: Protocol Version 15: 17-December-2021 
 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol MO29983, Final Version 15
PROTOCOL
TITLE:
AN OPEN LABEL, SINGLE ARM, MULTICENTER, 
SAFETY STUDY OF ATEZOLIZUMAB IN LOCALLY 
ADVANCED OR METASTATIC UROTHELIAL OR 
NON-UROTHELIAL CARCINOMA OF THE 
URINARY TRACT
PROTOCOL NUMBER:
MO29983
VERSION NUMBER:
15
EUDRACT NUMBER:
2016-002625-11
IND NUMBER:
120827
TEST PRODUCT:
Atezolizumab (MPDL3280A; RO5541267) 
MEDICAL MONITOR:
Dr. 
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below.
 
EU QPPV
17-Dec-2021 18:24:05
Approver's Name
Title
Date and Time (UTC)
16-Dec-2021 19:20:23
Company Signatory


Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol MO29983, Final Version 15                                                                               2
PROTOCOL HISTORY
Protocol
Associated Country and/or Region-Specific Protocols 
Version
Date Final
Country and/or Region
Version
Date Final
15
See electronic date 
stamp on title page
Canada 
16
TBD
13
3 March 2021
Canada
14
4 March 2021
11
22 October 2019
Canada
12
22 October 2019
9
8 October 2018
Canada
10
8 October 2018
7
22 February 2018
Canada
8
7 March 2018
5
19 May 2017
Canada
6
6 July 2017 
3
23 November 2016
Canada
4
31 January 2017
2
25 August 2016


1
22 July 2016




Atezolizumab—F. Hoffmann-La Roche Ltd
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Rationale for Revisions
PROTOCOL AMENDMENT, VERSION 15:
RATIONALE

Protocol MO29983 has been primarily amended to align with Atezolizumab 
Investigator’s Brochure Version 18 and update the document with the recent Roche 
Atezolizumab protocol template. Changes to the protocol, along with rationale for 
each change, are summarized below. 

Benefitrisk assessment and guidance on concomitant administration of coronavirus 
disease 2019 vaccines with atezolizumab has been added (Sections 1.4 and 4.4.1).

Language has been added to indicate that sites can confirm that appropriate 
temperature conditions have been maintained during IMP transit either by time 
monitoring (shipment arrival date and time) or temperature monitoring (Section 
4.3.3).

If a patient withdraws from the study, public information source may be used to 
obtain information about survival status (Section 4.6.1)

The document has been updated to align with the current Roche Atezolizumab 
protocol template in Section 1.3, 4 and 5. 

The Roche Global Policy on Continued Access to Investigational Medicinal Product
for eligible patients has been added (Section 4.3.4).

The responsibilities of the Principal Investigator and the role of the Medical Monitor 
during study conduct have been clarified (Section 5.1.2, Appendix 5 and Appendix 
11).

The serious adverse events and adverse events of special interest reporting 
timelines after the final dose of study drug or until initiation of new systemic 
anti-cancer therapy is corrected in Section 5.4.2.2 and 5.6.

Language has been clarified that study adverse event reports will not be derived 
from patient reported outcome (PRO) data by the Sponsor; sites are not expected to 
review the PRO data for adverse events (Section 5.3.5.13).

Language has been added for consistency with Roche's current data retention 
policy and to accommodate more stringent local requirements (if applicable) 
(Section 7.5).

Language has been added to indicate that the study will comply with applicable 
local, regional, and national laws (Section 8.1).

The language regarding the informed consent form revision and the re-consenting in 
accordance with the local applicable laws and IRB/EC policy has been clarified
(Section 8.2).

The language regarding the study data management, sharing and application has
been added (Sections 8.4 and 9.6).

The guidelines for management of suspected anaphylactic reaction has been 
updated in Appendix 6. 


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Rationale for Revisions

The medical term “primary biliary cirrhosis” has been replaced by the term “primary 
biliary cholangitis” to align with the updated preferred term in MedDRA (Appendix 8).

The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator's Brochure, Version 18 (Appendix 11).

The study synopsis has been simplified by deleting information regarding IMP 
preparation, administration, and concomitant therapy, because the relevant 
information already is available in the main body of the protocol.
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
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TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................. 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 24
1.1
Urothelial Carcinoma of the Urinary Tract.............................. 24
1.2
Non-Urothelial Cancer of the Urinary Tract............................ 26
1.3
Atezolizumab......................................................................... 28
1.3.1
PD-L1 Expression as a Biomarker......................................... 28
1.3.2
Clinical Development Program .............................................. 29
1.3.3
Efficacy.................................................................................. 31
1.3.4
Safety .................................................................................... 32
1.4
Study Rationale and Benefit-Risk Assessment...................... 35
2.
OBJECTIVES AND ENDPOINTS ............................................................... 39
2.1
Primary Objective .................................................................. 39
2.2
Secondary Objectives............................................................ 39
2.3
Exploratory Objectives........................................................... 40
2.4
Biomarker Objectives............................................................. 40
3.
STUDY DESIGN......................................................................................... 40
3.1
Description of the Study......................................................... 40
3.2
End of Study and Length of Study......................................... 41
3.3
Rationale for Study Design.................................................... 41
3.3.1
Rationale for Patient Population and Analysis 
Groups................................................................................... 41
3.3.2
Rationale for an Open-Label Single-Arm Design................... 42
3.3.3
Rationale for Atezolizumab Dose and Schedule.................... 42
3.3.4
Rationale for Biomarker Assessments in Tumor 
Samples................................................................................. 43
3.3.5
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 44
3.3.6
Rationale for Testing Atezolizumab in Patients 
with UC Who Have Failed Prior Therapy............................... 44
3.3.7
Rationale for the Use of Modified Response 
Criteria (Immune Based)........................................................ 45


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3.3.8
Rationale for Allowing Patients to Continue 
Atezolizumab Treatment Beyond Initial 
Progression ........................................................................... 45
4.
MATERIALS AND METHODS .................................................................... 46
4.1
Patients.................................................................................. 46
4.1.1
Inclusion Criteria.................................................................... 46
4.1.2
Exclusion Criteria................................................................... 48
4.2
Method of Treatment Assignment and Blinding..................... 52
4.3
Study Treatment.................................................................... 52
4.3.1
Formulation, Packaging, and Handling.................................. 52
4.3.2
Dosage, Administration, and Compliance.............................. 52
4.3.3
Investigational Medicinal Product Accountability ................... 53
4.3.4
Post-Trial Access to Atezolizumab ........................................ 54
4.4
Concomitant Therapy ............................................................ 55
4.4.1
Permitted Therapy................................................................. 55
4.4.2
Prohibited Therapy ................................................................ 56
4.5
Study Assessments ............................................................... 57
4.5.1
Informed Consent Forms and Screening Log........................ 58
4.5.2
Medical History and Demographic Data ................................ 58
4.5.3
Physical Examinations........................................................... 58
4.5.4
Vital Signs.............................................................................. 58
4.5.5
Tumor and Response Evaluations......................................... 59
4.5.6
Ongoing Tumor Assessments ............................................... 60
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 60
4.5.8
Electrocardiograms................................................................ 61
4.5.9
Patient-Reported Outcomes .................................................. 62
4.5.10
Optional Samples for Research Biosample 
Repository ............................................................................. 62
4.5.10.1
Overview of the Research Biosample Repository.................. 62
4.5.10.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 63
4.5.10.3
Sample Collection.................................................................. 63
4.5.10.4
Confidentiality........................................................................ 64


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4.5.10.5
Consent to Participate in the Research 
Biosample Repository............................................................ 64
4.5.10.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 65
4.5.10.7
Monitoring and Oversight....................................................... 65
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 65
4.6.1
Patient Discontinuation.......................................................... 65
4.6.2
Study Treatment Discontinuation........................................... 66
4.6.3
Study and Site Discontinuation.............................................. 69
5.
ASSESSMENT OF SAFETY....................................................................... 69
5.1
Safety Plan ............................................................................ 69
5.1.1
Risks Associated with Atezolizumab ..................................... 70
5.1.2
Management of Patients Who Experience 
Specific Adverse Events........................................................ 70
5.2
Safety Parameters and Definitions ........................................ 73
5.2.1
Adverse Events ..................................................................... 73
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 73
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 74
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 75
5.3.1
Adverse Event Reporting Period ........................................... 75
5.3.2
Eliciting Adverse Event Information....................................... 76
5.3.3
Assessment of Severity of Adverse Events ........................... 76
5.3.4
Assessment of Causality of Adverse Events ......................... 76
5.3.5
Procedures for Recording Adverse Events............................ 77
5.3.5.1
Infusion-Related Reactions and Cytokine-
Release Syndrome................................................................ 77
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 78
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 78
5.3.5.4
Persistent or Recurrent Adverse Events................................ 79
5.3.5.5
Abnormal Laboratory Values ................................................. 79


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5.3.5.6
Abnormal Vital Sign Values ................................................... 80
5.3.5.7
Abnormal Liver Function Tests.............................................. 80
5.3.5.8
Deaths ................................................................................... 81
5.3.5.9
Preexisting Medical Conditions.............................................. 81
5.3.5.10
Lack of Efficacy or Worsening of Locally 
Advanced or Metastatic Urothelial or Non-
Urothelial Carcinoma of the Urinary Tract.............................. 82
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 82
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 82
5.3.5.13
Patient-Reported Outcome Data ........................................... 83
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 Drug Initiation.................... 84
5.4.2.2
Events That Occur after Study Drug Initiation........................ 84
5.4.3
Reporting Requirements for Pregnancies.............................. 84
5.4.3.1
Pregnancies in Female Patients............................................ 84
5.4.3.2
Abortions ............................................................................... 85
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 85
5.5
Follow-Up of Patients after Adverse Events .......................... 85
5.5.1
Investigator Follow-Up........................................................... 85
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................................................................. 86
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 87
6.1
Determination of Sample Size ............................................... 88
6.2
Analysis of the Conduct of the Study..................................... 88
6.3
Summaries of Treatment Group ............................................ 89
6.4
Primary Safety Analysis......................................................... 89


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6.5
Efficacy Analyses .................................................................. 90
6.6
Subgroup Analyses ............................................................... 91
6.7
Biomarker Analyses............................................................... 91
6.8
Interim Analyses .................................................................... 92
7.
DATA COLLECTION AND MANAGEMENT ............................................... 92
7.1
Data Quality Assurance......................................................... 92
7.2
Electronic Case Report Forms............................................... 92
7.3
Source Data Documentation.................................................. 93
7.4
Use of Computerized Systems .............................................. 93
7.5
Retention of Records............................................................. 94
8.
ETHICAL CONSIDERATIONS.................................................................... 94
8.1
Compliance with Laws and Regulations ................................ 94
8.2
Informed Consent.................................................................. 94
8.3
Institutional Review Board or Ethics Committee.................... 95
8.4
Confidentiality........................................................................ 96
8.5
Financial Disclosure .............................................................. 96
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 97
9.1
Study Documentation ............................................................ 97
9.2
Protocol Deviations................................................................ 97
9.3
Management of Study Quality ............................................... 97
9.4
Site Inspections ..................................................................... 97
9.5
Administrative Structure......................................................... 97
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 98
9.7
Protocol Amendments ........................................................... 99
10. REFERENCES ......................................................................................... 100
LIST OF TABLES
Table 1
Phase II Single-Agent Trials in Previously Treated Patients ....... 26
Table 2
Example Criteria for PD-L1 Expression Assessment on IC......... 29


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Table 3
Treatment-Related Adverse Events in 310 Patients who 
Received Atezolizumab in IMvigor 210 (14 September 2015 
Data Cut)..................................................................................... 34
Table 4
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 76
Table 5
Causal Attribution Guidance ....................................................... 77
Table 6
Two-Sided Clopper-Pearson 95% Confidence Intervals for 
Adverse Event Rate Estimates ................................................... 88
LIST OF FIGURES
Figure 1. 
Change in Sum of the Diameters Over Time by Best 
Response in the PD-L1 IC2/3 group and Overall Survival in 
PD-L1 Immune Cell Groups........................................................ 32
Figure 2
Study Schema............................................................................. 41
Figure 3
Conditions for Continuing Atezolizumab in the Presence of 
Increased Radiographic Tumor Size........................................... 68
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 105
Appendix 2
Modified Response Evaluation Criteria in Solid Tumors ........... 110
Appendix 3
Response Evaluation Criteria in Solid Tumors, Version 1.1: 
Excerpt from Original Publication.............................................. 118
Appendix 4
Patient-Reported Outcomes Instruments.................................. 130
Appendix 5
Preexisting Autoimmune (Chronic Inflammatory) Diseases ...... 135
Appendix 6
Anaphylaxis Precautions........................................................... 137
Appendix 7
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 138
Appendix 8
Non-Urothelial Tumors of the  Urinary Tract That are Eligible 
for This Study............................................................................ 139
Appendix 9
Age-Adjusted Charlson Comorbidity Index Worksheet ............. 140
Appendix 10
Corticosteroid Dose Equivalents............................................... 145
Appendix 11
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 146


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PROTOCOL ACCEPTANCE FORM
TITLE:
AN OPEN LABEL, SINGLE ARM, MULTICENTER, 
SAFETY STUDY OF ATEZOLIZUMAB IN LOCALLY 
ADVANCED OR METASTATIC UROTHELIAL OR 
NON-UROTHELIAL CARCINOMA OF THE 
URINARY TRACT
PROTOCOL NUMBER:
MO29983
VERSION NUMBER:
15
EUDRACT NUMBER:
2016-002625-11
IND NUMBER:
120827
TEST PRODUCT:
Atezolizumab (MPDL3280A; RO5541267)
MEDICAL MONITOR:
Dr. 
SPONSOR:
PHASE:
F. Hoffmann-La Roche Ltd
IIIB
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by your local study monitor to the contact provided below.
(Name) 
(Address)


Atezolizumab—F. Hoffmann-La Roche Ltd
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PROTOCOL SYNOPSIS
TITLE:
AN OPEN LABEL, SINGLE ARM, MULTICENTRE, SAFETY STUDY 
OF ATEZOLIZUMAB IN LOCALLY ADVANCED OR METASTATIC 
UROTHELIAL OR NON-UROTHELIAL CARCINOMA OF THE 
URINARY TRACT
PROTOCOL NUMBER:
MO29983
VERSION NUMBER:
15
EUDRACT NUMBER:
2016-002625-11
IND NUMBER:
120827
TEST PRODUCT:
Atezolizumab (MPDL3280A; RO5541267)
PHASE:
IIIB
INDICATION:
Advanced or metastatic urothelial or non-urothelial carcinoma of the 
urinary tract
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study is being conducted to evaluate the safety of atezolizumab as second-line treatment 
for locally advanced or metastatic urothelial or non-urothelial carcinoma of the urinary tract.  The 
study will also evaluate treatment efficacy and explore potential tumor biomarkers related to 
atezolizumab.  Specific objectives and corresponding endpoints for the study are outlined 
below.
Primary Objective
The primary objective of this study is to evaluate the safety of atezolizumab based on the 
following endpoints:

Nature, severity, duration, frequency and timing of adverse events (AEs)

Changes in vital signs, physical findings, and clinical laboratory results during and following 
atezolizumab administration
Secondary Objectives
The secondary objectives of the study include evaluation of the efficacy of atezolizumab based 
on the following disease response endpoints:

Overall survival (OS), defined as the time from initiation of study treatment to death from 
any cause

Progression-free survival (PFS), defined as the time from initiation of study treatment to the 
first occurrence of disease progression or death from any cause, whichever occurs first.  
PFS will be calculated based on disease status evaluated by the investigator according to 
RECIST v1.1, and also by disease status evaluated by the investigator according to 
modified RECIST

Overall response rate (ORR), defined as the proportion of patients with a best overall 
response of either complete response (CR) or partial response (PR).  ORR will be 
calculated based on disease status evaluated by the investigator according to RECIST 
v1.1, and also by disease status evaluated by the investigator according to modified 
RECIST


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
Disease control rate (DCR), defined as the sum of the CR, PR and stable disease (SD) 
rates.  DCR will be calculated based on disease status evaluated by the investigator 
according to RECIST v1.1, and also by disease status evaluated by the investigator 
according to modified RECIST

Duration of response (DoR), defined as the time from first occurrence of a documented 
response to disease progression or death from any cause, whichever occurs first.  Duration 
of response will be calculated based on disease status evaluated by the investigator 
according to RECIST v1.1, and also by disease status evaluated by the investigator 
according to modified RECIST
Additional secondary study objectives include the evaluation of efficacy of atezolizumab 
according to the following patient-reported outcomes (PROs; Appendix 4):

Change from baseline in health-related quality of life (HRQoL), as assessed using the 
EORTC Quality-of-Life Questionnaire Core 30 (QLQ-C30)

EuroQol EQ-5D-5L-assessed utility
Exploratory Objectives
Exploratory study objectives may include evaluations of atezolizumab efficacy according to 
additional efficacy endpoints.
Biomarker Objectives
The biomarker objectives of the study are as follows:

To evaluate PD-L1 prevalence based on retrospective evaluation of PD-L1 expression in 
tumor tissue measured by IHC.  PD-L1 testing may be conducted on a subset of samples at 
local laboratories for inter-laboratory concordance evaluation 

The study also includes exploratory biomarker objectives to examine centrally assessed 
biomarkers and biomarker profiles in tumor tissue, and to correlate these with safety and/or 
efficacy outcomes.  Biomarkers and biomarker profiles may be assessed using various 
methodologies including, but not limited to, IHC (single and multiplex, e.g., PD-L1 
expression and immune cell infiltration analyses), RNA and DNA analysis (e.g., mutation 
and expression analyses)
Study Design
Description of Study
Study MO29983 is an open label, single-arm, multicenter study of the safety of atezolizumab as 
second-line treatment for patients with locally advanced or metastatic urothelial or non-urothelial 
carcinoma of the urinary tract.  The study includes evaluation of the efficacy of atezolizumab 
and potential tumor biomarkers associated with atezolizumab.  An overview of study design is 
shown in the Synopsis Figure.
Study screening will take place within 28 days prior to initiation of study treatment.  Eligible 
patients will be enrolled and begin treatment with 1200 mg atezolizumab IV every 3 weeks.  The 
single agent study treatment will continue until investigator-assessed loss of clinical benefit, 
unacceptable toxicity, investigator or patient decision to withdraw from therapy, or death 
(whichever occurs first).
During the study treatment period, patients will be followed for safety based on AE assessments 
including vital signs, physical findings and clinical laboratory test results.  Efficacy will be 
evaluated by the investigator according to both RECIST v1.1 (Appendix 3) and modified 
RECIST (Appendix 2).  Exploratory biomarker analyses will be conducted based on primary 
tumor tissue or biopsied metastatic tumor tissue collected at baseline and an optional tumor 
sample collected at the second study treatment cycle.  
Following discontinuation of study treatment, safety assessments will be conducted 30 days 
after the last study drug administration or until initiation of other anti-cancer therapy (whichever 
occurs first).  Thereafter, patients will be followed for disease progression (unless this has 


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already occurred), SAEs, AEs of special interest, anti-cancer therapy and survival.  Follow-up 
will continue for up to four years after the last patient is enrolled in the study.
An iDMC established for the study will review all AEs, SAEs and AEs of special interest and 
cumulative safety data.
Synopsis Figure. Study Schema
ECOG PS, Eastern Cooperative Oncology Group performance status; MVAC, methotrexate, 
vinblastine, doxorubicin, and cisplatin; GC, gemcitabine and cisplatin.
Number of Patients
Approximately 1000 patients with locally advanced or metastatic urothelial or non-urothelial 
carcinoma of the urinary tract who progressed on one to three prior combination lines of 
systemic therapy for inoperable, locally advanced or metastatic urothelial or non-urothelial 
carcinoma of the urinary tract will be enrolled in this study.  Patients who discontinue the study 
prior to study treatment initiation will not be replaced.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:
1.
Signed informed consent form
2.
Age ≥ 18 years
3.
Is, according to the investigator’s judgment, able to comply with the study protocol 
4.
Histologically documented locally advanced (T4b, any N; or any T, N 2−3) or metastatic 
(M1, Stage IV) urothelial or non-urothelial carcinoma of the urinary tract
–
Urinary tract carcinoma includes carcinoma of the bladder, ureter, urethra, and renal 
pelvis
–
Primary non-urothelial carcinoma includes all sub-types listed in the WHO classification 
(see Appendix 8)
Bellini collecting duct tumors are allowed if independently reviewed by two expert 
pathologists from different sites
–
Lymphoma, sarcoma, and renal cell carcinoma are excluded
5.
Patients with measurable and/or non-measurable disease according to RECIST v1.1 are 
allowed


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6.
Must have progressed during or following treatment with at least one (and not more than 3) 
prior treatments for inoperable, locally advanced or metastatic urothelial or non-urothelial 
carcinoma of the urinary tract
–
Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed 
within 12 months of treatment will be considered as having a first line of treatment for 
metastatic disease
–
Patients who were intolerant to prior systemic treatment are allowed as long as they 
had received at least 2 treatment cycles
–
Platinum- or non-platinum-based chemotherapy regimens are allowed
–
Low-dose chemotherapy given as radiosensitizer for curative treatment of localized 
disease does not count as a line of systemic chemotherapy
7.
Representative formalin-fixed paraffin-embedded (FFPE) tumor specimen block available 
for submission 
–
Only tissue from core needle (with ≥ 3 cores), punch, incisional, excisional, or forceps 
biopsies will be accepted.  Fine-needle aspiration, brushing, bone tissue, and lavage 
samples are not acceptable
–
If an appropriate tumor specimen is not available, a sample will be collected by biopsy 
during the study screening period
–
ONLY at sites where local laws and regulations prohibit the sending of tumor specimen 
blocks to an outside central laboratory, specimen slides are acceptable.  A minimum of 
15 unstained serially-cut sections must be prepared and sent per tumor sample.  For 
details, please refer to the Sample Handling Manual
8.
Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1 or 2
9.
Life expectancy ≥ 12 weeks
10. Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 2 weeks prior to the first study treatment:
–
Absolute neutrophil count ≥ 1500 cells/µL (without granulocyte colony-stimulating 
factor support within 2 weeks prior to the first study treatment)
–
White blood cell count > 2500/µL
–
Lymphocyte count ≥ 500/µL
–
Platelet count ≥ 100,000/µL (without transfusion within 2 weeks prior to the first study 
treatment)
–
Hemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic treatment 
to meet this criterion)
–
Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase 
≤ 2.5 times the upper limit of normal (ULN), with the following exceptions:
Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN
Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 × 
ULN
–
Serum bilirubin ≤ 1.5 ×ULN. Patients with known Gilbert disease who have serum 
bilirubin level ≤ 3 × ULN may be enrolled
–
Calculated creatinine clearance ≥ 15 mL/min (Cockcroft-Gault formula)
–
International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 
1.5 ×ULN.  This applies only to patients who are not receiving therapeutic 
anticoagulation; patients receiving therapeutic anticoagulation must be on a stable 
dose
11. Patients with treated, asymptomatic central nervous system (CNS) metastases are eligible, 
provided they meet all of the following criteria: 
–
Evaluable disease outside the CNS 


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–
No history of intracranial or spinal cord hemorrhage 
–
No evidence of significant vasogenic edema 
–
No stereotactic radiation within 7 days or whole-brain radiation or neurosurgical 
resection within 2 weeks before the start of study treatment 
–
Have had a screening CNS radiography ≥2 weeks since completion of radiotherapy or 
surgical resection 
–
Radiographic demonstration of interim stability (i.e. no progression) between the 
completion of CNS-directed therapy and the screening radiographic study 
Note: Patients on stable doses of anticonvulsants or on prednisone doses (or dose 
equivalents) of ≤ 20 mg/day are allowed 
12. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of 1% 
per year during the treatment period and for at least 5 months after the last dose of 
atezolizumab
–
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 
(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 trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
1.
Treatment with more than three prior lines of systemic therapy for inoperable, locally 
advanced or metastatic urothelial or non-urothelial carcinoma of the urinary tract
2.
Treatment with any other investigational agent or participation in another clinical trial with 
therapeutic intent within 4 weeks prior to study treatment initiation
–
Patients who were in another clinical trial with therapeutic intent within 4 weeks of 
study treatment initiation but were not on active drug in that prior trial are eligible
–
Patients who were in another clinical trial with therapeutic intent within 4 weeks of 
study treatment initiation but were in the follow-up phase of that prior trial and had 
stopped receiving active drug 4 or more weeks before study treatment initiation are 
eligible
3.
Treatment with chemotherapy within 2 weeks prior to study treatment initiation
4.
Treatment with radiotherapy ongoing at the time of study entry (for CNS-directed 
radiotherapy, please refer to Inclusion Criterion 11) 
5.
Pregnant or lactating, or intending to become pregnant during the study
–
Women who are not postmenopausal (postmenopausal defined as ≥ 12 months of 
non-therapy-induced amenorrhea) or surgically sterile must have a negative serum 
pregnancy test result within 2 weeks prior to initiation of study drug
6.
Evidence of significant uncontrolled concomitant disease that could affect compliance with 
the protocol, including significant liver disease (such as cirrhosis, uncontrolled major seizure 
disorder, or superior vena cava syndrome)


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7.
Malignancies other than the one studied in this protocol within 5 years prior to 
Cycle 1, Day 1
–
Patients with localized low risk prostate cancer (defined as Stage ≤ pT2b, Gleason 
score ≤ 7, and prostate-specific antigen [PSA] at prostate cancer diagnosis 
≤20 ng/mL) treated with curative intent and without PSA recurrence are eligible
–
Patients with pre-existing low risk prostate cancer (defined as Stage T1/T2a, Gleason 
score ≤ 6, and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active 
surveillance are eligible
–
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of 
metastasis or death < 5% at 5 years) are eligible provided they meet all of the following 
criteria:
Malignancy treated with expected curative intent (such as adequately treated 
carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal 
carcinoma in situ treated surgically with curative intent)
No evidence of recurrence or metastasis by follow-up imaging and any disease-
specific tumor markers
8.
Significant cardiovascular disease, such as New York Heart Association cardiac disease 
≥Class III, myocardial infarction within 3 months, unstable arrhythmias, or unstable angina
–
Patients with known coronary artery disease or left ventricular ejection fraction < 50% 
must be on a stable medical regimen that is optimized in the opinion of the treating 
physician, in consultation with a cardiologist if appropriate
9.
Significant renal disorder indicating a need for renal transplant
10. Signs or symptoms of severe infection within 2 weeks prior to initiation of study treatment, 
including but not limited to, hospitalization for complications of infection, bacteremia, or 
severe pneumonia
11. Major surgical procedure within 4 weeks prior to study treatment initiation or anticipation of 
need for a major surgical procedure during the course of the study other than for diagnosis
12. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins
13. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation
14. History of autoimmune disease (Appendix 5) are allowed if controlled and on stable 
treatment (i.e., same treatment, same dose) for the last 12 weeks, with the exception of:
–
Patients taking concurrent abatacept or belatacept treatment, unless therapy has been 
withdrawn for > 8 weeks
–
Patients with a history of serious or life threatening immune-related events
–
No more than 1 concomitant autoimmune disease at the time of study entry is allowed 
unless one of them is: 
Autoimmune-related hypothyroidism on a stable dose of thyroid replacement 
hormone 
Controlled Type I diabetes mellitus on a stable dose of insulin regimen
A medical history of such entities as atopic disease or childhood arthralgias, 
where the clinical suspicion of autoimmune disease is low.  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)
Vitiligo
15. Prior allogeneic stem cell or solid organ transplantation
16. History of idiopathic pulmonary fibrosis (including pneumonitis, drug-induced pneumonitis, 
organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest computed tomography (CT) scan


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–
History of radiation pneumonitis in the radiation field (fibrosis) is permitted
17. Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen 
[HBsAg] test at screening) or hepatitis C
–
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as having a negative HBsAg test and a positive antibody to hepatitis B core antigen 
[anti-HBc] antibody test) are eligible
–
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV RNA
18. Active tuberculosis
19. Administration of a live, attenuated vaccine within 4 weeks prior to study treatment initiation
–
Influenza vaccination should be given during influenza season only (e.g., 
approximately October to March in the Northern Hemisphere and April through 
September in the Southern Hemisphere) and must not be a live, attenuated vaccine. 
–
Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 
weeks prior to study treatment initiation or at any time during the study treatment, and 
so for 5 months thereafter
20. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
anti−CTLA-4, anti−PD-1, and anti−PD-L1 therapeutic antibodies
–
Patients who have received prior treatment with anti-CTLA-4 may be enrolled provided 
at least 5 half-lives (approximately 75 days) have elapsed from the last dose of 
anti−CTLA-4 to the first dose of atezolizumab and there was no history of severe 
immune-related adverse effects from anti-CTLA-4 (NCI CTCAE Grade 3 or 4)
21. Treatment with systemic immunostimulatory agents (including, but not limited to, interferons 
or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to 
initiation of study treatment
–
Prior cancer vaccines and cellular immunotherapy are permitted
22. Specifically for patients without autoimmune disease: treatment with systemic 
corticosteroids or other systemic immunosuppressive medications (including, but not limited 
to, prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, 
thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to study treatment 
initiation or anticipated requirement for systemic immunosuppressive medications during 
the study treatment period
–
For patients with CNS metastases, use of prednisone at a dose (or dose equivalent) of 
≤ 20 mg/day is acceptable 
–
Chronic use of prednisone or equivalent should be discussed with the Medical Monitor
–
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and 
low-dose supplemental corticosteroids for adrenocortical insufficiency and topical 
steroids for cutaneous diseases are allowed.
Note: For patients with autoimmune disease, immunosuppressive medications are 
permitted if the patient has controlled autoimmune disease and stable treatment (i.e., same 
treatment, same dose) for the previous 12 weeks.
End of Study
The end of study will occur when all patients enrolled have either died, withdrawn consent, are 
lost to follow up, or have been followed for 48 months since the last study patient is enrolled, 
whichever occurs first.


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Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 6 years.
Investigational Medicinal Product
The investigational medicinal product (IMP) for this study is atezolizumab.
Statistical Methods
All qualitative data will be presented in contingency tables, using absolute and relative 
frequencies, unless otherwise stated.  Percentages will be rounded to the first decimal place, 
and therefore may not always add up to 100%.  When applicable, 95% confidence intervals (CI) 
will be presented with estimates of proportions. 
All quantitative data will be summarized via relevant descriptive statistics, such as number of 
observations with available measurements, mean, standard deviation, median, first and third 
quartiles (Q1 and Q3) when applicable, and minimum and maximum. 
Time to event data will be summarized via Kaplan-Meier (KM) estimates/curves and median 
with corresponding 95% CI.
All analyses will be performed in SAS, version 9.3.
Primary Analysis
The primary endpoint of the study is the incidence of treatment-emergent AEs.  Verbatim 
descriptions of AEs will be mapped to MedDRA thesaurus terms and graded according to the 
National Cancer Institute Common Terminology Criteria version 4.0.  Multiple occurrences of 
the same event will be counted once at the maximum severity.
Other safety variables will include:

Drug exposure (treatment duration, number of doses, dose intensity and dose 
modifications/discontinuations, with reasons)

All AEs

SAEs

AEs (grade 3–5)

AEs of special interest

AEs leading to study drug discontinuation or interruption

Changes in vital signs from baseline

Changes in physical findings from baseline

Changes in selected laboratory parameters from baseline

Deaths and cause of death

Concomitant medications
The incidence of AEs will be summarized by frequency tables.  Corresponding 95% Clopper-
Pearson confidence intervals (CIs) will be presented, as applicable.  Time to first incidence of 
selected event types will also be estimated and presented graphically using the Kaplan-Meier 
method.
Treatment exposure, discontinuation rate, and cause of death will be analyzed by frequency 
tables.  When appropriate, median time on treatment will be estimated by the Kaplan-Meier 
approach or univariate statistics, presenting mean, median, quartiles, minimum, maximum and 
standard deviation.
Changes in vital signs and physical findings from baseline will be tabulated and presented 
graphically when applicable.
Worst grades for laboratory parameters and newly occurring Grade 3 and 4 laboratory values 
during treatment will be summarized by frequency tables. 
Concomitant medications recorded during the study will be summarized by frequency tables.


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Determination of Sample Size  
This is a single-arm safety study.  There is no formal statistical hypothesis and all analyses will 
be descriptive.  The results for the primary safety variables will be presented via percentages 
and corresponding 95% Clopper-Pearson CIs.
A sample size of approximately 1000 patients is planned for this study.  The precision of rare 
AE incidence estimates presented by two-sided exact 95% Clopper-Pearson CIs are shown in 
the Synopsis Table.
Synopsis Table. Two-Sided Clopper-Pearson 95% Confidence Intervals for Adverse 
Event Rate Estimates
Number of Patients with at 
Least One Event 
(Expected)
N=1000
Expected
Event Rate
(%)
Lower limit
of CI
(%)
Upper limit
of CI 
(%)
12
1.2
0.62
2.09
10
1.0
0.48
1.83
8
0.8
0.35
1.57
6
0.6
0.22
1.3
5
0.5
0.16
1.16
4
0.4
0.11
1.02
3
0.3
0.06
0.87
2
0.2
0.02
0.72
1
0.1
0.00
0.56
CI = confidence interval.
Therefore, for a sample size of 1000 patients and an expected AE incidence of 0.5%, based on 
the half-width of the Clopper-Pearson 95% confidence interval, the true AE rate can be 
estimated with a precision of:  ±(1.16% – 0.16%)/2 % = ±0.5 %.
Interim Analyses
An Independent Data Monitoring Committee (iDMC) will conduct interim reviews of accumulated 
safety data.  The first review will be performed three months after enrollment of the first patient.  
The iDMC will then decide on the basis of the initial reviewed data when to meet the following 
time, but at minimum, the iDMC will perform another overall safety review after 500 patients 
have been followed up for 3 months.  Ad hoc iDMC review meetings may occur as needed at 
any time during the study period.  In case of important safety findings, the iDMC may also 
request to review efficacy data for an overall assessment of the risk-benefit profile to the 
patients.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ACCI
Age-adjusted Charlson comorbidity index
AE
adverse event
ADA
anti-drug antibody
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CarboGem
carboplatin and gemcitabine
CBC
complete blood count
CI
confidence interval
ClinRO
clinician-reported outcome
COPD
chronic obstructive pulmonary disease
COVID-19
Coronavirus disease 2019
CR
complete response
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
DCR
disease control rate
DoR
duration of response
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EORTC
European Organisation for the Research and 
Treatment of Cancer
Fc
crystallizable fragment
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
GC
gemcitabine and cisplatin
HBsAg
hepatitis B virus surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
Human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life


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Abbreviation
Definition
IC
tumor-infiltrating immune cells
ICH
International Conference on Harmonisation
iDMC
Independent Data Monitoring Committee
IFN
interferon
IgG1
immunoglobulin G, subclass 1
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug (application)
INR
International Normalised Ratio
IRB
Institutional Review Board
IRF
independent review facility
ITT
intent-to-treat
IV
intravenous
LDH
LHL
MAS
lactate dehydrogenase
hemophagocytic lymphohistiocytosis
macrophage activation syndrome
M-CAVI
methotrexate, carboplatin, and vincristine
MRI
magnetic resonance imaging
MVAC
methotrexate, vinblastine, doxorubicin, and cisplatin
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PD-1
programmed cell death protein 1
PD-L1
programmed death-ligand 1
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO
patient-reported outcome
PSA
prostate-specific antigen
Q1 & Q3
first and third quartiles
q3w
every 3 weeks
QLQ-30
Quality-of-Life Questionnaire Core 30
QTcF
QT interval corrected using Fridericia’s formula
RBC
red blood cell
RBR
Research Biosample Repository


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Abbreviation
Definition
RECIST
Response Evaluation Criteria in Solid Tumors
SD
stable disease
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SITC
Society for Immunotherapy for Cancer
SCC
squamous cell carcinoma
SUSAR
suspected unexpected serious adverse reaction
TC
tumor cells
TSH
thyroid stimulation hormone
UC
urothelial carcinoma of the urinary tract
ULN
upper limit of normal
WBC
white blood cell


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1.
BACKGROUND
Bladder cancer is the ninth most common cancer in the world 
(World Cancer Research Fund International 2016). In 2012, an estimated 14.1 million 
people worldwide had bladder cancer, of whom 330,380 were newly diagnosed; in the 
same year, 123,051 deaths were attributable to the disease 
(International Agency for Research on Cancer 2016; 
World Cancer Research Fund International 2016). In the United States, estimates are 
that 76,960 new cases of bladder cancer will be diagnosed in 2016 (about 58,950 in men 
and 18,010 in women), and 16,390 deaths will occur due to the disease 
(American Cancer Society 2016a).
1.1
UROTHELIAL CARCINOMA OF THE URINARY TRACT
Urothelial carcinoma of the urinary tract (UC), also termed transitional cell carcinoma, is 
the most common cancer of the urinary system, responsible for more than 90% of 
diagnosed cases in the industrialized world.  The bladder is the predominant location for 
UC, but tumors can also originate in the renal pelvis, urethra, or ureter, which are also 
lined by urothelial cells.  The 5-year relative survival rate in patients with metastatic UC 
is approximately 15%, compared to approximately 77% in a population comprising all 
stages of UC (American Cancer Society 2016b). Prognostic factors for poor survival in 
patients with metastatic UC include advanced stage of disease at the time of initial 
diagnosis, Karnofsky Performance Status < 80%, and visceral metastasis (i.e., lung, 
liver, or bone; (Bajorin et al. 1999)).  The presence of any of these unfavorable features 
was associated with a median survival of 4 months, compared with 18 months in 
patients without these features (Loehrer et al. 1992).
Patients with previously untreated UC typically receive platinum-based chemotherapy.  
The first evidence that chemotherapy produced a significant benefit in patients with 
advanced UC came in the mid-1980s with the publication of two studies showing that the 
combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) produced 
overall response rates greater than 70%, with approximately 35% of patients achieving a 
complete response (CR) (Sternberg et al. 1985; Sternberg et al. 1989). Subsequently, 
two prospective randomized Phase III trials demonstrated the superiority of MVAC with 
regard to overall survival (OS) in patients with advanced disease (Logothetis et al. 1990; 
Loehrer et al. 1992).  
In an effort to develop a less toxic regimen, the combination of gemcitabine and cisplatin 
(GC) was tested against MVAC in the Phase III setting following the demonstration of 
activity in earlier phase trials.  In the Phase III trial, patients allocated to GC had a similar 
OS to those randomized to MVAC (14.0 months for GC vs. 15.2 months for MVAC; 
hazard ratio [HR] = 1.09; 95% confidence interval (CI): 0.88, 1.34, p=0.66), with less 
Grade 3 or 4 toxicity (including neutropenia, neutropenic sepsis, and mucositis) (von der 
Maase et al. 2005).  As a result, GC has largely displaced MVAC as the standard of 
care.


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Despite the efficacy of first-line regimens for patients with advanced UC, nearly all 
patients experience disease progression and require second-line therapy. There are 
currently no approved second-line therapies for UC in the United States and only one 
approved agent, vinflunine, in the European Union.  
While several chemotherapeutic agents have been studied in the second-line setting 
over the last two decades, the overall response rates are low (see Table 1) and 
associated with considerable toxicity.  No survival benefit has been demonstrated with 
second-line chemotherapy.  Consequently, the National Comprehensive Cancer 
Network guidelines recommend participation in a clinical trial of new agents.  If no trials 
are available, treatment with a single-agent taxane is preferred for palliation.  Additional 
recommended palliative options include single-agent cisplatin, carboplatin, doxorubicin, 
ifosfamide, pemetrexed, methotrexate, and vinblastine.  European Society of Medical 
Oncology and European Association of Urology clinical practice guidelines recommend 
vinflunine, but also highlight that other agents used in this space may have similar 
benefit and recommend clinical trials of other treatments (Bellmunt et al. 2009; Stenzl et 
al. 2011).  
The registrational Phase III study of vinflunine as a second-line agent compared 
vinflunine versus best supportive care alone in 370 patients progressing after a platinum-
containing therapy.  The intent-to-treat (ITT) analysis showed an improvement in 
response rate (8.6% vs. 0%), but did not show a statistically significant OS benefit for 
vinflunine compared with placebo (6.9 vs. 4.6 months, HR=0.88; 95% CI: 0.69, 1.12; 
p=0.287).  Key toxicities included Grade 3 or 4 neutropenia (50%), febrile neutropenia 
(6%), anemia (19%), fatigue (19%), and constipation (16%). 
A summary of single-agent Phase II trials of second-line therapy is provided in Table 1.


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Table 1
Phase II Single-Agent Trials in Previously Treated Patients
Second-Line Therapy Regimen
RR 
(%)
PFS
(months)
OS
(months)
Weekly paclitaxel (n=31)
10
2.2
7.2
Nab-paclitaxel (n=47)
28
6.0
10.8
Irinotecan (n=40)
5
2.1
5.4
Ixabepilone (n=42)
11.9
2.7
8.0
Bortezomib (n=25)
0
1.4
5.7
Pemetrexed (n=47)
27.7
2.9
9.6
Oxaliplatin (n=18)
6
1.5
7.0
Ifosfamide (n=56)
20
2.4
5.5
Lapatinib (n=59)
3
2
4.5
Pemetrexed (n=12)
8
⎯
⎯
Docetaxel (n=30)
13
⎯
9.0
Gemcitabine (n=35)
11
4.9
8.7
Gemcitabine (n=44)
22.5
⎯
5.0
Topotecan (n=44)
9.1
1.5
6.3
Ifosfamide+ gemcitabine (n=34)
21
4.0
9.0
Carboplatin + paclitaxel (n=44)
16
4.0
6.0
Vinflunine (n=51)
18
3.0
6.6
Vinflunine (n=253)
8.6
3.0
6.9
Gefitinib (n=31)
3
⎯
3.0
Sorafenib (n=27)
0
⎯
6.8
Sunitinib (n=45)
7
2.4
6.9
Pazopanib (n=41)
17.1
2.6
4.7
OS = overall survival; PFS = progression-free survival; RR = response rate.
Note: Adapted from (Sonpavde et al. 2010).
1.2
NON-UROTHELIAL CANCER OF THE URINARY TRACT
Several non-urothelial subtypes of bladder cancer are also observed in the clinic, 
including squamous cell carcinoma (SCC) (1%–2% of all cases), adenocarcinoma (1% 
of all cases), small cell carcinoma (< 1% of all cases), and other rarer forms 
(American Cancer Society 2016a).  Non-urothelial bladder cancer is more common in 
non-Western areas of the world (Chalasani et al. 2009).  The prognosis for most forms of 
advanced non-urothelial bladder cancer is poor, but few clinical trials have specifically 
focused on treatment of these specific populations (Sternberg and Swanson 1997; Abol-
Enein et al. 2007).


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Squamous Cell Carcinoma
Squamous cell carcinoma (SCC) of the urinary tract has a poor prognosis, with most 
patients dying within 1 to 3 years of diagnosis (Abol-Enein et al. 2007; Chalasani et al. 
2009).  The overall 5-year survival rate is estimated to be approximately 16%, with only 
8% of patients developing metastatic disease.  
Reported results on the effectiveness of external irradiation have been uniformly poor 
(Bessette et al. 1974; Rundle et al. 1982), but surgical treatment appears to provide 
better outcomes (Richie et al. 1976; Swanson et al. 1990; Stenzl et al. 2001; Nishiyama 
et al. 2004).  The role of neoadjuvant or adjuvant chemotherapy in the treatment of 
patients with pure SCC of the urinary tract is uncertain (Abol-Enein et al. 2007).  Data 
from clinical trials on the effectiveness of chemotherapy in advanced SCC of the urinary 
tract, particularly following its recurrence after doublet chemotherapy or MVAC, is 
limited.
Adenocarcinoma
Primary adenocarcinoma of the urinary tract has a poor prognosis, regardless of the 
modalities used for treatment (Abol-Enein et al. 2007; Chalasani et al. 2009).  The 5-
year survival rates range from 0% to 31%.  In a retrospective series of 48 patients 
treated for primary adenocarcinoma of the bladder, stage was the only factor that was
highly predictive of outcome.
Adenocarcinoma is not a radioresponsive disease: reported 5-year survival is <20% in 
patients treated with external irradiation alone (Abol-Enein et al. 2007).  Radical 
cystectomy with or without adjuvant therapy has been examined by several authors.  
Most published reports are based on few patients and involve short-term follow-up.  
Reported 5-year disease-free survival rates range from 0% to 80% (Abol-Enein et al. 
2007).
Experience in the use of chemotherapy for the treatment of patients with 
adenocarcinoma of the urinary tract is limited.  From results observed with 
gastrointestinal adenocarcinoma, combination chemotherapy based on 5-fluorouracil 
and cisplatin has been attempted by several investigators.  Most published series 
involve small numbers, and the response is universally unsatisfactory (Nevin et al. 1974; 
Nocks et al. 1983; Logothetis et al. 1985).
Small Cell Carcinoma
The small number of reports on patients with small cell carcinoma of the urinary tract
suggests that it behaves similarly to small cell carcinoma of the lung (Abol-Enein et al. 
2007).  Overall, local treatment yields poor survival rates, and systemic therapy provides 
improvement.  In general, however, treatment of small cell carcinoma of the urinary tract 
has received relatively limited examination in clinical trials.


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1.3
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 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, triple-negative breast cancer, hepatocellular 
carcinoma, and melanoma.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies.
1.3.1
PD-L1 Expression as a Biomarker 
In an increasing number of studies, expression of PD-L1 has been associated with poor 
prognosis in UC:

Nakanishi et al. found that PD-L1 expression was significantly associated with a 
high frequency of disease recurrence and poor survival rate in UC (Nakanishi et al. 
2007).  Multivariate analysis also showed PD-L1 expression to be a more significant 
prognostic factor than tumor grade

Zhang et al. observed PD-L1 expression in 43% of primary bladder cancers and 
demonstrated that immunohistochemistry (IHC) positivity and intensity was 
associated with tumor grade and staging (Zhang et al. 2013)

Faraj et al. showed high intratumoral CD8+ T cell density to be associated with 
better OS and disease-specific survival in advanced bladder cancer (Faraj et al. 
2015)

Bellmunt et al. reported that PD-L1 is widely expressed on tumor cells and tumor-
infiltrating mononuclear cells in urothelial cancers (Bellmunt et al. 2015).  PD-L1 
expression on tumor cells was not predictive of overall OS, but PD-L1 expression on 
tumor-infiltrating mononuclear cells did associate with longer survival in patients 
who developed metastases


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The SP142 PD-L1 immunohistochemistry (IHC) assay (Investigational Use Only; 
Ventana Companion Diagnostics Pharma Services, Tucson, AZ) is one assay that is 
used to assess PD-L1 expression in tumors.  This specific and sensitive assay has been 
designed to quantify PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune 
cells (IC) in human formalin-fixed, paraffin-embedded (FFPE) tumor-tissue samples, 
utilizing the SP142 rabbit monoclonal antibody as primary antibody in the staining 
reaction (Herbst et al. 2014).  Additional anti-PD-L1 antibodies, including but not limited 
to SP263, are under investigation for PD-L1 assessment.  
As the expression level of PD-L1 on urothelial TC has not been correlated with OS (see, 
e.g., (Bellmunt et al. 2015)) the SP142 PD-L1 IHC assay is currently used in UC patients 
solely to quantitate PD-L1 positivity on IC.  The IHC-based scoring criteria for PD-L1 
expression are presented in Table 2.  
Table 2
Example Criteria for PD-L1 Expression Assessment on IC
Description of IHC Scoring Criteria
PD-L1 
Expression 
Level
Absence of any discernible PD-L1 staining OR presence of discernible PD-L1 
staining of any intensity in ICs covering < 1% of tumor area occupied by tumor 
cells, associated intratumoral, and contiguous peri-tumoral desmoplastic 
stroma
IC0
Presence of discernible PD-L1 staining of any intensity in ICs covering between 
≥ 1% and < 5% of tumor area occupied by tumor cells, associated intratumoral, 
and contiguous peri-tumoral desmoplastic stroma
IC1
Presence of discernible PD-L1 staining of any intensity in ICs covering between 
≥ 5% and < 10% of tumor area occupied by tumor cells, associated 
intratumoral, and contiguous peri-tumoral desmoplastic stroma
IC2
Presence of discernible PD-L1 staining of any intensity in ICs covering ≥ 10% 
of tumor area occupied by tumor cells, associated intratumoral, and contiguous 
peri-tumoral desmoplastic stroma
IC3
IC = tumor-infiltrating immune cell; IHC = immunohistochemistry; PD-L1 = programmed death-
ligand 1.
Note: Cutoffs for PD-L1 positivity are being evaluated in ongoing trials.
The relationship between PD-L1 expression on IC and atezolizumab efficacy in patients 
with UC is presented below (Section 1.3.3).  
1.3.2
Clinical Development Program
Four ongoing studies are currently examining the efficacy and safety of atezolizumab in 
advanced UC, either as monotherapy or in combination with other agents.  


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Phase Ia Study PCD4989g
Ongoing Study PCD4989g is a multicenter, first-in-human, open-label, dose-escalation 
study evaluating the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of biologic activity of atezolizumab 
administered as a single agent by intravenous (IV) infusion every 3 weeks (q3w) to 
patients with locally-advanced or metastatic solid malignancies or hematologic 
malignancies.  Ongoing expansion cohorts are studying the efficacy in patients with 
pancreatic cancer, bladder cancer, breast cancer, esophageal cancer, prostate cancer, 
small cell lung cancer, malignant lymphoma, multiple myeloma, and other less common 
tumor types.
As of 2 December 2014, efficacy analyses were performed on 87 patients with locally 
advanced or metastatic UC who were followed up for a minimum of 12 weeks.  
Responses were observed in all PD-L1 subgroups (ranging from 13.3% to 66.7%), with 
higher objective response rates (ORRs) associated with higher PD-L1 expression on IC.
Phase II Study GO29293 (IMvigor 210)
Ongoing Study GO29293 (IMvigor 210) is a single-arm, open label, Phase II study to 
assess the clinical benefit of atezolizumab as a single agent in patients with locally 
advanced or metastatic UC.  The co-primary endpoints were independent review facility 
(IRF)-assessed ORR according to Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) and investigator-assessed ORR according to modified 
RECIST criteria.  Approximately 400 patients have been enrolled into two separate 
cohorts: approximately 100 with advanced disease who are treatment-naive but cisplatin 
ineligible (Cohort 1); and 311 who progressed on prior platinum-based chemotherapy 
(Cohort 2).  Results from Cohort 2 were recently published (Rosenberg et al. 2016) and 
will be described in detail below ( Section 1.3.3). 
Phase III Study GO29294 (IMvigor 211)
Ongoing Study GO29294 (IMvigor 211) is a two-arm, open label, randomized, Phase III 
study to assess the efficacy and safety of atezolizumab compared with chemotherapy 
(vinflunine, paclitaxel, or docetaxel) in patients with locally advanced or metastatic UC 
who have progressed after previous platinum-based chemotherapy.  The primary 
endpoint of the study is investigator-assessed OS, defined as the time between the date 
of randomization and death due to any cause.
Phase III Study WO30070
Ongoing Study WO30070 is a Phase III, multicenter, randomized, placebo-controlled, 
double-blind study to evaluate the safety and efficacy of atezolizumab/gemcitabine/ 
carboplatin versus placebo/gemcitabine/carboplatin in patients with locally advanced or 
metastatic UC who have not received prior systemic therapy and who are ineligible to 
receive cisplatin-based therapy.  The co-primary endpoints of the study are PFS and 
OS.


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Please refer to the Atezolizumab Investigator’s Brochure for more details regarding 
atezolizumab clinical studies.
1.3.3
Efficacy
IMvigor 210 (Study GO29293) is a single-arm, open-label, Phase II study to assess the 
clinical benefit of atezolizumab as a single agent in patients with locally advanced or 
metastatic UC.  The co-primary endpoints of the study were IRF-assessed ORR 
according to RECIST v1.1 and investigator-assessed ORR according to modified 
RECIST criteria.  Results from Cohort 2, which contained patients whose disease had 
progressed after previous platinum-based chemotherapy (see Section 1.3.2), were 
recently published (Rosenberg et al. 2016). 
Between 13 May 2014, and 19 Nov 2014, 486 patients were screened and 316 patients 
were enrolled into IMvigor 210.  Of these, 311 patients received atezolizumab treatment 
(five enrolled patients later did not meet eligibility criteria and were not dosed with study 
drug).  
The primary analysis (data cutoff 05 May 2015) showed that treatment with 
atezolizumab resulted in significantly improved ORR for each pre-specified immune cell 
group when compared with a historical control ORR of 10% (IC2/3: 27% [95% CI 19–
37%], p<0.0001; IC1/2/3: 18% [13–24%], p=0.0004).  The same was true for the entire 
population of patients (15% [11–20], p=0.0058).  With longer follow-up by independent 
review (data cutoff 14 September 2015), ORRs were 26% (95% CI 18–36%) in the IC2/3 
group, 18% (13–24%) in the IC1/2/3 group, and 15% (11–19%) overall in all 310 
patients. Ongoing responses were recorded in 38 (84%) of 45 responders after a median 
follow-up of 11.7 months (95% CI 11.4–12.2 months). 
Further details of the response to atezolizumab in IMvigor 210 are presented in Figure 1.


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Figure 1. Change in Sum of the Diameters Over Time by Best Response in 
the PD-L1 IC2/3 group and Overall Survival in PD-L1 Immune Cell 
Groups
IC = immune cell
Note: The above figure presents the percentage change in the sum of longest diameters by 
IRF-assessed RECIST v1.1 in the IC2/3 group by (A) responders, (B) patients with stable 
disease, and (C) patients with progressive disease. Patients without a measurable 
baseline tumor assessment or without post-baseline tumor measurements were not included. 
(D) Kaplan-Meier overall survival curves for the IC0, IC1, and IC2/3 groups.
1.3.4
Safety 
Safety information for atezolizumab has been gleaned from studies across the entire 
development program, including those where atezolizumab is investigated in 
combination with other unapproved agents.  As of May 2016, atezolizumab has been 
administered to approximately 6050 patients with solid tumors and hematologic 
malignancies.
Study PCD4989g, in which atezolizumab is being used as a single agent in patients with 
locally advanced or metastatic solid tumors or hematologic malignancies, provides the 


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majority of data (with 558 safety evaluable patients as of the data extraction date of 
11 May 2015) for the safety profile of atezolizumab as monotherapy.  Currently, no 
maximum tolerated dose, no dose-limiting toxicities and no clear dose-related trends in 
the incidence of adverse events (AEs) have been determined.  Fatigue, decreased 
appetite, nausea and cough were commonly reported adverse events in single and 
combination therapy.  The overall immune-mediated adverse events reported for 
atezolizumab were considered mild to moderate in severity, and the majority of patients 
were able to continue on atezolizumab therapy.
Adverse Events
In PCD4989g of the 558 safety evaluable treated patients 376 patients (67.4%) reported 
at least one treatment-related adverse event, Grade 34 AEs were reported in 239 
patients (42.8%) of which 66 (11.8%) were considered related.  Grade 3 and 4 AEs 
considered related by the investigator included dyspnea, pneumonitis, increased alanine 
aminotransferase (ALT), increased aspartate aminotransferase (AST), increased 
gamma-glutamyl transferase (GGT), lymphocyte count decreased, cardiac tamponade, 
asthenia, autoimmune hepatitis, pneumonia, influenza, and hypoxia.  More detailed 
information is provided in the latest version of the IB.
Immune-mediated Adverse Events
Given the mechanism of action of atezolizumab, events associated with inflammation 
and/or immune-mediated adverse events have been closely monitored during the 
atezolizumab clinical program.  These include potential dermatologic, hepatic, endocrine 
and respiratory events.  Events of immune-mediated hepatitis, pneumonitis, colitis, 
pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, 
Guillain-Barré syndrome, myasthenic syndrome/myasthenia gravis, meningoencephalitis 
and infusion-related reactions are considered potential adverse drug reactions 
associated with atezolizumab.
IMvigor 210 (Cohort 2)
The median duration of treatment in IMvigor 210 was 12 weeks (range 0–66 weeks) at 
the study’s cutoff date (14 September 2015).  All-cause, any grade AEs were reported in 
300 (97%) of 310 patients, with 170 (55%) patients experiencing a grade 3–4 AE.  Two-
hundred fifteen (69%) patients had a treatment-related AE of any grade, and 50 (16%) 
had a grade 3–4 treatment-related AE (Table 3).


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Table 3
Treatment-Related Adverse Events in 310 Patients who Received 
Atezolizumab in IMvigor 210 (14 September 2015 Data Cut)
Any grade
n (%)
Grade 3–4
n (%)
Any adverse event
215 (69%)
50 (16%)
Fatigue
93 (30%)
5 (2%)
Nausea
42 (14%)
0
Decreased appetite
36 (12%)
2 (1%)
Pruritis
31 (10%)
1 (<1%)
Pyrexia
28 (9%)
1 (<1%)
Diarrhea
24 (8%)
1 (<1%)
Rash
23 (7%)
1 (<1%)
Arthralgia
21 (7%)
2 (1%)
Vomiting
18 (6%)
1 (<1%)
Dyspnea
10 (3%)
2 (1%)
Anaemia
9 (3%)
3 (1%)
Aspartate aminotransferase increased
10 (3%)
2 (1%)
Pneumonitis
7 (2%)
2 (1%)
Hypotension
5 (2%)
2 (1%)
Hypertension
3 (1%)
3 (1%)
Colitis
3 (1%)
2 (1%)
Adverse events reported up until data cutoff on 14 September 2015
Ninety-three (30%) patients had an AE leading to dose interruption, and 11 (4%) had an 
AE that led to treatment withdrawal.  Treatment-related serious adverse events (SAEs) 
were reported in 34 (11%) of 310 patients.  No cases of febrile neutropenia were 
reported, and no treatment-related deaths occurred during the study. 
Twenty (6%) patients had an immune-mediated AE of any grade, with pneumonitis (n=5 
[2%]), dyspnea (n=3 [1%]) and increased aspartate aminotransferase (n=3 [1%]) being 
the most common.  Thirteen (4%) patients had a grade 3–4 immune-mediated AE of any 
cause, including colitis, autoimmune hepatitis, hepatitis, cytokine release syndrome, 
pericardial effusion, and paraplegia (n=1 for each).  No immune-mediated renal toxicity 
was observed.  Sixty-nine (22%) of 310 patients had an AE that necessitated systemic 
steroid use.
Please refer to the Atezolizumab Investigator’s Brochure for more information on the 
safety of atezolizumab across the clinical development program, including the 
occurrence of serious, related and unexpected events.


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1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
In clinical trials, treatment with atezolizumab has produced positive clinical responses in 
multiple cancer types (see Atezolizumab Investigator’s Brochure).  
In the case of UC, the benefit-risk profile of atezolizumab treatment compared to 
historical controls has been favorable in patients with advanced stage UC who had 
progressed during or following treatment with a platinum-based chemotherapy regimen 
or were cisplatin-ineligible.  Thus, in the IMvigor 210 study, treatment of 310 previously-
treated, advanced UC patients with atezolizumab resulted in statistically significant 
improvements in RECIST v1.1 ORR compared to historical controls in two pre-specified 
immune cell groups (IC2/3 and IC1/2/3), as well as in the entire study population 
(Rosenberg et al. 2016).  Moreover, the safety profile of atezolizumab was manageable.  
Thus, most treatment-related AEs were mild to moderate in nature, with fatigue, nausea, 
decreased appetite, pruritus, pyrexia, diarrhea, rash, and arthralgia among the most 
common any-grade AEs.  Twenty (6%) patients had an immune-mediated AE of any 
grade, no cases of febrile neutropenia were reported, and no renal toxicity was 
observed.  The preceding results indicate that atezolizumab will likely provide an 
important new treatment modality for advanced UC in the future, a prospect that is under 
active investigation in ongoing clinical trials.  
Appropriate to their early stage in the clinical development plan, prior atezolizumab UC 
studies have had stringent enrollment criteria.  In part this was done to ensure optimal 
safety conditions for the participants, i.e., to screen out participants with greater 
morbidity who might have been less tolerant of atezolizumab or more susceptible to AEs 
arising during the course of the study.  For example:

Participants were typically required to have an ECOG performance status of 0 or 1, 
meaning their disease at baseline imparted relatively limited impact on daily living 
abilities (ECOG performance statuses of 2 were allowed in some cohorts of earlier 
studies)

Participants were prohibited from having an autoimmune disease.  Treatment of 
autoimmune diseases typically requires immunosuppressive therapies, the effects of 
which remain uncharacterized, vis-à-vis, atezolizumab immunotherapy.  It is also 
imperfectly understood how checkpoint inhibition with atezolizumab may impact 
symptoms and progression of autoimmune diseases.  For similar reasons, 
participants in prior studies were required to have disease that did not require 
treatment with systemic corticosteroids and/or other systemic immunosuppressive 
medications

Participants were not allowed to have severely reduced kidney function (i.e., 
glomerular filtration rate ≤30 mL/min), a condition associated with poor health in 
general and a potentially increased risk of immune-mediated renal toxicity

Participants were not allowed to be positive for HIV 


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Because cancer of the urinary tract is a heterogeneous disease (Kaufman et al. 2009), 
earlier atezolizumab studies were also restricted to relatively specific classes of patients, 
thereby limiting the number of additional factors that could complicate the final analyses.  
For example:

Participants were only enrolled with advanced urothelial carcinoma.  This restriction 
was easily tenable based on the fact that > 90% of bladder cancer cases have a 
urothelial histology (American Cancer Society 2016a), ensuring that the majority of 
clinical cases were being addressed in the trials

Participants were required to have advanced on platinum-doublet therapy prior to 
entering the studies.  This again made sense since platinum-doublet is standard 
first-line treatment of advanced UC (Bellmunt et al. 2014) and, thus, the majority of 
clinical cases should have been eligible for the study

Finally, participants were prohibited from enrolling with CNS metastases, except in 
some highly defined situations if the metastases were asymptomatic.  Although rare, 
CNS metastases in bladder cancer appear to be increasing in incidence and are 
associated with significant health burden and poor outcomes (Dhote et al. 1998; 
Protzel et al. 2002; Boyle et al. 2013; Chung et al. 2013).  From both a safety 
perspective and a scientific perspective (e.g., the role of the blood-brain barrier in 
antibody drug delivery), inclusion of this class of patients in earlier atezolizumab 
trials was deemed premature
Given the high unmet need for new therapies for advanced bladder cancer, it is of 
considerable interest to evaluate atezolizumab in a population of bladder cancer patients 
that mimics more closely a standard clinical population.  As a first step in this process, 
the primary objective of Study MO29983 will be to analyze the safety of atezolizumab in 
a population of bladder cancer patients that includes patients who would have been 
screened out of many of the previous studies.  The large majority of eligibility criteria in 
Study MO29983 remain unchanged from earlier trials and the safety of participants 
remains the highest priority.  However, a small number of criteria have been broadened:

Patients with a baseline ECOG performance status of 2 will now be eligible for 
enrollment, in addition to patients with ECOG performance statuses of 0 and 1

CNS metastases will be allowed at baseline, if stable

Patients with a renal clearance of ≥ 15 mL/min (rather than ≥ 30 mL/min) and/or a 
history of renal failure will be allowed in the study

Prior treatment with non-platinum regimens will be allowed

Patients with CNS metastases will be allowed to receive steroid treatments if the 
dose of prednisone is ≤ 20 mg/day (or equivalent)

Patients with underlying controlled and stable autoimmune diseases will be allowed

Patients with non-urothelial carcinoma of the urinary tract will be permitted to enroll 
in the trial


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
Patients with HIV will be eligible, based on evidence suggesting that the 
PD-L1/PD-1 pathway may be operative in HIV infection and that PD-L1/PD-1 
inhibition may have a role in reducing viral load
In addition to assessing safety, the current study will have secondary objectives to 
assess response and patient-reported outcomes, which will further advance the 
understanding of atezolizumab therapy in patients with cancer of the urinary tract.  
Finally, in exploratory analyses, the study will assess PD-L1 prevalence in tumor tissue 
using an IHC assay and will correlate a panel of biomarkers with efficacy and safety 
outcomes.  These studies will continue to expand our understanding of atezolizumab 
and lay the groundwork for future clinical trials.
For additional rationale statements explaining the current study design, please refer to 
Section 3.3.
Several steps will be taken to ensure the safety of participants in MO29983.  First, 
administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies 
(Section 4.3.1).  Second, identified and potential risks associated with atezolizumab 
treatment will continue to be closely monitored throughout this study ( Section 5.1.1).  
Third, the study will have an independent data monitoring committee (iDMC) to assess 
safety signals on an ongoing basis.  Finally, the study contains protocol-specified drug 
interruption criteria designed to ensure safety (Section 5.1.2).  
Overall, the efficacy and safety data in ongoing studies have shown a favorable 
benefit/risk ratio for atezolizumab treatment in patients with bladder cancer.  With the 
above safety precautions in place, the estimated benefits of atezolizumab treatment 
outweigh the risks in this study, especially given the potential of atezolizumab—and the 
dearth of effective therapeutic agents currently available—in patients who have 
advanced urothelial and non-urothelial carcinoma of the urinary tract.
COVID-19 Benefit–Risk Assessment
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable population, 
with the potential for more severe clinical outcomes from severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear whether or 
how systemic cancer therapies such as chemotherapy, targeted therapy, or 
immunotherapy impact the incidence or severity of SARS-CoV-2 infection.
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 


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(Clone 13) (Frebel et al. 2012).  However, there are insufficient and inconsistent clinical 
data to assess if outcome from SARS-CoV-2 infection is altered by cancer 
immunotherapy.
Severe SARS-CoV-2 infection appears to be associated with a cytokine-release 
syndrome (CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
interferon-(IFN)-(Merad and Martin 2020).  While it is not known, there may be a 
potential for an increased risk of an enhanced inflammatory response if a patient 
develops acute SARS-CoV-2 infection while receiving atezolizumab.  At this time, there 
is insufficient evidence for causal association between atezolizumab and an increased 
risk of severe outcomes from SARS-CoV-2 infection.
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 
features for SARS-CoV-2 infection related interstitial pneumonia.  Thus, investigators 
should use their clinical judgment when evaluating and managing patients with 
pulmonary symptoms.
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination 
(Society for Immunotherapy of Cancer [SITC] 2020).
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended 
for all patients with cancer receiving active therapy (including immune checkpoint 
inhibitors), with the understanding that there are limited safety and efficacy data in 
such patients (NCCN 2021).  Given the lack of clinical data, currently no 
recommendations can be made regarding the optimal sequence of COVID-19
vaccination in patients who are receiving cancer immunotherapy (SITC 2020).  For 
patients enrolling in this study and receiving atezolizumab treatment, a decision to 
administer the vaccine to a patient should be made on an individual basis by the 
investigator in consultation with the patient.
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab treatment to receive 
COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection and 
potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region.
SITC and NCCN recommendations along with institutional guidelines should be used 
by the investigator when deciding on administering COVID-19 vaccines.  When 


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administered, COVID-19 vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a concomitant 
medication and should be documented as such (see Section 4.4.1). 
2.
OBJECTIVES AND ENDPOINTS
This study is being conducted to evaluate the safety of atezolizumab as second-line 
treatment for locally advanced or metastatic urothelial or non-urothelial carcinoma of the 
urinary tract.  The study will also evaluate treatment efficacy and explore potential tumor 
biomarkers related to atezolizumab.  Specific objectives and corresponding endpoints for 
the study are outlined below.
2.1
PRIMARY OBJECTIVE
The primary objective of this study is to evaluate the safety of atezolizumab based on 
the following endpoints:

Nature, severity, duration, frequency and timing of adverse events (AEs)

Changes in vital signs, physical findings, and clinical laboratory results during and 
following atezolizumab administration
2.2
SECONDARY OBJECTIVES
The secondary objectives of the study include evaluation of the efficacy of atezolizumab 
based on the following disease response endpoints:

Overall survival (OS), defined as the time from initiation of study treatment to death 
from any cause

Progression-free survival (PFS), defined as the time from initiation of study 
treatment to the first occurrence of disease progression or death from any cause, 
whichever occurs first.  PFS will be calculated based on disease status evaluated by 
the investigator according to RECIST v1.1, and also by disease status evaluated by 
the investigator according to modified RECIST

Overall response rate (ORR), defined as the proportion of patients with a best 
overall response of either complete response (CR) or partial response (PR).  ORR 
will be calculated based on disease status evaluated by the investigator according 
to RECIST v1.1, and also by disease status evaluated by the investigator according 
to modified RECIST

Disease control rate (DCR), defined as the sum of the CR, PR and stable disease 
(SD) rates.  DCR will be calculated based on disease status evaluated by the 
investigator according to RECIST v1.1, and also by disease status evaluated by the 
investigator according to modified RECIST

Duration of response (DoR), defined as the time from first occurrence of a 
documented response to disease progression or death from any cause, whichever 
occurs first.  Duration of response will be calculated based on disease status 
evaluated by the investigator according to RECIST v1.1, and also by disease status 
evaluated by the investigator according to modified RECIST


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Additional secondary study objectives include the evaluation of efficacy of atezolizumab 
according to the following patient-reported outcomes (PROs; Appendix 4):

Change from baseline in health-related quality of life (HRQoL), as assessed using 
the EORTC Quality-of-Life Questionnaire Core 30 (QLQ-C30)

EuroQol EQ-5D-5L-assessed utility
2.3
EXPLORATORY OBJECTIVES
Exploratory study objectives may include evaluations of atezolizumab efficacy according 
to additional efficacy endpoints.
2.4
BIOMARKER OBJECTIVES
The biomarker objectives of the study are as follows:

To evaluate PD-L1 prevalence based on retrospective evaluation of PD-L1 
expression in tumor tissue measured by IHC.  PD-L1 testing may be conducted on a 
subset of samples at local laboratories for inter-laboratory concordance evaluation 

To examine centrally assessed biomarkers and biomarker profiles in tumor tissue, 
and to correlate these with safety and/or efficacy outcomes.  Biomarkers and 
biomarker profiles may be assessed using various methodologies including, but not 
limited to, IHC (single and multiplex, e.g., PD-L1 expression and immune cell 
infiltration analyses), RNA and DNA analysis (e.g., mutation and expression 
analyses)
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
Study MO29983 is an open label, single-arm, multicenter study of the safety of 
atezolizumab as second-line treatment for patients with locally advanced or metastatic 
urothelial or non-urothelial carcinoma of the urinary tract.  The study includes evaluation 
of the efficacy of atezolizumab and potential tumor biomarkers associated with 
atezolizumab.  An overview of study design is shown in Figure 2.
Study screening will take place within 28 days prior to initiation of study treatment.  
Eligible patients will be enrolled and begin treatment with 1200 mg atezolizumab IV 
every 3 weeks.  The single agent study treatment will continue until investigator-
assessed loss of clinical benefit, unacceptable toxicity, investigator or patient decision to 
withdraw from therapy, or death (whichever occurs first).
During the study treatment period, patients will be followed for safety based on AE 
assessments including vital signs, physical findings and clinical laboratory test results.  
Efficacy will be evaluated by the investigator according to both RECIST v1.1 
(Appendix 3) and modified RECIST (Appendix 2).  Exploratory biomarker analyses will 
be conducted based on primary tumor tissue or biopsied metastatic tumor tissue 


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collected at baseline and an optional tumor sample collected at the second study 
treatment cycle.  
Following discontinuation of study treatment, safety assessments will be conducted 
30 days after the last study drug administration or until initiation of other anti-cancer 
therapy (whichever occurs first).  Thereafter, patients will be followed for disease 
progression (unless this has already occurred), SAEs, AEs of special interest, anti-
cancer therapy and survival.  Follow-up will continue for up to four years after the last 
patient is enrolled in the study.
An iDMC established for the study will review all AEs, SAEs and AEs of special interest 
and cumulative safety data.
Figure 2
Study Schema
ECOG PS, Eastern Cooperative Oncology Group performance status; MVAC, methotrexate, 
vinblastine, doxorubicin, and cisplatin; GC, gemcitabine and cisplatin.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of study will occur when all patients enrolled have either died, withdrawn
consent, are lost to follow up, or have been followed for 48 months since the last study 
patient is enrolled, whichever occurs first.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 6 years.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Patient Population and Analysis Groups
Please refer to Section 1.3, Study Rationale and Benefit Risk Assessment.


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3.3.2
Rationale for an Open-Label Single-Arm Design
The primary objective of this study is to assess the safety profile of atezolizumab in a 
noncomparative fashion.  Thus, as all patients are pre-specified to receive active 
treatment, the study will have an open-label and non-randomized design. 
3.3.3
Rationale for Atezolizumab Dose and Schedule
The fixed dose of 1200 mg (equivalent to an average body weight-based dose of 
15 mg/kg) was selected on the basis of both nonclinical studies and available clinical 
data from Study PCD4989g as described below.
The target exposure for atezolizumab was projected on the basis of nonclinical tissue 
distribution data in tumor-bearing mice, target-receptor occupancy in the tumor, the 
observed atezolizumab interim pharmacokinetics in humans, and other factors.  The 
target trough concentration (Ctrough) was projected to be 6 µg/mL on the basis of several 
assumptions, including: 1) 95% tumor-receptor saturation is needed for efficacy, and 2) 
the tumor-interstitial concentration to plasma ratio is 0.30 based on tissue distribution 
data in tumor-bearing mice.
The atezolizumab dose is also informed by available clinical activity, safety, PK, and 
immunogenicity data.  Anti-tumor activity has been observed across doses from 1 mg/kg 
to 20 mg/kg.  The maximum tolerated dose of atezolizumab was not reached, and no 
dose-limiting toxicities have been observed at any dose in Study PCD4989g.  Available 
preliminary PK data (0.03–20 mg/kg) from Study PCD4989g suggest that for doses ≥ 1 
mg/kg, overall atezolizumab exhibits pharmacokinetics that are both linear and 
consistent with typical IgG1 antibodies.  
Detectable anti-drug antibodies (ADAs) were observed in patients at all dose levels but 
were associated with changes in pharmacokinetics for some patients in only the lower 
dose cohorts (0.3, 1, and 3 mg/kg).  It is unclear from currently available data in these 
lower dose cohorts if administration of higher doses to patients with both detectable 
ADAs and reduced exposure would necessarily restore exposure to expected levels.  No 
clear relationship between the development of measurable ADAs and safety or efficacy 
has been observed.  Available data suggest that the development of detectable ADAs 
does not appear to have a significant impact on the pharmacokinetics for doses from 10 
to 20 mg/kg in most patients.  Correspondingly, patients dosed at the 10-, 15-, and 20-
mg/kg dose levels have maintained target trough levels of drug despite the detection of 
ADAs.  
Currently available PK and ADA data suggest that the 15-mg/kg atezolizumab q3w 
regimen (or fixed-dose equivalent) for Phase II and Phase III studies would be sufficient 
to both maintain Ctrough ≥6 µg/mL and further safeguard against both interpatient 
variability and the potential effect of ADAs that could lead to subtherapeutic levels of 
atezolizumab relative to the 10-mg/kg atezolizumab q3w regimen (or fixed-dose 
equivalent).  From inspection of available observed Ctrough data, moving further to the 20-


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mg/kg atezolizumabq3w regimen does not appear to be warranted to maintain targeted 
Ctrough levels relative to the proposed 15-mg/kg atezolizumab q3w level.
Simulations do not suggest any clinically meaningful differences in exposure following a 
fixed dose or a dose adjusted for weight.  On the basis of this analysis, a fixed dose of 
1200 mg has been selected (equivalent to an average body weight-based dose of 
15 mg/kg).
Selection of an every-21-day dosing interval is supported by this preliminary PK 
evaluation and allows for a convenient integration with common chemotherapeutic 
regimens.
3.3.4
Rationale for Biomarker Assessments in Tumor Samples
Cancer of the urinary tract is a heterogeneous disease (Kaufman et al. 2009), and 
PD-L1 expression has been shown to vary among patients (Rosenberg et al. 2016).  
Published results have demonstrated that response to atezolizumab correlated with 
expression levels of PD-L1 in UC tumors (Rosenberg et al. 2016). 
Further defining the relationship between atezolizumab treatment outcomes in bladder 
cancer and PD-L1 expression is important for at least two reasons: first, it will advance 
the understanding of how best to use PD-L1 expression levels as a potentially predictive 
marker of atezolizumab treatment success; and second, it will add to the understanding 
of the basic biology underlying immune checkpoints and their role in cancer.  
Therefore, to address these issues, a maximum of three FFPE tumor specimens will be 
collected from each patient at the following timepoints:
1.
A mandatory representative formalin-fixed paraffin-embedded (FFPE) tumor tissue 
block (e.g., archival primary tumor or metastatic lesion) must be submitted.  If a 
tumor block is not available, tumor FFPE tissue obtained by biopsy during screening 
will be submitted
2.
Only in patients who are eligible for the study and who submit archival tissue, an 
optional tumor biopsy may be collected during screening, as well
3.
In patients who had a screening biopsy, an optional tumor sample may be collected 
ideally from the same lesion at Cycle 2, Day 1 (± 1 week), if feasible
Only tissue from core needle (with ≥ 3 cores), will be accepted.  Cytological samples 
(such as, for example, from fine-needle aspirations) and bone tissue are not acceptable.
The archival and screening tissue sample will be used, for example, to correlate baseline 
levels of PD-L1 with subsequent safety and efficacy outcomes (the screening sample 
may also be used for other exploratory analyses).  The optional samples at Cycle 2 will 
be used to investigate changes in the tumor microenvironment induced by atezolizumab 
treatment. 


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In addition to PD-L1, other biomarkers may be examined in this study on an exploratory 
basis. This may be accomplished by IHC and/or by a variety of DNA- and RNA-based 
profiling methodologies.  These analyses are of significant interest for their potential of 
revealing molecular mechanisms involved in advanced bladder cancer carcinogenesis 
and susceptibility to atezolizumab treatment. 
3.3.5
Rationale for Patient-Reported Outcome Assessments
PROs provide an understanding of a treatment’s impact from the patient’s perspective, 
an important consideration in many of today’s quality initiatives (Institute of Medicine 
(U.S.). Committee on Quality of Health Care in America. 2001).  Currently, there are no 
fully validated PRO instruments to measure symptoms and HRQoL specifically for
patients with advanced/metastatic urothelial or non-urothelial carcinoma of the urinary 
tract. This study will therefore use two general instruments that have been widely used 
in assessing self-reported outcomes in patients with cancer (Appendix 4):

EORTC QLQ-C30: The EORTC QLQ-C30 was developed to assess quality of life in 
cancer patients (European Organisation for Research and Treatment of Cancer 
2016).  The instrument incorporates nine multi-item scales: five functional scales 
(physical, role, cognitive, emotional, and social); three symptom scales (fatigue, 
pain, and nausea and vomiting); and a global health and quality-of-life scale 
(Aaronson et al. 1993).  Several single-item symptom measures are also included

EQ-5D-5L: The EQ-5D-5L is a self-report health status questionnaire that consists 
of six questions used to calculate a health utility score for use in health economic 
analysis (EuroQol 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013).  
There are two components to the EuroQol EQ-5D: a five-item health state profile 
that assesses mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, as well as a visual analog scale that measures health state.  
Published weighting systems allow for creation of a single summary score.  Overall 
scores range from 0 to 1, with low scores representing a higher level of dysfunction.  
The EQ-5D will be utilized in this study for economic modeling
3.3.6
Rationale for Testing Atezolizumab in Patients with UC Who 
Have Failed Prior Therapy
Despite recent improvements in treatment, the prognosis for patients with advanced UC 
remains dismal, with median OS of approximately 15 months (Garcia and Dreicer 2006).  
Patients who receive second-line treatment for their disease have an even worse 
prognosis, with median survival duration of approximately 79 months (Sonpavde et al. 
2010).  Approved therapies are associated with significant toxicities (e.g., neuropathy, 
febrile neutropenia, myelosuppression, and alopecia) that negatively impact quality of 
life.  Therefore, there is a continuing need for more efficacious, better-tolerated 
treatments for patients with advanced UC who have failed prior platinum therapy.


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3.3.7
Rationale for the Use of Modified Response Criteria (Immune 
Based)
Cancer immunotherapies may result in early apparent radiographic progression 
(pseudoprogression/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. 2010; 
Pennock et al. 2012).  Unconventional response patterns have been described in 
patients treated with anti−cytotoxic T lymphocyte−associated antigen 4 (Wolchok et al. 
2009) and have been observed in the preliminary experience with atezolizumab in 
Study PCD4989g.  Therefore, modified RECIST will be used in this study to 
accommodate the possible appearance of new lesions and to allow the apparent 
increase in tumor burden to be confirmed at a subsequent assessment prior to 
designation of progressive disease.
3.3.8
Rationale for Allowing Patients to Continue Atezolizumab 
Treatment Beyond Initial Progression
Anti-tumor immune responses such as those associated with atezolizumab may result in 
objective responses that are delayed and that can be preceded by initial apparent 
radiological progression.  This initial apparent progression may occur as a result of either 
delayed anti-tumor activity and/or robust tumor immune cell infiltration with a 
concomitant increase in tumor size (pseudo-progression).  In addition, lesions that might 
otherwise be undetectable with conventional imaging may increase in size as a result of 
these processes and be recorded as new lesions (Hales et al. 2010).
For example, in IMvigor 210, 121 of the 311 enrolled patients with advanced UC were 
treated beyond progression for a median of 7.8 weeks (range 0–51 weeks), of whom 20 
(17%) subsequently experienced target lesion reduction of at least 30% from their 
baseline scans (Rosenberg et al. 2016).  Likewise, in Study PCD4989g, several patients 
with NSCLC who progressed by RECIST v1.1 criteria continued on atezolizumab 
treatment and demonstrated durable anti-tumor activity.  In some responding patients, 
the growth of known lesions or the appearance of new radiographic lesions were shown 
to contain immune cells and no viable cancer cells on biopsy.
Because progressive disease (by initial radiographic evaluation) does not necessarily 
reflect therapeutic failure, conventional response criteria may not adequately assess the 
activity of immunotherapeutic agents.  This study will therefore allow patients to remain 
on atezolizumab after apparent radiographic progression, provided the benefit-risk ratio 
is judged to be favorable.  Patients should be discontinued for unacceptable toxicity or 
symptomatic deterioration attributed to disease progression as determined by the 
investigator after an integrated assessment of radiographic data and clinical status 
(see Section 4.6.2).


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4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 1000 patients with locally advanced or metastatic urothelial or non-
urothelial carcinoma of the urinary tract who progressed on one to three prior lines of 
systemic therapy for inoperable, locally advanced or metastatic urothelial or non-
urothelial carcinoma of the urinary tract will be enrolled in this study.  Patients who 
discontinue the study prior to study treatment initiation will not be replaced.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:
1.
Signed informed consent form
2.
Age18 years
3.
Is, according to the investigator’s judgment, able to comply with the study protocol 
4.
Histologically documented locally advanced (T4b, any N; or any T, N 2−3) or 
metastatic (M1, Stage IV) urothelial or non-urothelial carcinoma of the urinary tract
–
Urinary tract carcinoma includes carcinoma of the bladder, ureter, urethra, and 
renal pelvis
–
Primary non-urothelial carcinoma includes all sub-types listed in the WHO 
classification (see Appendix 8)
Bellini collecting duct tumors are allowed if independently reviewed by 
two expert pathologists from different sites
–
Lymphoma, sarcoma, and renal cell carcinoma are excluded
5.
Patients with measurable and/or non-measurable disease according to RECIST 
v1.1 are allowed
6.
Must have progressed during or following treatment with at least one (and not more 
than 3) prior treatments for inoperable, locally advanced or metastatic urothelial or 
non-urothelial carcinoma of the urinary tract
–
Patients who received prior adjuvant/neoadjuvant chemotherapy and 
progressed within 12 months of treatment will be considered as having a first 
line of treatment for metastatic disease
–
Patients who were intolerant to prior systemic treatment are allowed as long as 
they had received at least 2 treatment cycles
–
Platinum- or non-platinum-based chemotherapy regimens are allowed
–
Low-dose chemotherapy given as radiosensitizer for curative treatment of 
localized disease does not count as a line of systemic chemotherapy
7.
Representative formalin-fixed paraffin-embedded (FFPE) tumor specimen block 
available for submission.


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–
Only tissue from core needle (with ≥3 cores), punch, incisional, excisional, or 
forceps biopsies will be accepted.  Fine-needle aspiration, brushing, bone 
tissue, and lavage samples are not acceptable
–
If an appropriate tumor specimen is not available, a sample will be collected by 
biopsy during the study screening period
–
ONLY at sites where local laws and regulations prohibit the sending of tumor 
specimen blocks to an outside central laboratory, specimen slides are 
acceptable.  A minimum of 15 unstained serially-cut sections must be prepared
and sent per tumor sample.  For details, please refer to the Sample Handling 
Manual
8.
Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1 or 2
9.
Life expectancy 12 weeks
10. Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained within 2 weeks prior to the first study treatment:
–
Absolute neutrophil count 1500 cells/µL (without granulocyte colony-
stimulating factor support within 2 weeks prior to the first study treatment)
–
White blood cell count 2500/µL
–
Lymphocyte count 500/µL
–
Platelet count ≥100,000/µL (without transfusion within 2 weeks prior to the first 
study treatment)
–
Hemoglobin ≥9.0 g/dL (patients may be transfused or receive erythropoietic 
treatment to meet this criterion)
–
Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline 
phosphatase 2.5 times the upper limit of normal (ULN), with the following 
exceptions:
Patients with documented liver metastases: AST and/or ALT5 × ULN
Patients with documented liver or bone metastases: alkaline phosphatase 
5 × ULN
–
Serum bilirubin 1.5 ×ULN.  Patients with known Gilbert disease who have 
serum bilirubin level ≤3 × ULN may be enrolled
–
Calculated creatinine clearance 15 mL/min (Cockcroft-Gault formula)
–
International normalized ratio (INR) and activated partial thromboplastin time 
(aPTT) 1.5 ×ULN.  This applies only to patients who are not receiving 
therapeutic anticoagulation; patients receiving therapeutic anticoagulation must 
be on a stable dose
11. Patients with treated, asymptomatic central nervous system (CNS) metastases are 
eligible, provided they meet all of the following criteria: 
–
Evaluable disease outside the CNS 


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–
No history of intracranial or spinal cord hemorrhage 
–
No evidence of significant vasogenic edema 
–
No stereotactic radiation within 7 days or whole-brain radiation or neurosurgical 
resection within 2 weeks before the start of study treatment 
–
Have had a screening CNS radiography2 weeks since completion of 
radiotherapy or surgical resection 
–
Radiographic demonstration of interim stability (i.e. no progression) between 
the completion of CNS-directed therapy and the screening radiographic study 
Note: Patients on stable doses of anticonvulsants or on prednisone doses (or dose 
equivalents) of 20 mg/day are allowed 
12. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of 1% per year during the treatment period and for at least 5 months after the last 
dose of atezolizumab
–
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 (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 trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
1.
Treatment with more than three prior lines of systemic therapy for inoperable, locally 
advanced or metastatic urothelial or non-urothelial carcinoma of the urinary tract
2.
Treatment with any other investigational agent or participation in another clinical trial 
with therapeutic intent within 4 weeks prior to study treatment initiation
–
Patients who were in another clinical trial with therapeutic intent within 4 weeks 
of study treatment initiation but were not on active drug in that prior trial are 
eligible
–
Patients who were in another clinical trial with therapeutic intent within 4 weeks 
of study treatment initiation but were in the follow-up phase of that prior trial and 
had stopped receiving active drug 4 or more weeks before study treatment 
initiation are eligible


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3.
Treatment with chemotherapy within 2 weeks prior to study treatment initiation
4.
Treatment with radiotherapy ongoing at the time of study entry (for CNS-directed 
radiotherapy, please refer to Inclusion Criterion 11) 
5.
Pregnant or lactating, or intending to become pregnant during the study
–
Women who are not postmenopausal (postmenopausal defined as 12 months 
of non-therapy-induced amenorrhea) or surgically sterile must have a negative 
serum pregnancy test result within 2 weeks prior to initiation of study drug
6.
Evidence of significant uncontrolled concomitant disease that could affect 
compliance with the protocol, including significant liver disease (such as cirrhosis, 
uncontrolled major seizure disorder, or superior vena cava syndrome)
7.
Malignancies other than the one studied in this protocol within 5 years prior to 
Cycle 1, Day 1
–
Patients with localized low risk prostate cancer (defined as Stage pT2b, 
Gleason score 7, and prostate-specific antigen [PSA] at prostate cancer 
diagnosis 20 ng/mL) treated with curative intent and without PSA recurrence 
are eligible
–
Patients with pre-existing low risk prostate cancer (defined as Stage T1/T2a, 
Gleason score 6, and PSA 10 ng/mL) who are treatment-naive and 
undergoing active surveillance are eligible
–
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk 
of metastasis or death 5% at 5 years) are eligible provided they meet all of the 
following criteria:
Malignancy treated with expected curative intent (such as adequately 
treated carcinoma in situ of the cervix, basal or squamous cell skin 
cancer, or ductal carcinoma in situ treated surgically with curative intent)
No evidence of recurrence or metastasis by follow-up imaging and any 
disease-specific tumor markers
8.
Significant cardiovascular disease, such as New York Heart Association cardiac 
disease Class III, myocardial infarction within 3 months, unstable arrhythmias, or 
unstable angina
–
Patients with known coronary artery disease or left ventricular ejection fraction 
50% must be on a stable medical regimen that is optimized in the opinion of the 
treating physician, in consultation with a cardiologist if appropriate
9.
Significant renal disorder indicating a need for renal transplant
10. Signs or symptoms of severe infection within 2 weeks prior to initiation of study 
treatment, including but not limited to, hospitalization for complications of infection, 
bacteremia, or severe pneumonia


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11. Major surgical procedure within 4 weeks prior to study treatment initiation or 
anticipation of need for a major surgical procedure during the course of the study 
other than for diagnosis
12. History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins
13. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese 
hamster ovary cells or any component of the atezolizumab formulation
14. History of autoimmune disease (Appendix 5) are allowed if controlled and on stable 
treatment (i.e., same treatment, same dose) for the last 12 weeks, with the 
exception of:
–
Patients taking concurrent abatacept or belatacept treatment, unless therapy 
has been withdrawn for 8 weeks
–
Patients with a history of serious or life threatening immune-related events
–
No more than 1 concomitant autoimmune disease at the time of study entry is 
allowed unless one of them is: 
Autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone 
Controlled Type I diabetes mellitus on a stable dose of insulin regimen
A medical history of such entities as atopic disease or childhood 
arthralgias, where the clinical suspicion of autoimmune disease is low.  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)
Vitiligo
15. Prior allogeneic stem cell or solid organ transplantation
16. History of idiopathic pulmonary fibrosis (including pneumonitis, drug-induced 
pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic 
organizing pneumonia), or evidence of active pneumonitis on screening chest 
computed tomography (CT) scan
–
History of radiation pneumonitis in the radiation field (fibrosis) is permitted
17. Patients with active hepatitis B (defined as having a positive hepatitis B surface 
antigen [HBsAg] test at screening) or hepatitis C
–
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as having a negative HBsAg test and a positive antibody to hepatitis B 
core antigen [anti-HBc] antibody test) are eligible
–
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction (PCR) is negative for HCV RNA
18. Active tuberculosis


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19. Administration of a live, attenuated vaccine within 4 weeks prior to study treatment 
initiation
–
Influenza vaccination should be given during influenza season only (e.g., 
approximately October to March in the Northern Hemisphere and April through 
September in the Southern Hemisphere) and must not be a live, attenuated 
vaccine 
–
Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) 
within 4 weeks prior to study treatment initiation or at any time during the study 
treatment, and so until 5 months thereafter
20. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including anti−CTLA-4, anti−PD-1, and anti−PD-L1 therapeutic antibodies
–
Patients who have received prior treatment with anti-CTLA-4 may be enrolled 
provided at least 5 half-lives (approximately 75 days) have elapsed from the 
last dose of anti−CTLA-4 to the first dose of atezolizumab and there was no 
history of severe immune-related adverse effects from anti-CTLA-4 
(NCI CTCAE Grade 3 or 4)
21. Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is 
shorter, prior to initiation of study treatment
–
Prior cancer vaccines and cellular immunotherapy are permitted
22. Specifically for patients without autoimmune disease: treatment with systemic 
corticosteroids or other systemic immunosuppressive medications (including, but not 
limited to, prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks 
prior to study treatment initiation or anticipated requirement for systemic 
immunosuppressive medications during the study treatment period
–
For patients with CNS metastases, use of prednisone at a dose (or dose 
equivalent) of 20 mg/day is acceptable 
–
Chronic use of prednisone or equivalent should be discussed with the Medical 
Monitor
–
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension, and low-dose supplemental corticosteroids for adrenocortical 
insufficiency and topical steroids for cutaneous diseases are allowed.
Note: For patients with autoimmune disease, immunosuppressive medications are 
permitted if the patient has controlled autoimmune disease and stable treatment 
(i.e., same treatment, same dose) for the previous 12 weeks.


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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label (unblinded) study in which all subjects will be assigned to receive 
the same treatment, i.e., atezolizumab.
4.3
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is atezolizumab.
4.3.1
Formulation, Packaging, and Handling
The atezolizumab drug product will be provided in a single-use, 20-cc USP/Ph. Eur. 
Type 1 glass vial as a colorless to slightly yellow, sterile, preservative-free clear liquid 
solution intended for IV administration.  The vial is designed to deliver 20.0 mL (1200 
mg) of atezolizumab solution, but may contain more than the stated volume to enable 
delivery of the entire 20.0 mL volume.  The atezolizumab drug product is formulated as 
60 mg/mL atezolizumab in 20 mM histidine acetate, 120 mM sucrose, 0.04% 
polysorbate 20, pH 5.8.
Atezolizumab must be refrigerated at 2°C–8°C (36°F–46°F) upon receipt until use.  
Atezolizumab vials should not be used beyond the expiration date provided by the 
manufacturer.  No preservative is used in the atezolizumab drug product; therefore, each 
vial is intended for single use only.  Vial contents should not be frozen or shaken and 
should be protected from direct sunlight.
For further details, see the Atezolizumab Pharmacy Manual and Investigator’s Brochure.
4.3.2
Dosage, Administration, and Compliance
The dose of atezolizumab in this study will be 1200 mg administered by intravenous 
infusion every 3 weeks (21 [± 3] days).  No other dilution of the vial contents is required 
out of the infusion bag dilution.
Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies.
For more detailed information on drug preparation, storage and administration, refer to 
the Atezolizumab Investigator’s Brochure and Pharmacy Manual.
The initial dose of atezolizumab will be delivered over 60 (± 15) minutes.  If the first 
infusion is tolerated without infusion-associated AEs, the second infusion may be 
delivered over 30 (± 10) minutes.  If the 30-minute infusion is well tolerated, all 
subsequent infusions may be delivered over 30 (± 10) minutes.  For the first infusion, the 
patient’s vital signs (heart rate, respiratory rate, blood pressures, and temperature) 
should be determined within 60 minutes before, during (every 15 [± 5] minutes), and 30 
(± 10) minutes after the infusion.  For subsequent infusions, vital signs will be collected 
within 60 minutes before the infusion, during the infusion if clinically indicated, and within 
30 (± 10) minutes after the infusion.  


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Patients will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms.
No premedication will be allowed for the first dose of atezolizumab.  Premedication may 
be administered for Cycles ≥ 2 at the discretion of the treating physician.  The 
management of infusion-related reactions will be according to severity as follows:

In the event that a patient experiences a mild (NCI CTCAE Grade 1) infusion-related 
event, the infusion rate should be reduced to half the rate being given at the time of 
event onset.  Once the event has resolved, the investigator should continue to 
deliver the infusion at the reduced rate for 30 minutes (± 10) minutes.  If tolerated, 
the infusion rate may then be increased to the original rate

In the event that a patient experiences a moderate infusion-related event (NCI 
CTCAE Grade 2) or flushing, fever, or throat pain, the patient should have his or her 
infusion immediately interrupted and should receive aggressive symptomatic 
treatment.  The infusion should be restarted only after the symptoms have 
adequately resolved to baseline grade.  The infusion rate at restart should be half of 
the infusion rate that was in progress at the time of the onset of the infusion-related 
event

For severe or life-threatening infusion-related events (NCI CTCAE Grade 3 or 4), 
the infusion should be stopped immediately, and aggressive resuscitation and 
supportive measures should be initiated.  Patients experiencing severe or life-
threatening infusion-related events will not receive further infusion and will be further 
managed as clinically indicated until the event resolves
For anaphylaxis precautions, see Appendix 6.
Guidelines for dosage modification, treatment interruption or discontinuation, and the 
management of specific adverse events are provided in Section 5.1.2.
Any overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration electronic Case Report Form (eCRF).  AEs associated with an 
overdose or incorrect administration of study drug should be recorded on the Adverse 
Event eCRF.
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, 
storage and administration.
4.3.3
Investigational Medicinal Product Accountability
The Investigational medicinal product (IMP) required for completion of this study 
(atezolizumab) will be provided by the Sponsor.  
The study site (i.e., investigator or other authorized personnel [e.g., pharmacist]) is 
responsible for maintaining records of IMP delivery to the site, IMP inventory at the 
site, IMP use by each patient, and disposition or return of unused IMP, thus enabling 


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reconciliation of all IMP received, and for ensuring that patients are provided with
doses specified by the protocol.
The study site should follow all instructions included with each shipment of IMP. The 
study site will acknowledge receipt of IMP supplied by the Sponsor, using the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and 
time) or temperature monitoring, for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions, with access limited to the investigator 
and authorized staff.
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs.
IMP will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMP received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Trial Access to Atezolizumab
The Sponsor will offer continued access to Roche IMP (atezolizumab) free of charge to
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (atezolizumab) after completing the 
study if all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them


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A patient will not be eligible to receive Roche IMP (atezolizumab) after completing the 
study if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the 
IMP is not effective for UC

The Sponsor has reasonable safety concerns regarding the IMP as treatment for UC

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
Patients may be eligible to receive atezolizumab as part of an extension study, if no 
other option in the country is possible.
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the screening evaluation 
and the 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 who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine and/or famotidine or another H2 
receptor antagonist, as per standard practice (equivalent medications may be 
substituted per local practice).  Serious infusion-associated events manifested by 
dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation or respiratory distress should be managed with supportive therapies as 
clinically indicated (e.g., supplemental oxygen and β2-adrenergic agonists; see 
Appendix 6).
Systemic corticosteroids and tumor necrosis factor−α inhibitors may attenuate potential 
beneficial immunologic effects of treatment with atezolizumab, but may be administered 
at the discretion of the treating physician after consultation with the Medical Monitor (see 
Exclusion Criterion 21 [Section 4.1.2]).  If feasible, alternatives to corticosteroids should 
be considered.  Premedication may be administered for cycles ≥ 2 at the discretion of 
the treating physician after consultation with the Medical Monitor.  The use of inhaled 
corticosteroids for COPD and mineralocorticoids (e.g., fludrocortisone) and low-dose 
corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency is 


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allowed.  Megestrol administered as an appetite stimulant is acceptable while the patient 
is enrolled in the study.
Colony-stimulating factors, such as granulocyte colony-stimulating factor and 
erythropoietin, should only be used according to manufacturers’ labels and the ASCO 
and ASCO/ASH guidelines (Smith et al. 2006; Rizzo et al. 2010).  
Inactivated vaccinations (such as influenza, COVID-19) are permitted. Live, 
attenuated vaccines are not permitted (see Section 4.4.2).
Patients experiencing a mixed response requiring local therapy for control of three or 
fewer lesions may still be eligible to continue study treatment at the investigator's 
discretion.  The Medical Monitor is available to advise as needed.  Patients who receive 
local therapy directed at a target lesion will no longer be evaluable for radiographic 
response but will remain evaluable for progression.
Patients who use hormonal therapy with gonadotropin-releasing hormone agonists or 
antagonists for prostate cancer, oral contraceptives, hormone-replacement therapy, 
prophylactic or therapeutic anticoagulation therapy (such as low molecular weight 
heparin or warfarin at a stable dose level), or other allowed maintenance therapy (see 
Section 4.1.2) should continue their use.
All concomitant medications should be reported to the investigator and recorded on the 
appropriate eCRF.
4.4.2
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:

Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, or investigational 
agents (except for maintenance therapies outlined in Section 4.1.1 and 4.1.2)
–
After completion of Cycle 1, certain forms of radiotherapy may be considered 
for palliation if patients are deriving benefit (e.g., treatment of known bone 
metastases or symptomatic hematuria) 

Traditional herbal medicines are not recommended 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

Patients who are receiving a receptor activator of nuclear factor kappa B ligand 
inhibitor (denosumab) prior to enrollment must be willing and eligible to receive a 
bisphosphonate instead while on study; denosumab could potentially alter the 
activity and the safety of atezolizumab

Patients should not receive abatacept or belatacept treatment (those who were 
receiving it must stop it > 8 weeks before study entry)


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Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to 
initiation of study treatment, during atezolizumab treatment, and for 5 months after the 
discontinuation of atezolizumab.
Patients are not allowed to receive immunostimulatory agents, including but not limited 
to interferon (IFN)-α, IFN-γ, or IL-2, during the entire study. These agents, in 
combination with atezolizumab, could potentially increase the risk for autoimmune 
conditions.
With the exception of autoimmune disease patients, patients should not receive 
immunosuppressive medications, including but not limited to cyclophosphamide, 
azathioprine, methotrexate, and thalidomide.  These agents could potentially alter the 
activity and the safety of atezolizumab.  
Systemic corticosteroids, immunosuppressive medications, and TNF-inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids, immunosuppressive 
medications, or TNF-inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered.  If the alternatives are not feasible, systemic 
corticosteroids, immunosuppressive medications, and TNF-inhibitors may be 
administered at the discretion of the investigator after consultation with the Medical 
Monitor.  If feasible, alternatives to these agents should be considered.
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy.
Patients with CNS metastases are allowed to receive anticonvulsants and steroid 
treatments if the dose of prednisone is ≤20 mg / day (or equivalent). 
In addition, all patients (including those who discontinue the study early) should not 
receive other immunostimulatory agents for 10 weeks after the last dose of 
atezolizumab.
The above list of medications is not necessarily comprehensive.  The investigator should 
consult the prescribing information for any concomitant medication and contact the 
Medical Monitor if questions arise regarding medications not listed above.
4.5
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of assessments performed during the study.


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4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases (including autoimmune diseases), 
surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, and 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 the screening visit.  A history of pleural or pericardial 
effusion or of ascites requiring intervention should be entered in the medical history.
Cancer history will include an assessment of prior treatment with bacillus Clamette-
Guerin (BCG).
To further evaluate medical history, Investigators should determine an age-adjusted 
Charlson comorbidity index for each subject during screening (Koppie et al. 2008).  
Refer to Appendix 9 for the AACI worksheet.
Demographic data will include age, ECOG performance status, sex, and self-reported 
race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurological systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.  Height and weight should be 
measured and recorded in the eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressures while the patient is in a seated position, and temperature.


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For the first infusion, the patient’s vital signs (heart rate, respiratory rate, blood 
pressures, and temperature) must be determined within 60 minutes before, during (every 
15 [± 5] minutes), and 30 (± 10) minutes after the infusion.  For subsequent infusions, 
vital signs will be collected within 60 minutes before infusion, during the infusion if 
clinically indicated, and within 30 (± 10) minutes after the infusion.  
4.5.5
Tumor and Response Evaluations
Screening assessments must include CT scans (with oral/IV contrast unless 
contraindicated) or MRI of the chest, abdomen, and pelvis.  A spiral CT scan of the chest 
may be obtained, but is not a requirement.
A CT (with contrast if not contraindicated) or MRI scan of the brain is required for 
patients with known CNS metastases, or to confirm or refute a diagnosis of CNS 
metastases at baseline in the event of symptoms or suspicion of CNS metastases.  
Patients with active CNS metastases are eligible for this study if non-symptomatic, 
treated and stable (please refer to Inclusion Criterion 11).  If a CT scan for tumor 
assessment is performed in a positron emission tomography (PET)/CT scanner, the CT 
acquisition must be consistent with the standards for a full-contrast diagnostic CT scan.
Bone scans (Technetium-99m [TC-99m]) or sodium fluoride PET (NaF-PET) should be 
performed at screening if clinically indicated.  If bone metastases are present at 
screening and cannot be seen on CT or MRI scans, or if clinically indicated, TC-99m or 
NaF-PET bone scans should be repeated when complete response is identified in target 
disease or when progression in bone is suspected.
CT scans of the neck or extremities should also be performed if clinically indicated and 
followed throughout the study if there is evidence of disease at screening.  At the 
investigator’s discretion, other methods of assessment of measurable disease as per 
RECIST v1.1 may be used.
Results of standard of care tests or examinations performed prior to obtaining Informed 
Consent and ≤ 28 days prior to study entry may be used for the purposes of Screening 
rather than repeating such tests.
For subsequent tumor assessments, procedures for tumor assessment should be 
performed as clinically indicated.  The same radiographic procedure used to assess 
disease sites at screening should be used throughout the study (e.g., the same contrast 
protocol for CT scans).  All known sites of disease must be documented at screening 
and reassessed at each subsequent tumor evaluation.  Response will be assessed by 
the investigator using RECIST v1.1 and modified RECIST (see Appendix 2 and 
Appendix 3).  The same evaluator should perform assessments if possible to ensure 
internal consistency across visits.


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At the investigator’s discretion, CT scans should be repeated at any time if progressive 
disease is suspected.
Patients who continue treatment beyond radiographic disease progression will be 
monitored with a follow-up scan at the next scheduled tumor assessment when the scan 
frequency is every 9 weeks.  If the scan frequency is every 12 weeks (see Appendix 1), 
the follow-up scan must be performed at 9 weeks (± 2 weeks) as an unscheduled tumor 
assessment or earlier if clinically indicated.
4.5.6
Ongoing Tumor Assessments
Patients who discontinue study treatment early during the initial treatment stage for 
reasons other than disease progression (e.g., toxicity) should continue to undergo 
scheduled tumor assessments (See Appendix 1) until the patient dies, experiences 
confirmed disease progression, withdraws consent, until study termination, or until the 
study closes, whichever occurs first.
Patients who start a new anti-cancer therapy in the absence of disease progression 
should continue to be followed for progression according to the protocol schedule of 
response assessments, unless consent is withdrawn or the patient experiences disease 
progression or death or until study termination or withdrawal from study, whichever 
occurs first.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count) 

Serum chemistries (glucose, BUN or urea, creatinine, sodium, potassium, 
magnesium, bicarbonate, calcium, phosphorus, total bilirubin, ALT, AST, alkaline 
phosphatase, LDH, total protein, and albumin) 

Coagulation panel (aPTT and INR) 

Serum pregnancy test (for women of childbearing potential, including 
premenopausal women who have had a tubal ligation) 

Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) 

Thyroid function testing (thyroid-stimulating hormone [TSH], free T3, free T4) 

Hepatitis B virus (HBV) serology (HBsAg, antibodies against HBsAg) 

Hepatitis C virus (HCV) serology (anti-HCV) – prior to inclusion only.  Patients 
positive for HCV antibody must be tested for HCV using RNA polymerase chain 
reaction


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
All patients will be tested for human immunodeficiency virus (HIV) prior to inclusion 
into the study (in accordance with national and/or institutional guidelines), but HIV-
positive patients will not be excluded from the clinical trial
Samples for exploratory biomarker analyses will be sent to one or several central 
laboratories for analysis:

Central laboratories will coordinate the collection of archival, fresh and leftover 
tumor tissue for biomarker assessments (e.g., but not limited to, PD-L1 expression 
and biomarkers/profiles).  Leftover material derivatives thereof will be transferred to 
the Research Biosample Repository, if the subject provides consent.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Exploratory biomarker research may include, but will not be limited to, the following 
analyses:

PD-L1 IHC assessment

Tumor DNA isolation for tumor mutation detection

Tumor RNA isolation for expression profiling
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.10.5), biological samples will be 
destroyed 5 years after the final Clinical Study Report has been completed, with the 
following exception:

Archival leftover tumor tissue that remains after 15 slides have been collected will 
be returned to the study site, if requested 
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.
Data arising from sample analysis, will be subject to the confidentiality standards 
described in Section 8.4.
4.5.8
Electrocardiograms
A 12-lead ECG will be obtained at specified timepoints, as outlined in the Schedule of 
Assessments (see Appendix 1), and may be obtained at unscheduled timepoints as 
indicated. 
ECG recordings must be performed after the patient has been resting in a supine 
position for at least 10 minutes.


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For safety monitoring purposes, the investigator 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.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.  
4.5.9
Patient-Reported Outcomes
PRO data will be collected via questionnaires to document the treatment benefit and 
more fully characterize the safety profile of atezolizumab.  The questionnaires, translated 
into the local language as required, will be completed in their entirety at specified 
timepoints during the study. To ensure instrument validity and that data standards meet 
health authority requirements, questionnaires will be self-administered or interviewer-
administered (as appropriate) before the patient or clinician receives any information on 
disease status, prior to the performance of non-PRO assessments, and prior to the 
administration of study treatment, unless otherwise specified.  
Two PRO questionnaires will be used in this study:

The EORTC QLQ-C30, which was developed to assess quality of life of cancer 
patients (European Organisation for Research and Treatment of Cancer 2016).  The 
EORTC QLQ-C30 incorporates nine multi-item scales: five functional scales 
(physical, role, cognitive, emotional, and social); three symptom scales (fatigue, 
pain, and nausea and vomiting); and a global health and quality-of-life scale 
(Aaronson et al. 1993).  Several single-item symptom measures are also included.

In addition, subjects in this study will complete the EuroQol 5-Dimension 
Questionnaire (EQ-5D-5L).  The EQ-5D-5L is a self-report health status 
questionnaire that consists of six questions used to calculate a health utility score 
for use in health economic analysis (EuroQol 1990; Brooks 1996; Herdman et al. 
2011; Janssen et al. 2013).  There are two components to the EuroQol EQ-5D: a 
five-item health state profile that assesses mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression, as well as a visual analogue scale (VAS) 
that measures health state.  Published weighting systems allow for creation of a 
single summary score.  Overall scores range from 0 to 1, with low scores 
representing a higher level of dysfunction.  The EQ-5D will be utilized in this study 
for economic modeling.
4.5.10
Optional Samples for Research Biosample Repository
4.5.10.1
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 biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens 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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RBR specimens will be used to achieve the following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.10.2
Approval by the Institutional Review Board or Ethics 
Committee
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 Institutional Review Board or Ethics Committee (IRB/EC) and, if 
applicable, an appropriate regulatory body.  If a site has not been granted approval for 
RBR sampling, this section of the protocol (Section 4.5.10) will not be applicable at that 
site.
4.5.10.3
Sample Collection
The following optional samples will be stored in the RBR and used for research 
purposes, including, but not limited to, research on biomarkers related to atezolizumab 
and locally advanced or metastatic urothelial or non-urothelial carcinoma of the urinary 
tract:

Leftover FFPE tissue freshly collected during screening and at Cycle 2, Day 1 (with 
the exception of archival FFPE blocks, which can be returned to sites upon request) 
after study-related tests have been performed
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants 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.
The above samples may be sent to one or more laboratories for DNA and RNA 
extraction to enable analysis of tumor mutations via next-generation sequencing (NGS), 
or other genetic analysis methods, as well as for gene expression or protein analyses.
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 


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dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.10.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses, data derived from RBR 
specimens 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 specimens 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.
4.5.10.5
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 specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the Sample Informed 
Consent/Withdrawal eCRF.


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In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.10.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason.  
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 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 Sample Informed Consent/Withdrawal eCRF.  If a patient wishes to 
withdraw consent to the testing of his or her RBR samples after closure of the site, the
investigator must inform the Sponsor by emailing the study number and patient 
number to the following email address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from 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.
4.5.10.7
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 specimens 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/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance


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Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this 
request must be documented in the source documents and signed by the investigator.  
Subjects who discontinue will be asked to provide consent allowing the Study 
Investigator and/or F. Hoffman-La Roche Ltd to collect follow up information regarding 
disease progression and survival.  Patients who withdraw from the study will not be 
replaced.
If a patient withdraws from the study, the study staff may use a public information 
source (e.g., country records) to obtain information about survival status.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment (but will continue to receive tumor 
assessments) if they experience any of the following:

Intolerable toxicity related to study treatment

Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment

Use of another systemic anti-cancer therapy (see Section 4.4.2)

Pregnancy

Radiographic disease progression per RECIST v1.1
Exception: Patients will be permitted to continue atezolizumab after 
RECIST v1.1 criteria for progressive disease are met if they meet all of the 
following criteria (see Figure 3 for schematic representation):
o
Evidence of clinical benefit (defined as the stabilization or 
improvement of disease-related symptoms) as assessed by the 
investigator
o
Absence of symptoms and signs (including worsening of laboratory 
values [e.g., new or worsening hypercalcemia]) indicating 
unequivocal progression of disease
o
No decline in ECOG performance status that can be attributed to 
disease progression
o
Absence of tumor progression at critical anatomical sites (e.g., 
leptomeningeal disease) that cannot be readily managed and 
stabilized by protocol-allowed medical interventions prior to repeat 
dosing
Patients who demonstrate confirmed radiographic disease progression may be 
considered for continued study treatment at the discretion of the investigator, 
provided they continue to meet all the criteria above


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The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.


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Figure 3
Conditions for Continuing Atezolizumab in the Presence of 
Increased Radiographic Tumor Size
ECOG PS, Eastern Cooperative Oncology Group performance status; ICF, Informed Consent 
Form; RECIST v1.1, Response Evaluation Criteria in Solid Tumors, Version 1.1.


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4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice

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 derived from clinical experience with 
atezolizumab in completed and ongoing studies.  The anticipated important safety risks 
are outlined below (see Section 5.1.1).
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of carefully chosen inclusion and exclusion criteria and close 
monitoring of patients during the study.  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.  
After initiation of study treatment, all adverse events will be reported until 30 days after 
the last dose of study treatment or until initiation of new anti-cancer therapy, whichever 
occurs first.  SAEs and adverse events of special interest will continue to be reported 
until 90 days after the last dose of study treatment or until initiation of new anti-cancer 
therapy, whichever occurs first.  
Guidelines for managing anticipated adverse events, including criteria for dosage 
modification and treatment interruption or discontinuation, are provided below 
(Section 5.1.2), in Appendix 11, and in Section 6 of latest version of the Atezolizumab 
Investigator’s Brochure.  Refer to Protocol Sections 5.2–5.6 for details on safety 
reporting during the study.


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In the setting of a pandemic or epidemic, screening for active infections (including 
SARS-CoV-2) prior to and during study participation should be considered according to 
local or institutional guidelines or guidelines of applicable professional societies (e.g., 
American Society of Clinical Oncology or European Society for Medical Oncology).
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines IL-6, IL-10, IL-2, and IFN-(Merad and Martin 2020).  If a patient 
develops suspected CRS during the study, a differential diagnosis should 
includeSARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator judgment.  If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines.
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, 
myositis, and severe cutaneous adverse reactions.  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. 
Refer to Appendix 11 and Section 6 of the latest version of the Atezolizumab 
Investigator’s Brochure for a detailed description of anticipated safety risks for 
atezolizumab, including the occurrence of serious, related and unexpected events.
Guidelines for managing patients who experience anticipated adverse events are 
provided in Appendix 11.
5.1.2
Management of Patients Who Experience Specific Adverse 
Events
Dose Modifications
There will be no dose modifications for atezolizumab in this study.
Treatment Interruption
Atezolizumab may be temporarily suspended in patients who experience toxicity 
considered to be related to study treatment.  If atezolizumab is withheld for 12 weeks, 
the patient will be discontinued from study drug. Atezolizumab can be resumed after 
being withheld for 12 weeks if the patient is likely to derive clinical benefit.  The 
decision to re-challenge patients with atezolizumab should be based on investigator’s 
assessment of benefitrisk and documented by the investigator. The Medical Monitor is
available to advise as needed.  Atezolizumab treatment may be suspended for reasons 
other than toxicity (e.g., surgical procedures).If a patient must be tapered off steroids 


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that have been used to treat adverse events, then atezolizumab may be withheld for 
more than 12 weeks from the last dose until the steroids are discontinued or reduced to 
a prednisone dose (or dose equivalent) of ≤10 mg/day.  For patients with CNS 
metastases or autoimmune disease who require chronic steroid therapy, who have been 
receiving additional steroids to treat adverse events, and who now require a reduction in 
steroid dosage, atezolizumab may be withheld for more than 12 weeks from the last 
dose until the steroid dosage has returned to its baseline value.  The investigator will 
determine the acceptable length of treatment interruption.  The acceptable length of 
treatment interruption must be based on an assessment of benefitrisk by the 
investigator and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed.
For the management of atezolizumab related adverse events please refer to 
Appendix 11 and Section 6 of the latest version of the Investigator’s Brochure.
For patients developing a new autoimmune disease not listed in Appendix 11 and 
Section 6 of the latest version of the Atezolizumab Investigator’s Brochure, or for 
patients with an autoimmune disease who develop a flare, the following dosing guidance 
should be applied:

Grade 1 event: atezolizumab dosage should be maintained

Grade 2 or 3 event: atezolizumab should be suspended until the subject responds to 
treatment of the autoimmune disease and the disease becomes stable (see rules 
above regarding maximum suspended time).  The subject should be referred to an 
appropriate specialist

Grade 4 event: atezolizumab should be permanently discontinued and the subject 
should be referred to an appropriate specialist
Severe Cutaneous Adverse Events
Severe cutaneous adverse reactions (SCARs) are a heterogeneous group of 
immunologically mediated drug eruptions.  Although rare, these events are potentially 
fatal, and mainly constituted by erythema multiforme, acute generalized exanthematous 
pustulosis, Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and 
drug rash with eosinophilia and systemic symptoms (DRESS).

For suspected SCARs, patients should be referred to a dermatologist for further 
diagnosis and management 

Atezolizumab should be withheld for patients with suspected SJS or TEN

Atezolizumab should be permanently withdrawn for any grade confirmed SJS or 
TEN

Caution should be used when considering the use of atezolizumab in a patient who 
has previously experienced a severe or life-threatening skin adverse reaction on 
prior treatment with other immune-stimulatory anticancer agents


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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.  
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.
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 in appendix 11.


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
SAEs and adverse events of special interest, performing protocol-specified safety 
laboratory assessments, measuring protocol-specified vital signs, and conducting other 
protocol-specified tests that are deemed critical to the safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10.

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)


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
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:

Pneumonitis

Colitis

Endocrinopathies: diabetes mellitus, pancreatitis, adrenal Insufficiency, 
hypothyroidism/hyperthyroidism and hypophysitis

Hepatitis

Transaminitis Grade ≥ 2 (AST or ALT >3x ULN and bilirubin >2x ULN ) OR AST/ALT 
>10x ULN 

Systemic lupus erythematosus

Neurological: Guillian-Barre Syndrome, myasthenic syndrome or myasthenia gravis, 
meningoencephalitis

Nephritis

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)

Myositis

Myopathies, including rhabdomyolysis

Vasculitis


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
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, HLH, and MAS

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 (seeSection 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Cardiac toxicities of Grade ≥ 2 (e.g., atrial fibrillation, myocarditis, pericarditis)

Autoimmune flare of Grade ≥3
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 Electronic Case Report Form (eCRF) and 
reported to the Sponsor in accordance with instructions provided in this section and in 
Sections 5.4.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 30 days after the 
last dose of study drug and 90 days for serious adverse events or adverse events of 
special interest.  
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 National Cancer Institute Common 
Terminology for Adverse Events, Version 4.0 (NCI CTCAE v4.0) will be used for 
assessing adverse event severity.  Table 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 4
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 


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accordingly.  The following guidance should be taken into consideration (see also 
Table 5):

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 5
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug 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 the study drug, 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 the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug 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 the study drug 
(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 the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
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. Use NCI 
CTCAE (v4.0) terminology each time it is possible.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions and Cytokine-Release Syndrome
There may be significant overlap in signs and symptoms of IRRs and cytokine-release 
syndrome (CRS).  While IRRs occur during or within 24 hours after treatment 
administration, time to onset of CRS may vary.  Differential diagnosis should be applied, 
particularly for late-onset CRS (occurring more than 24 hours after treatment 
administration), to rule out other etiologies such as delayed hypersensitivity reactions, 


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sepsis or infections, HLH, tumor lysis syndrome, early disease progression, or other 
manifestations of systemic inflammation.
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 on the 
Adverse Event eCRF as a diagnosis (e.g., "infusion-related reaction" or "cytokine-
release syndrome").  Avoid ambiguous terms such as "systemic reaction."  Cases of 
late-onset CRS should be reported as "cytokine-release syndrome" on the Adverse 
Event eCRF.  Associated signs and symptoms of an IRR should be recorded on the 
dedicated Infusion-Related Reaction eCRF.
If a patient experiences both a local and systemic reaction to a single administration of 
study treatment, each reaction should be recorded separately on the Adverse Event 
eCRF, with associated signs and symptoms of an IRR also recorded separately on the 
dedicated Infusion-Related Reaction eCRF.
In recognition of the challenges in clinically distinguishing between IRRs and CRS, 
consolidated guidelines for medical management of IRRs and CRS are provided in 
Appendix 11.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events, 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.


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
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should not be recorded 
as a separate event on the Adverse Event eCRF, but the “intermittent” box should be 
ticked.
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 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.


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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
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 (3xULN) in combination with either an elevated 
total bilirubin (2 xULN) 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 xULN in combination with total bilirubin 
2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 xULN in combination with clinical jaundice


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The most appropriate diagnosis or, if a diagnosis cannot be established, the abnormal 
laboratory values 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), either as a 
serious adverse event (see Section 5.2.2) or a non-serious adverse event of special 
interest (see Section 5.2.3).
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 locally advanced or metastatic urothelial or non-
urothelial carcinoma of the urinary tract should be recorded only on the Study 
Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).  An iDMC will monitor the 
frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
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," “flare,” etc.).


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5.3.5.10
Lack of Efficacy or Worsening of Locally Advanced or 
Metastatic Urothelial or Non-Urothelial Carcinoma of the 
Urinary Tract
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 RECIST and modified RECIST.  In rare cases, the 
determination of clinical progression will be based on symptomatic deterioration.  
However, every effort should be made to document progression through use of objective 
criteria.  If there is any uncertainty as to whether an event is due to disease progression, 
it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or to perform an efficacy assessment 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
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 


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recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, 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).
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data. Sites are not expected to review the 
PRO data for adverse events.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events, including SUSARs (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites 
Medical Monitor(/Roche Medical Responsible):
Dr 
(Primary)
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 


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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 Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the final dose of study drug 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 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the electronic data capture (EDC) system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting serious adverse events that occur > 90 days after the last dose 
of study treatment 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 through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 5 months after the last dose of study drug.  A Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 


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investigators.  Pregnancy should not be recorded on the Adverse Event eCRF.  The 
investigator should discontinue study drug 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.  
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth.
5.4.3.2
Abortions
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 


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follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the reporting period for serious adverse events and adverse events of 
special interest (defined as 90 days after the final dose of study drug 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 study drug treatment, the event should be reported through use of the 
Adverse Event eCRF.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the reference safety information
contained in the Atezolizumab Investigator's Brochure, which serves as the reference 
document for this study:
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.


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Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An IDMC will monitor the incidence of the above-listed anticipated events during the 
study.  An aggregate report of any clinically relevant imbalances that do not favor the 
test product will be submitted to health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
This is an open-label, single-arm safety study.  
Analysis populations
This study will include the following analysis populations:

Safety population: The primary analysis population for this study will include all 
enrolled patients who have received at least one dose of atezolizumab.  The safety 
population will be used for all baseline and safety analyses, unless otherwise stated

Intent-to-treat population: The intent-to-treat (ITT) population will include all enrolled 
patients.  The ITT population will be used for all efficacy analyses, unless otherwise 
stated.  In case the difference between the ITT and safety populations is 5 or fewer 
patients, all efficacy analyses will be based only on the safety population
A per-protocol population will not be defined for this study.  However all major deviations 
(at study entry and on study) will be summarized and reported.
General Analyses Methods
Unless otherwise stated, all statistical analyses specified in the subsequent sections will 
be based on the following general methods.
All qualitative data will be presented in contingency tables, using absolute and relative 
frequencies, unless otherwise stated.  Percentages will be rounded to the first decimal 
place and, therefore, may not always add up to 100%.  When applicable, 95% 
confidence intervals (CI) will be presented with estimates of proportions. 
All quantitative data will be summarized via relevant descriptive statistics, such as 
number of observations with available measurements, mean, standard deviation, 
median, first and third quartiles (Q1and Q3) when applicable, minimum and maximum. 
Time to event data will be summarized via Kaplan-Meier (KM) estimates/curves and 
median with corresponding 95% CI.
All analyses will be performed in SAS version 9.3.
Timing of the Analyses
The primary analysis will occur 6 months after the last patient has been enrolled.  


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The final analysis will occur at the end of the study, i.e., approximately 4 years after 
enrollment of the last study patient.
In addition, iDMC interim safety reviews will occur at minimum 3 months after the first 
patient was enrolled and 3 months after 500 patients have been enrolled and followed 
up for safety.  Additional analyses might also be conducted if recommended or required 
by the iDMC or Steering Committee.
6.1
DETERMINATION OF SAMPLE SIZE
This is a single-arm safety study.  There is no formal statistical hypothesis and all 
analyses will be descriptive.  The results for the primary safety variables will be 
presented via percentages and corresponding 95% Clopper-Pearson CIs.
A sample size of approximately 1000 patients is planned for this study.  The precision of 
rare AE incidence estimates presented by two-sided exact 95% Clopper-Pearson CIs 
are shown in Table 6.
Table 6
Two-Sided Clopper-Pearson 95% Confidence Intervals for 
Adverse Event Rate Estimates
Number of Patients with at 
Least One Event (Expected)
N=1000
Expected
Event Rate
(%)
Lower limit
of CI
(%)
Upper limit
of CI 
(%)
12
1.2
0.62
2.09
10
1.0
0.48
1.83
8
0.8
0.35
1.57
6
0.6
0.22
1.3
5
0.5
0.16
1.16
4
0.4
0.11
1.02
3
0.3
0.06
0.87
2
0.2
0.02
0.72
1
0.1
0.00
0.56
CI = confidence interval.
Therefore, for a sample size of 1000 patients and an expected AE incidence of 0.5%, 
based on the half-width of the Clopper-Pearson 95% confidence interval, the true AE 
rate can be estimated with precision of: ±(1.16% – 0.16%)/2 %= ±0.5 %.
6.2
ANALYSIS OF THE CONDUCT OF THE STUDY
Enrollment (by country, by site), screening failures, study treatment administration, and 
discontinuation (including reasons) from the study will be summarized using descriptive 
statistics.  


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6.3
SUMMARIES OF TREATMENT GROUP 
Demographic and other baseline characteristics (at patient and disease level), medical 
history, prior treatments (study and non-study condition related) will be presented 
descriptively using the overall safety population.  These may also be presented using the 
ITT population if the difference is more than 5 patients compared with the number of 
patients in the safety population.
6.4
PRIMARY SAFETY ANALYSIS
The primary endpoint of the study is the incidence of treatment-emergent AEs.  Verbatim 
descriptions of AEs will be mapped to MedDRA thesaurus terms and graded according 
to the National Cancer Institute Common Terminology Criteria version 4.0.  Multiple 
occurrences of the same event will be counted once at the maximum severity.
Other safety variables will include:

Drug exposure (e.g., treatment duration, number of doses, dose intensity and 
dose modifications/discontinuations, with reasons)

All AEs

SAEs

AEs (grade 3–5)

AEs of special interest

AEs leading to study drug discontinuation or interruption

Changes in vital signs from baseline

Changes in physical findings from baseline

Changes in selected laboratory parameters from baseline

Deaths and cause of death

Concomitant medications
The incidence of AEs will be summarized by frequency tables.  Corresponding 95% 
Clopper-Pearson confidence intervals (CIs) will be presented, as applicable.  Time to 
first incidence of selected event types will also be estimated and presented graphically 
using the Kaplan-Meier method.
Treatment exposure, discontinuation rate, and cause of death will be analyzed by 
frequency tables. When appropriate, median time on treatment and 95% CI will be 
estimated by the Kaplan-Meier approach or using univariate statistics, presenting mean, 
median, quartiles, minimum, maximum and standard deviation.
Changes in vital signs and physical findings from baseline will be tabulated and 
presented graphically when applicable.


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Worst grades for laboratory parameters and newly occurring Grade 3 and 4 laboratory 
values during treatment will be summarized by frequency tables. 
Concomitant medications recorded during the study will be summarized by frequency 
tables.
6.5
EFFICACY ANALYSES
Efficacy variables assessed in the study will include:

OS (defined in Section 2.1)

HRQoL, as assessed by QLQ-C30 questionnaire

PFS (defined in Section 2.1)

ORR (defined in Section 2.1)

DCR (defined in Section 2.1)

DoR (defined in Section 2.1)

Utilities collected using the EQ-5D-5L for pharmacoeconomic models
Further exploratory efficacy endpoints might also be considered, as applicable.
The intent-to-treat (ITT) population will be the main population for the efficacy variables.  
If the difference between the ITT and safety populations is 5 or fewer patients, all 
analyses will be based only on the safety population.
Estimates for the survival function for PFS, OS, and DoR will be obtained by the Kaplan-
Meier approach. 
The analysis of ORR will be assessed by best overall response (BOR), defined as a 
complete or partial response determined on two consecutive investigator assessments 
≥4 weeks apart in patients with measurable disease at baseline.  BOR rate will be 
defined as the percentage of patients who have a complete or partial response as their 
BOR.  Patients without a post-baseline tumor assessment will be considered non-
responders.  The number and proportion of responders and non-responders will be 
presented with the corresponding Clopper-Pearson 95% CI. 
DCR will be defined as the percentage of patients with a BOR of CR, PR, or SD and will 
be presented along with the 95% Clopper-Pearson CI.
Analyses on the PRO instruments will include summary statistics and change (absolute 
and percentage) from baseline, in addition to the time to event, such as time to 
deterioration, analysis.


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6.6
SUBGROUP ANALYSES
Key safety and/or efficacy parameters will also be analyzed by the following subgroups:

ECOG Performance status: 0–1 vs. 2 

Presence of CNS metastases at baseline: yes vs. no

Renal impairment at study entry: yes vs. no 

Patient requiring dialysis: yes vs. no

HIV status: negative vs. positive

History of autoimmune disease: yes vs. no

Progression on, or within 12 months of, prior platinum-based treatment: yes vs. no

Concomitant steroid treatment ongoing at baseline: yes vs. no 

History of non-urothelial urinary tract carcinoma histology: yes vs. no

Previous lines of cancer therapy (1 vs. 2 vs. 3)

Age-adjusted Charlson comorbidity index (AACI): ≤11 vs. > 11

PD-L1 expression: low vs. high (cut-offs to be defined)

Region (grouping countries into regions will be specified in the Statistical Analysis 
Plan)
All subgroup analyses will be based on the same methods as overall analyses of the 
primary and secondary variables.  In addition, graphical displays such as forest plots will 
be used to descriptively visualize the homogeneity of key safety and efficacy parameters 
(proportions and 95% CI, or KM medians and corresponding 95% CI, as applicable will 
be displayed) across different levels of the pre-specified subgroup variables.
6.7
BIOMARKER ANALYSES
The biomarker objectives of this trial include correlating clinical benefit (e.g., OS, PFS, 
ORR, DCR, and DoR) with baseline expression levels of various biomarkers and profiles 
including, but not limited to, tumor PD-L1 as assessed by IHC.  Biomarkers and 
biomarker profiles may be assessed using various methodologies including, but not 
limited to, IHC (single and multiplex e.g., PD-L1 expression and immune cell infiltration 
analyses), RNA and DNA analysis (e.g., mutation and expression analyses).
Different statistical methods will be used for the exploratory biomarker analyses, for 
example (but not limited to): frequencies and proportions (including 95% CI) of binary 
variables like response rates in different biomarker profile groups, and exact binomial 
tests to evaluate the associations of biomarkers and biomarker profiles with binary 
endpoints like objective response rates.  Estimations of time-to-event outcomes in 
different biomarker subgroups (including duration of response, progression-free survival, 
and overall survival) might be analyzed by Kaplan-Meier methods; medians and 
corresponding 95% CI will be reported by biomarker subgroups.  For continuous 


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biomarkers, such as tumor mutation burden, sliding window analyses might be used to 
determine the ideal cut-off.
6.8
INTERIM ANALYSES
The iDMC will conduct interim reviews of accumulated safety data.  The first review will 
be performed three months after enrollment of the first patient.  The iDMC will then 
decide on the basis of the initial reviewed data when to meet the following time, but at a 
minimum, the iDMC will perform another overall safety review after 500 patients have 
been followed up for 3 months.  Ad hoc iDMC review meetings may occur as needed at 
any time during the study period.  In case of important safety findings, the iDMC may 
also request to review efficacy data for an overall assessment of the risk-benefit profile 
to the patients.
Given the descriptive nature of this single-arm safety study, with the primary endpoint 
based on safety variables and the objective of the interim iDMC being to review safety, 
no adjustment for multiplicity is considered necessary.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
A contract research organization (CRO) will be responsible for the data management of 
this study, including quality checking of the data.  Data entered manually will be 
collected via EDC through use of eCRFs.  Sites will be responsible for data entry into the 
EDC system.  In the event of discrepant data, the CRO will request data clarification 
from the sites, which the sites will resolve electronically in the EDC system.  
The Sponsor will perform oversight of the data management of this study. The CRO will 
produce eCRF Specifications for the study based on Sponsor’s templates including 
quality checking to be performed on the data.  Central laboratory 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.
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the CRO.


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All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
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 inSection 7.5 .
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and Institutional Review board (IRB)/Ethics Committee (EC) 
review.  The study site must also allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.


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7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/ECapproved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 


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consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
If the Consent Forms are revised (through an amendment or an addendum) to 
communicate information that might affect a patient's willingness to continue in the 
study, the patient or a legally authorized representative must re-consent by signing the 
most current version of the Consent Forms or the addendum, in accordance with 
applicable laws and IRB/EC policy.
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.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 


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for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
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 the analyses, data derived from 
exploratory biomarker specimens 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 Roche policy on study data publication (see 
Section 9.6 ).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data, which may include imaging data, may be submitted to government or other 
health research databases or shared with researchers, government agencies, companies, 
or other groups that are not participating in this study.  These data may be combined 
with or linked to other data and used for research purposes, to advance science and 
public health, or for analysis, development, and commercialization of products to treat 
and diagnose disease.  In addition, redacted Clinical Study Reports and other summary 
reports will be provided upon request (see Section 9.6).
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 (i.e., last patient, last 
visit).


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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/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor has implemented a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity. The 
Sponsor identified potential risks associated with critical trial processes and data and 
implemented plans for evaluating and controlling these risks.  Risk evaluation and control 
included the selection of risk-based parameters (e.g., adverse event rate, protocol 
deviation rate) and the establishment of quality tolerance limits for these parameters. 
Detection of deviations from quality tolerance limits will trigger an evaluation to 
determine if action is needed.  Details on the establishment and monitoring of quality 
tolerance limits are provided in a Quality Tolerance Limit Management Plan.
9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd. and was 
designed in collaboration with outside guidance from a Steering Committee.  The 
Sponsor will provide clinical operations management, data management, and medical 
monitoring.  An iDMC will review SAEs and accumulating safety data.


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Approximately 200 sites in approximately 30 countries across Europe, North America, 
Latin America, North Africa, the Asia Pacific region, and the Middle East will participate 
to enroll approximately 1000 patients. 
Enrollment will occur through an IxRS system.  Central facilities will be used for certain 
study assessments throughout the study (e.g., specified laboratory tests and biomarker 
analyses) as specified in Section 4.5.  Accredited local laboratories will be used for 
routine monitoring; local laboratory ranges will be collected.  
9.6
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, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  Study data may be shared with others who 
are not participating in this study (see Section 8.4 for details), and redacted Clinical 
Study Reports and other summary reports will be made available upon request.  For 
more information, refer to the Roche Global Policy on Sharing of Clinical Study 
Information at the following Web site:
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.


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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.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Assessments (cont.)
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Abbreviations: aPTT: activated partial thromboplastin time; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EORTC: 
European Organisation for Research and Treatment of Cancer; INR: international normalized ratio; PD: progressive disease.
Note: Unless otherwise indicated, assessments scheduled on the study treatment days should be performed prior to initiation of study treatment 
infusion.
a.
Written informed consent is required for performing any study-specific tests or procedures.  Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent and within 28 days prior to study entry (except where otherwise specified) may be used for 
screening assessments rather than repeating such tests. 
b.
Medical history includes surgical and cancer histories.  Cancer history includes stage, date of diagnosis, and prior anti-cancer treatment.  
Reproductive status and smoking history should also be captured.  Demographic information includes age, sex, and self-reported 
race/ethnicity. 
c.
ECG recordings will be obtained during screening and when clinically indicated.  Patients should be resting and in a supine position for at least 
10 minutes prior to each ECG collection. 
d.
A representative formalin-fixed paraffin-embedded (FFPE) archival tumor block must be submitted.  If an archival tumor block is not available, 
a tumor FFPE block obtained by biopsy during screening must be submitted.  Only tissue from core needle (with ≥ 3 cores), will be accepted.  


Appendix 1
Schedule of Assessments (cont.)
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Cytological samples (such as, for example, from fine-needle aspirations) and bone tissue are not acceptable.  ONLY at sites where local laws 
and regulations prohibit the sending of tumor specimen blocks to an outside central laboratory, slides (≥15) are acceptable. 
Only for patients eligible for the study and who submitted archival tissue, an optional tumor biopsy may be taken during screening.   
e.
For patients who underwent screening biopsy, an optional tumor sample ideally from the same lesion may be taken at Cycle 2, Day 1 (± 1 
week), if feasible.
f.
A complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF.  At subsequent visits (or as clinically indicated), limited, 
symptom-directed physical examinations should be performed.  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.
g.
ECOG Performance Status, limited physical examination, and local laboratory assessments may be obtained ≤96 hours before Day 1 of each 
cycle.  It is not necessary to repeat these assessments again prior to Cycle 1 if they have been conducted for screening within this time period.
h.
Vital signs include respiratory rate, heart rate, systolic and diastolic blood pressures while the patient is in a seated position, and temperature.  
Treatment cycle Day 1 vital sign assessments will be done prior to study treatment. 
i.
HIV testing will be performed in accordance with national and/or institutional guidelines.  HBV serology includes HBsAg testing. HCV serology 
includes anti-HCV antibody testing and, if indicated due to anti-HCV antibody positivity, PCR testing for HCV RNA. See Section 4.5.7.
j.
Hematology consists of CBC (including RBC count), hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils, and other cells), and platelet count.  A manual differential may be done if clinically indicated.
k.
Serum chemistry includes glucose, BUN or urea, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, phosphorus, total bilirubin, 
ALT, AST, alkaline phosphatase, LDH, total protein, and albumin. 
l.
Urinalysis includes specific gravity, pH, glucose, protein, ketones, and blood.
m. A serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and 
documented as negative within 14 days prior to Day 1.  On-study pregnancy tests performed every treatment cycle can be conducted with 
serum or urine.
n.
The same radiographic procedure should be used throughout the study for each patient.  A CT (with contrast) or MRI of the head must be 
included in screening tumor assessments for patients with known or suspected CNS disease.  Results must be reviewed by the investigator 
before dosing at the next cycle.  Patients who continue treatment beyond radiographic disease progression assessed per RECIST v1.1 should 
be monitored with a follow-up scan at the next scheduled tumor assessment when the scan frequency is every 9 weeks.  If the scan frequency 
is every 12 weeks, a follow-up scan is recommended at 9 weeks (± 2 weeks) as an unscheduled tumor assessment or earlier if clinically 
indicated.  Investigators may perform additional scans or more frequent assessments if clinically indicated.
o.
Concomitant medications include any prescription medications, over-the-counter medications, or herbal remedies.  At screening, any 
medications the patient has used within the 7 days prior to the screening visit should be documented.  At subsequent visits, changes to current 
medications or medications used since the last documentation of medications will be recorded.


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
109/Protocol MO29983, Version 15
p.
After informed consent has been obtained, but prior to initiation of study drug, only SAEs caused by a protocol-mandated intervention should 
be reported.  After initiation of study drug, all SAEs and AEs of special interest, regardless of relationship to study drug, will be reported until 90 
days after the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  All other AEs, regardless of relationship to 
study drug, will be reported until 30 days after the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  After 
this period, the investigator should report any SAEs or AEs of special interest believed to be related to prior study drug treatment.  The 
investigator should follow each AE 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 SAEs considered to be related to 
study drug or study-related procedures until a final outcome can be reported.
q.
Survival and new anti-cancer therapy follow-up information will be collected via telephone contact, patient medical records, and/or clinic visits 
approximately every 3 months until death, loss to follow-up, end of study, patient withdrawal or study termination by the Sponsor, whichever 
occurs first.


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Appendix 2
Modified Response Evaluation Criteria in Solid Tumors
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents like atezolizumab, which can produce delayed 
responses that may be preceded by initial apparent radiological progression, including 
the appearance of new lesions.  Therefore, modified response criteria have been 
developed that account for the possible appearance of new lesions and allow 
radiological progression to be confirmed at a subsequent assessment.
Modified Response Evaluation Criteria in Solid Tumors (RECIST) is derived from 
RECIST, Version 1.1 (RECIST v1.1) conventions1 and immune-related response criteria2
(irRC).  When not otherwise specified, RECIST v1.1 conventions will apply.
Modified RECIST and RECIST, Version 1.1:  Summary of Changes
RECIST v1.1
Modified RECIST
New lesions after baseline
Define progression.
New measurable lesions are 
added into the total tumor 
burden and followed.
Nontarget lesions
May contribute to the 
designation of overall 
progression
Contribute only in the 
assessment of a complete 
response
Radiographic progression
First instance of 20% 
increase in the sum of 
diameters or unequivocal 
progression in nontarget 
disease
Determined only on the basis 
of measurable disease; may 
be confirmed by a 
consecutive assessment 4 
weeks from the date first 
documented 
RECIST Response Evaluation Criteria in Solid Tumors.
DEFINITIONS OF MEASURABLE/NONMEASURABLE LESIONS
All measurable and nonmeasurable lesions should be assessed at screening and at the 
protocol-specified tumor assessment timepoints.  Additional assessments may be 
                                           
1
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
2
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
antiPD-1 antibody in cancer. N Engl J Med 2012;366:244354.
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Can Res 2009;15:741220.


Appendix 2
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
111/Protocol MO29983, Version 15
performed, as clinically indicated for suspicion of progression.  The investigator will 
evaluate response to treatment with use of modified RECIST.
MEASURABLE LESIONS
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable)
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, 
a lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and follow-up, 
only the short axis will be measured and followed.  
NONMEASURABLE LESIONS
Nonmeasurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 but 15 mm), as well as truly 
nonmeasurable lesions.  Lesions considered truly nonmeasurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
BONE LESIONS
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions.
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.


Appendix 2
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
112/Protocol MO29983, Version 15
Blastic bone lesions are nonmeasurable.
CYSTIC LESIONS
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they 
are, by definition, simple cysts.
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions.
LESIONS WITH PRIOR LOCAL TREATMENT
Tumor lesions situated in a previously irradiated area or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable.
TUMOR RESPONSE EVALUATION
DEFINITIONS OF TARGET/NONTARGET LESIONS
Target Lesions
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as nonmeasurable lesions (even if the size is 10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition, should lend 
themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, in 
which circumstance, the next largest lesion that can be measured reproducibly should 
be selected.
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  As noted above, 
pathological nodes that are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of 15 mm by CT scan.  Only the short 


Appendix 2
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
113/Protocol MO29983, Version 15
axis of these nodes will contribute to the baseline sum.  The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor.  
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis. For 
example, an abdominal node that is reported as being 20 mm30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 
short axis 10 mm but 15 mm) should be considered nontarget lesions.  Nodes that 
have a short axis of 10 mm are considered non-pathological and should not be 
recorded or followed. 
Lesions irradiated within 3 weeks prior to Cycle 1, Day 1 may not be counted as target 
lesions.
Nontarget Lesions
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as nontarget lesions and should also be recorded at baseline.  Measurements 
are not required.
It is possible to record multiple nontarget lesions involving the same organ as a single 
item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”). 
After baseline, changes in nontarget lesions will contribute only in the assessment 
of complete response (i.e., a complete response is attained only with the complete 
disappearance of all tumor lesions, including nontarget lesions) and will not be used 
to assess progressive disease.
New Lesions
During the study, all new lesions identified and recorded after baseline must be 
assessed at all tumor assessment timepoints.  New lesions will be evaluated for 
measurability with use of the same criteria applied to prospective target lesions at 
baseline per RECIST v1.1 (e.g., nonlymph node lesions must be 10mm; see note for 
new lymph node lesions below).  Up to a maximum of five new lesions total (and a 
maximum of two lesions per organ), all with measurements at all timepoints, can be 
included in the tumor response evaluation.  New lesion types that would not qualify as 
target lesions per RECIST v1.1 cannot be included in the tumor response evaluation.


Appendix 2
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
114/Protocol MO29983, Version 15
CALCULATION OF SUM OF THE DIAMETERS
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated as a measure of tumor burden.  
The sum of the diameters is calculated at baseline and at each tumor assessment for 
the purpose of classification of tumor responses.
Sum of the Diameters at Baseline:  The sum of the diameters for all target lesions 
identified at baseline prior to treatment on Day 1.
Sum of the Diameters at Tumor Assessment:  For every on-study tumor assessment 
collected per protocol or as clinically indicated, the sum of the diameters at tumor 
assessment will be calculated using tumor imaging scans.  All target lesions selected at 
baseline and allup to fivenew measurable lesions (with a maximum of two new 
lesions per site) that have emerged after baseline will contribute to the sum of the 
diameters at tumor assessment.  Hence, each net percentage change in tumor burden 
per assessment with use of modified RECIST accounts for the size and growth kinetics 
of both old and new lesions as they appear.
Note:  In the case of new lymph nodes, RECIST v1.1 for measurability (equivalent to 
baseline target lesion selection) will be followed.  That is, if at first appearance the short 
axis of a new lymph node lesion is 15 mm, it will be considered a measurable new 
lesion and will be tracked and included in the sum of diameters.  Thereafter, the lymph 
node lesion will be measured at subsequent timepoints and measurements will be 
included in the sum of diameters, even if the short axis diameter decreases to 15 mm 
(or even 10 mm).  However, if it subsequently decreases to 10 mm and all other 
lesions (including nontarget lesions) are no longer detectable (or have also decreased to 
a short axis diameter of 10 mm if lymph nodes) then a response assessment of CR 
may be assigned.
If at first appearance the short axis of a new lymph node is 10 mm and 15 mm, the 
lymph node will not be considered measurable but will still be considered a new lesion.  
It will not be included in the sum of diameters unless it subsequently becomes 
measurable (short axis diameter 15 mm).
The appearance of new lymph nodes with a diameter of 10 mm should not be 
considered pathological and not be considered a new lesion.


Appendix 2
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
115/Protocol MO29983, Version 15
RESPONSE CRITERIA
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Lymph nodes that 
shrink to 10 mm short axis are considered normal.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of all 
target and all new measurable lesions, taking as reference the baseline sum of 
diameters, in the absence of CR.
Note:  The appearance of new measurable lesions is factored into the overall tumor 
burden but does not automatically qualify as progressive disease until the sum of the 
diameters increases by 20% when compared with the sum of the diameters at nadir.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of the diameters while 
on study.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of all 
target and all new measurable lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
Impact of New Lesions on Modified RECIST
New lesions alone do not qualify as progressive disease.  However, their contribution 
to total tumor burden is included in the sum of the diameters, which is used to determine 
the overall modified RECIST tumor response. 
EVALUATION OF BEST OVERALL RESPONSE USING MODIFIED RECIST
TIMEPOINT RESPONSE
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
MISSING ASSESSMENTS AND INEVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is 
not evaluable (NE) at that timepoint.  If only a subset of lesion measurements are made 
at an assessment, usually the case is also considered NE at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response.  This would be most likely 
to happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm 


Appendix 2
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
116/Protocol MO29983, Version 15
with three measured lesions and at follow-up only two lesions were assessed but those 
gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion.
% Change in Sum of the Diameters 
(Including Measurable New Lesions 
When Present)
Nontarget Lesion 
Response
Overall Modified RECIST 
Timepoint Response
100% a
CR
CR
100% a
Non-CR or not all 
evaluated
PR
30%
Any
PR
30% to 20%
Any
SD
Not all evaluated
Any
NE
20%
Any
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; RECIST Response Evaluation Criteria in Solid Tumors; SDstable disease.
a When lymph nodes are included as target lesions, the % change in the sum of the 
diameters may not be 100% even if complete response criteria are met since a normal 
lymph node is defined as having a short axis of 10 mm.  Any pathological lymph 
nodes (whether target or nontarget) must have reduction in short axis to 10 mm in 
order to meet the definition of CR.
BEST OVERALL RESPONSE:  ALL TIMEPOINTS
The best overall response is determined once all the data for the patient are known.
The best overall response according to modified RECIST is interpreted as below:

CR:  Complete disappearance of all tumor lesions (target and nontarget) and no 
new measurable or unmeasurable lesions, confirmed by a consecutive assessment 
4 weeks from the date first documented.  All lymph nodes short axes must be 
10 mm.

PR:  Decrease in the sum of the diameters of all target and all new measurable 
lesions 30% relative to baseline, in the absence of CR, confirmed by a consecutive 
assessment 4 weeks from the date first documented.  

SD: Criteria for CR, PR, and PD are not met. 


Appendix 2
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
117/Protocol MO29983, Version 15

PD:  Increase in the sum of the diameters of all target and all new measurable 
lesions 20% relative to the nadir, which may be confirmed by a consecutive 
assessment 4 weeks from the date first documented as follows: 
The confirmatory assessment shows an additional measurable increase in 
tumor burden as measured by the sum of the diameters of all target and all new 
measurable lesions.
This protocol allows patients to continue to receive study treatment even after confirmed 
radiographic PD per modified RECIST, and patients may achieve a best overall 
response of PR or CR based on tumor regression achieved at any time prior to study 
treatment discontinuation.


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Appendix 3
Response Evaluation Criteria in Solid Tumors, Version 1.1: 
Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1 1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
nonmeasurable as follows:
Measurable Tumor Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
of: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable)

20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Nontarget Lesions” for information on lymph node 
measurement.
Nonmeasurable Tumor Lesions
Nonmeasurable tumor lesions encompass small lesions (longest diameter 10 mm 
or pathological lymph nodes with 10 to 15 mm short axis), as well as truly 
nonmeasurable lesions.  Lesions considered truly nonmeasurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
                                           
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: Revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47.
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
119/Protocol MO29983, Version 15
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone lesions:

Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are nonmeasurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor nonmeasurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if noncystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable.
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS 
Measurement of Lesions
All measurements should be recorded in metric notation, with use of calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
120/Protocol MO29983, Version 15
Method of Assessment
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study.  
Imaging-based evaluation should always be the preferred option.
Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is suggested.
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a noncontrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether noncontrast CT or MRI (enhanced or nonenhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease and should be 
optimized to allow for comparison with the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of nontarget disease or new lesions since the same lesion may appear 
to have a different size with use of a new modality.
Ultrasound.  Ultrasound is not useful in the assessment of lesion size and should not be 
used as a method of measurement.


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
121/Protocol MO29983, Version 15
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.
TUMOR RESPONSE EVALUATION
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above.
BASELINE DOCUMENTATION OF TARGET AND NONTARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means in instances where patients have only one or two 
organ sites involved, a maximum of two lesions (one site) and four lesions (two sites), 
respectively, will be recorded.  Other lesions (albeit measurable) in those organs will be 
recorded as nonmeasurable lesions (even if the size is 10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but additionally, should lend 
themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, 
in which circumstance the next largest lesion that can be measured reproducibly should 
be selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, this 
is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, 
or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
122/Protocol MO29983, Version 15
but 15 mm) should be considered nontarget lesions.  Nodes that have a short axis 
10 mm are considered nonpathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as nontarget lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple nontarget lesions involving the same organ as 
a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
RESPONSE CRITERIA
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  disappearance of all target lesions
Any pathological lymph nodes (whether target or nontarget) must have 
reduction in short axis to 10 mm.

Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  at least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest sum on study (nadir), 
including baseline
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
123/Protocol MO29983, Version 15
Special Notes on the Assessment of Target Lesions
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if CR criteria are met since a normal lymph node is defined as having a short axis 
10 mm.
Target Lesions That Become Too Small to Measure.  While on study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on the CT scan that the radiologist may not feel comfortable assigning 
an exact measure and may report them as being too small to measure.  When this 
occurs, it is important that a value be recorded on the eCRF as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and below measurable limit (BML) should 
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well and BML should also be ticked.) 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may 
be maintained that would aid in obtaining maximal diameter measurements of 
each individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the coalesced lesion.
Evaluation of Nontarget Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of nontarget lesions.  Whereas some nontarget lesions may actually be 


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Excerpt from Original Publication (cont.)
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measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the timepoints specified in the protocol.

CR:  disappearance of all nontarget lesions and (if applicable) normalization of 
tumor marker level)
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  persistence of one or more nontarget lesion(s) and/or (if 
applicable) maintenance of tumor marker level above the normal limits

PD:  unequivocal progression of existing nontarget lesions
The appearance of one or more new lesions is also considered progression.
Special Notes on Assessment of Progression of Nontarget Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the nontarget disease, there must be an overall 
level of substantial worsening in nontarget disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more nontarget lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in nontarget 
disease in the face of SD or PR of target disease will therefore be extremely rare.
When the Patient Has Only Nonmeasurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance, there 
is no measurable disease assessment to factor into the interpretation of an increase in 
nonmeasurable disease burden.  Because worsening in nontarget disease cannot be 
easily quantified (by definition:  if all lesions are truly nonmeasurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if 
the increase in overall disease burden based on the change in nonmeasurable disease 
is comparable in magnitude to the increase that would be required to declare PD for 
measurable disease, that is, an increase in tumor burden representing an additional 
73% increase in volume (which is equivalent to a 20% increase in diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from “trace” 
to “large” or an increase in lymphangitic disease from localized to widespread or may 
be described in protocols as “sufficient to require a change in therapy.”  If unequivocal 
progression is seen, the patient should be considered to have had overall PD at that 
point.  Whereas it would be ideal to have objective criteria to apply to nonmeasurable 
disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial.


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
125/Protocol MO29983, Version 15
When the patient has bone lesions at baseline.  When a bone scan is the sole 
indicator of progression, progression in bone will be defined as when at least two or 
more new lesions are seen on bone scan compared with screening.  In situations where 
the scan findings are suggestive of a flare reaction, or apparent new lesion(s) which may 
represent trauma, these results must be confirmed with other imaging modalities such as 
MRI or fine-cut CT to constitute progression.  Only a single new bone lesion on bone 
scan is required for progression if the lesion can be correlated on CT, MRI or plain film.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a CT 
scan report as a “new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
New osteoblastic bone lesions identified on plain films, CT, or MRI will not be considered 
progression in an otherwise stable or responding subject, if, in the opinion of the 
physician, the osteoblastic lesion appears to be healing or a response to therapy.
EVALUATION OF RESPONSE
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have nonmeasurable (therefore nontarget) disease only, Table 2 is to be 
used.


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
126/Protocol MO29983, Version 15
Table 1
Timepoint Response:  Patients with Target Lesions
(with or without Nontarget Lesions)
Target Lesions
Nontarget Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not 
all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; 
PRpartial response; SDstable disease.
Table 2
Timepoint Response:  Patients with Nontarget Lesions Only
Nontarget Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for nontarget 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some trials; thus, assigning “stable disease” 
when no lesions can be measured is not advised.
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing 


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
127/Protocol MO29983, Version 15
lesion(s) would not change the assigned timepoint response.  This would be most likely 
to happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm 
with three measured lesions and, during the study, only two lesions were assessed, but 
those gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more nontarget lesions are not assessed, the response for 
nontarget lesions should be “unable to assess” except where there is clear progression.  
Overall response would be “unable to assess” if either the target response or the 
nontarget response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that timepoint.


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
128/Protocol MO29983, Version 15
Table 3
Best Overall Response When Confirmation Is Required
Overall Response at 
First Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration 
for SD was met; otherwise, PD
CR
PD
SD, provided minimum duration 
for SD was met; otherwise, PD
CR
NE
SD, provided minimum duration 
for SD was met; otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration 
for SD was met; otherwise, PD
PR
NE
SD, provided minimum duration 
for SD was met; otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR).  Best response would depend on whether 
the minimum duration for SD was met.  However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR, at the first timepoint.  Under these circumstances, the original CR should be 
changed to PR and the best response is PR.
NOTE: In this study, stable disease must persist for at least 4 weeks (minimum duration) to be 
considered a bona fide SD. 
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
129/Protocol MO29983, Version 15
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and nontarget disease as shown in Table 1, Table 2, and Table 3.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or nontarget 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or nontarget lesion.


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Appendix 4
Patient-Reported Outcomes Instruments


Appendix 4
Patient-Reported Outcomes Instruments (Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
131/Protocol MO29983, Version 15  


Appendix 4
Patient-Reported Outcomes Instruments (Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
132/Protocol MO29983, Version 15


Appendix 4
Patient-Reported Outcomes Instruments (Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
133/Protocol MO29983, Version 15


Appendix 4
Patient-Reported Outcomes Instruments (Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
134/Protocol MO29983, Version 15


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 5
Preexisting Autoimmune (Chronic Inflammatory) Diseases
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with a history of immune 
deficiencies or autoimmune disease (see Table below) are allowed in the study. 
Patients with a history of more than one immune deficiency or autoimmune disease are 
excluded from participating in the study unless one of them is: 

Autoimmune-related hypothyroidism on a stable dose of thyroid replacement 
hormone 

Controlled Type I diabetes mellitus on a stable dose of insulin regimen

A medical history of such entities as atopic disease or childhood arthralgias where 
the clinical suspicion of autoimmune disease is low.  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).  

Vitiligo
The Medical Monitor is available to advise on any uncertainty over autoimmune 
exclusions.
Acute disseminated 
encephalomyelitis
Epidermolysis bullosa 
acquista
Ord’s thyroiditis
Addison’s disease
Gestational pemphigoid
Pemphigus
ANKA positive vasculitis
Giant cell arteritis
Pernicious anemia
Ankylosing spondylitis
Glomerulonephritis
Polyarteritis nodusa
Antiphospholipid antibody 
syndrome
Goodpasture’s syndrome
Polyarthritis
Aplastic anemia
Graves’ disease
Polychondritis
Autoimmune hemolytic 
anemia
Guillain-Barré syndrome
Polyglandular autoimmune 
syndrome
Autoimmune hepatitis
Hashimoto’s disease
Polymyositis
Autoimmune 
hypoparathyroidism
IgA nephropathy
Primary biliary cholangitis
Autoimmune hypophysitis
Inflammatory bowel disease
Psoriasis
Autoimmune myocarditis
Interstitial cystitis
Pyoderma gangrenosum
Autoimmune oophoritis
Kawasaki’s disease
Reactive arthritis
Autoimmune orchitis
Lambert-Eaton myasthenia 
syndrome
Rheumatoid arthritis
Autoimmune 
thrombocytopenic purpura
Lupus erythematosus
Sarcoidosis
Behcet’s disease
Lyme disease – chronic
Scleroderma


Appendx 5
Preexisting Autoimmune (Chronic Inflammatory) Disease (Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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Bullous pemphigold
Mixed connective tissue 
disease
Sjögren’s syndrome
Celiac disease
Mooren’s ulcer
Stiff-Person syndrome
Chronic fatigue syndrome
Morphea
Takayasu’s arteritis
Chronic inflammatory
demyelinating polyneuropathy
Multiple sclerosis
Ulcerative colitis
Chung-Strauss syndrome
Myasthenia gravis
Vitiligo
Crohn’s disease
Neuromyotonia
Vogt-Kovanagi-Harada 
disease
Dermatomyositis
Opsoclonus myoclonus 
syndrome
Wegener’s granulomatosis
Dysautonomia
Optic neuritis


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


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Appendix 7
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 8
Non-Urothelial Tumors of the 
Urinary Tract That are Eligible for This Study
Squamous neoplasms

Squamous cell carcinoma

Verrucous carcinoma

Squamous cell papilloma
Glandular neoplasms

Adenocarcinoma
–
Enteric
–
Mucinous
–
Signet-ring cell
–
Clear cell

Villous adenoma
Neuroendocrine tumors

Small cell carcinoma

Carcinoid

Paraganglioma
NOTE: Bellini collecting duct tumors are non-urothelial tumors of the urinary tract.
Based on: Pathology and Genetics of Tumours of the Urinary System and Male Genital 
Organs: World Health organization Classification of Tumours. Available at 
https://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb7/BB7.pdf.


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Appendix 9
Age-Adjusted Charlson Comorbidity Index Worksheet
The purpose of this worksheet is to assist you in calculating the score of the age-
adjusted Charlson Comorbidity Index (ACCI).  The form should be completed by the 
Principle Investigator or designated person.  
Patient Number:
Patient Age:
Condition
Weight
Calculate 
Score
Notes
1.    Myocardial infarction
1
2.    Congestive heart failure
1
3.    Peripheral vascular disease or 
       bypass
1
4.    Cerebrovascular disease or
       transient ischemic disease
1
CVA only
5.    Hemiplegia
2
If hemiplegia, do not count 
CVA separately
6.    Pulmonary disease/ asthma
1
7.    Diabetes
1
Diabetes only
7a.  Diabetes with end organ 
       damage
2
If end organ damage, do not 
count Diabetes separately
8.    Renal disease
2
9.    Mild liver disease
2
9a.  Severe liver disease
3
10.  Gastric or peptic ulcer
1
11.  Cancer (lymphoma, leukemia,
        solid tumor)
2
Non-metastatic cancer only 
A patient with non-
metastatic cancer only 
should be assigned a score 
of 2 on question 11 and a 
score of 0 on 11a
Points are additive by 
cancer type, i.e., if the 
patient has 2 types of non-
metastatic cancer, his or her 
score will be 4 
Includes the urothelial or 
non-urothelial cancer 
assessed in this study 


Appendix 9
Age-Adjusted Charlson Comorbidity Index Worksheet (Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
141/Protocol MO29983, Version 15
11a. Metastatic solid tumor
6
A patient with metastases 
from a single type of solid 
tumor should be assigned a 
score of 0 on question 11 
and a score of 6 on 11a 
Points are additive by 
cancer type, i.e., if the 
patient has metastases from 
2 types of solid tumors, his 
or her score will be 12
Includes the urothelial or 
non-urothelial cancer 
assessed in this study
12.  Dementia or Alzheimer’s
1
13.  Rheumatic or connective tissue
        disease
1
14.  HIV or AIDS
6
15.  Hypertension
1
16.  Skin ulcers/ cellulitis
2
17.  Depression
1
18.  Warfarin
1
1 point for each decade over age 40
age  40 – 49 years = 0
age  50 – 59 years = 1
age  60 – 69 years = 2
age  70 – 79 years = 3 
age  80 – 89 years = 4 
age  90 – 99 years = 5
TOTAL Score
1. Has the patient had a myocardial infarction?
Yes       No  
Criteria:  Myocardial infarction includes patients with one or more definite or probable myocardial 
infarction. These patients should have been hospitalized for chest pain or an equivalent clinical event 
and have had electrocardiographic and/ or enzyme changes. Patients with electrocardiographic 
changes alone who have no clinical history are not designated as having had an infarction
2.  Has the patient been hospitalized or treated for heart failure?
Yes       No  
Criteria:  Congestive heart failure includes patients who have had exertional or paroxysmal nocturnal 
dyspnea and who have responded symptomatically (or on physical examination) to digitalis, diuretics, 
or afterload reducing agents. It does not include patients who are on one of those medications but who 
have had no response and no evidence of improvement of physical signs with treatment.
3.  Does the patient have peripheral vascular disease?
Yes       No  
Criteria: Peripheral vascular includes patients with intermittent claudication or those who had a bypass 
for arterial insufficiency, those with gangrene or acute arterial insufficiency, and those with a treated or 
untreated thoracic or abdominal aneurysm (6 cm or more).


Appendix 9
Age-Adjusted Charlson Comorbidity Index Worksheet (Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
142/Protocol MO29983, Version 15
4.  Has the patient had a CVA or transient ischemic disease?
Yes       No  
Criteria: Cerebrovascular disease includes patients with a history of a cerebrovascular accident with 
minor or no residua, and patients who have had transient ischemic attacks. 
If the CVA resulted in hemiplegia, code only hemiplegia
5.  Does the patient have hemiplegia?
Yes       No  
Criteria: This includes patients with a hemiplegia or paraplegia, whether it occurred as a result of a 
cerebrovascular accident or other condition
6.  Does the patient have asthma, chronic lung disease, chronic 
bronchitis or emphysema?
Yes       No  
Criteria: Pulmonary disease includes patients with asthma, chronic bronchitis, emphysema, and other 
chronic lung disease who have ongoing symptoms such as dyspnea or cough, with mild or moderate 
activity.  This includes patients who are dyspneic with slight activity, with or without treatment and 
those who are dyspneic with moderate activity despite treatment, as well as patients who are dyspneic 
at rest, despite treatment, those who require constant oxygen, those with CO2 retention and those with 
a baseline PO2 below 50 torr.
7.  Does the patient have diabetes that requires treatment?
Yes       No  
Criteria: Diabetes includes all patients with diabetes treated with insulin or oral hypoglycemic, but not 
diet alone. Diabetes during pregnancy alone is not counted.
7a. Does the patient have end organ damage from diabetes?
Yes       No  
Criteria: This includes patients with retinopathy, neuropathy, or nephropathy attributable to diabetes.
8.  Does the patient have moderate or severe renal disease?
Yes       No  
Criteria: Moderate renal insufficiency includes patients with a serum creatinine >3 mg/dl. Severe renal 
disease includes patients on dialysis, those who had a transplant, and those with uremia.
9.  Does the patient have a chronic liver disease?
Yes       No  
Criteria: Mild liver disease consists of chronic hepatitis (B or C) or cirrhosis without portal hypertension.
9a. Does the patient have moderate to severe liver disease?
Yes       No  
Criteria: Moderate liver disease consists of cirrhosis with portal hypertension, but without bleeding. 
Severe liver disease consists of patients with ascites, chronic jaundice, portal hypertension or a history 
of variceal bleeding or those who have had liver transplant.
10. Has the patient had gastric or peptic ulcers?
Yes       No  
Criteria: Peptic ulcer disease includes patients who have required treatment for ulcer disease, 
including those who have bled from ulcers.


Appendix 9
Age-Adjusted Charlson Comorbidity Index Worksheet (Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
143/Protocol MO29983, Version 15
11. Has the patient had cancer?
Yes       No  
If yes, which:
Lymphoma? 
Leukemia?
Melanoma?
Prostate cancer?
Solid tumor (which?)    
       
Criteria: Lymphoma includes patients with Hodgkins, lymphosarcoma, Waldenstrom’s 
macroglobulinemia, myeloma, and other lymphomas. Leukemia includes patients with acute and 
chronic myelogenous leukemia, acute and chronic lymphocytic leukemia, and polycythemia vera.  
Solid tumor consists of patients with solid tumors without documented metastases, including breast, 
colon, lung, prostate, and a variety of other tumors.
11a. Does the patient have (or has he or she had) a metastatic 
solid tumor?
Breast
Colon
Prostate
Lung
Melanoma
Urothelial and/or 
non-urothelial cancer?
Other
Criteria:  Metastatic cancer includes patients with metastatic solid tumors, including breast, lung, colon 
and other tumors
12. Does the patient have Alzheimer’s, dementia from any 
etiology or any serious cognitive impairment?
Yes       No  
Criteria: Dementia includes patients with moderate to severe chronic cognitive deficit resulting in 
impaired function from any cause.
13. Does the patient have any rheumatic or connective tissue 
disease?
Yes       No  
Criteria: Rheumatologic disease includes patients with systemic lupus erythematous, polymyositis, 
mixed connective tissue disease, rheumatoid arthritis, polymyositis, polymyalgia rheumatica, vasculitis, 
sarcoidosis, Sjogrens syndrome or any other systemicvasculitis
14. Does the patient have HIV or AIDS?
Yes       No  
Criteria: Acquired immune deficiency syndrome includes patients with definite or probable AIDS, i.e. 
AIDS related complex, and those who are HIV positive and asymptomatic.
15. Does the patient have hypertension?
Yes       No  
Criteria: Hypertension includes patients who have systolic pressures >140 mm Hg and/ or diastolic 
pressures >90 mm Hg if without diabetes or renal disease, as well as controlled hypertensives; or 
patients with diabetes or renal disease who have systolic
pressures >140 mm Hg or diastolic pressures >80 mm Hg.
16. Has the patient had decubitus ulcers, peripheral skin ulcers 
or repeated episodes of cellulitis?
Yes       No  


Appendix 9
Age-Adjusted Charlson Comorbidity Index Worksheet (Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
144/Protocol MO29983, Version 15
Criteria: Partial thickness loss of skin over legs or back with open ulcers or two or more episodes of 
cellulitis requiring treatment with antibiotics, regardless of etiology.
17. Does the patient have depression?
Yes       No  
Criteria: Patients who are currently receiving treatment for depression, whether pharmacologic or 
psychotherapy, or cognitive behavioral therapy, or notes indicating that the patient has probable or 
definite depression.
18. Is the patient on warfarin or coumadin?
Yes       No  
CONDITIONS THAT ARE NOT ASSIGNED WEIGHTS:

Angina includes patients with chronic exertional angina, those who had coronary 
artery bypass graft, and those initially admitted with unstable angina

Arrhythmia includes patients with chronic atrial fibrillation or flutter, sick sinus 
syndrome, or ventricular arrhythmias requiring chronic treatment.

Valvular disease includes patients with hemodynamically significant aortic stenosis 
and/or insufficiency, those with significant mitral stenosis and/or insufficiency, and 
those with prosthetic aortic or mitral valves, asymmetric septal hypertrophy requiring 
treatment, or tricuspid insufficiency

Other neurologic conditions includes patients with Parkinson’s disease, uncontrolled 
seizures, or syncope without an identified cause or treatment

Other endocrine includes patients with hypopituitarism, adrenal insufficiency, and 
recurrent acidosis

Inflammatory bowel disease includes patients with ulcerative colitis or regional 
enteritis

Gastrointestinal bleeding includes those who have had bleeding requiring 
transfusions from causes other than ulcer disease

Coagulopathy includes patients with a circulating anticoagulant, or other 
coagulopathy


Atezolizumab—F. Hoffmann-La Roche Ltd
145/Protocol MO29983, Version 15
Appendix 10
Corticosteroid Dose Equivalents
Equivalent Dose
Steroid
1.2 mg
Betamethasone (long-acting)
1.5 mg
Dexamethasone (long-acting)
8 mg
Methylprednisolone (intermediate-acting)
8 mg
Triamcinolone (intermediate-acting)
10 mg
Prednisone (intermediate-acting)
10 mg
Prednisolone (intermediate-acting)
40 mg
Hydrocortisone (short-acting)
50 mg
Cortisone (short-acting)
http://emedicine.medscape.com/article/2172042-overview.


Atezolizumab—F. Hoffmann-La Roche Ltd
146/Protocol MO29983, Version 15
Appendix 11
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.  The decision to re-challenge patients with atezolizumab
should be based on investigator's assessment of benefitrisk and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab in this study.
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 10 mg/day oral prednisone or 
equivalent 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 patient is likely to derive clinical benefit.  The decision to 
re-challenge patients with atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by the investigator.  The Medical Monitor is available to 
advise as needed.  Atezolizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures).  The acceptable length of treatment interruption must 
be based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator. The Medical Monitor is available to advise as needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
147/Protocol MO29983, Version 15
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.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
148/Protocol MO29983, Version 15
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.

For Grade 1 pneumonitis, consider withholding atezolizumab.
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 12 mg/kg/day oral prednisone or equivalent.

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 or events with no improvement after 
48 72 hours of corticosteroids, 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 12 mg/kg/day IV methylprednisolone or 
equivalent.

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 based on an assessment of benefitrisk by the investigator and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
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.  The decision to re-
challenge patients with atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed.








Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
152/Protocol MO29983, Version 15
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 12 mg/kg/day oral prednisone or equivalent. 

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 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent
upon improvement.

If event resolves to Grade 1 or better, resume 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 based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. .
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.  The decision to re-challenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate). The Medical Monitor is 
available to advise as needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
153/Protocol MO29983, Version 15
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 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
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 based on 
an assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. .
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.  The decision to re-challenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
154/Protocol MO29983, Version 15
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.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
155/Protocol MO29983, Version 15
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH closely.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH closely.

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.

Consider patient referral to endocrinologist
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.

Consider patient referral to endocrinologist
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 based on an assessment of benefitrisk by the investigator and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
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.  The decision to
re-challenge patients with atezolizumab should be based on investigator's assessment 
of benefitrisk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
156/Protocol MO29983, Version 15
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 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event resolves to Grade 1 or better 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.

Initiate treatment with insulin if needed.

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

Evaluate for diabetic ketoacidosis and manage as per 
institutional guidelines.

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.  The acceptable length of the extended period of time 
must be based on an assessment of benefitrisk by the investigator and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
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.  The decision to
re-challenge patients with atezolizumab should be based on investigator's assessment 
of benefitrisk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
157/Protocol MO29983, Version 15
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 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

Initiate hormone replacement if clinically indicated.

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 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

Initiate hormone replacement if clinically indicated.
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 based on an assessment of benefitrisk by the investigator and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
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.  The decision to
re-challenge patients with atezolizumab should be based on investigator's assessment 
of benefitrisk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
158/Protocol MO29983, Version 15
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 12 mg/kg/day oral prednisone or equivalent.  

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a 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 based on an assessment of benefitrisk by the investigator and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
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.  The decision to re-challenge 
patients with atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
159/Protocol MO29983, Version 15
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.  
Myocarditis may also be a clinical manifestation of myositis and should be managed 
accordingly.  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.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
160/Protocol MO29983, Version 15  
Table 6 
Management Guidelines for Immune-mediated Myocarditis 
Event 
Management 
Immune-mediated 
myocarditis, Grade 1 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines. 
Immune-mediated 
myocarditis, Grade 2-4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. a 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. a 
 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 Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab documented by should be based on investigator's assessment of benefitrisk and 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed. 
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 


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
161/Protocol MO29983, Version 15
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 1.
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and IFN-(Merad and Martin 2020).  
If a patient develops suspected CRS during the study, a differential diagnosis should 
include SARS-Co V-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator judgment.  If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
162/Protocol MO29983, Version 15
Table 1
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.
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.

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. e

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.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
163/Protocol MO29983, Version 15
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Event
Management
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. e

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.

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. e

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.  For patients who are refractory to 
anti-cytokine therapy, experimental treatments f may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor.

Hospitalize patient until complete resolution of symptoms.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
164/Protocol MO29983, Version 15
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:  These management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for these management guidelines is based on ASTCT consensus grading 
for CRS.  NCI CTCAE v4.0 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 Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate).  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 assessing the benefitrisk ratio.
f
Refer to Riegler et al. (2019).


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
165/Protocol MO29983, Version 15
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 work-up 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 10 
mg/day oral prednisone or equivalent.
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 12 mg/kg/day oral 
prednisone or equivalent.

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.
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 based on an assessment of benefitrisk by 
the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
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.  The decision tore-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by the 
investigator (or an appropriate delegate).  The Medical Monitor is available to advise as needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
166/Protocol MO29983, Version 15
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-mediated 
pancreatitis, Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset.
a

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event 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
Immune-related mediated, 
Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
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 based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.
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.  The decision to re-challenge 
patients with atezolizumab should be based on investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate). The Medical Monitor is 
available to advise as needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
167/Protocol MO29983, Version 15
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self limiting, with or without pruritus.  Although 
uncommon, cases of severe cutaneous adverse reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis have been reported with atezolizumab.  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 for evaluation and, if 
indicated, biopsy.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if 
event does not improve.

If unresponsive to topical corticosteroids, consider oral 
prednisone 0.5 mg/kg/day.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist for evaluation and, if indicated, 
biopsy.

Initiate treatment with 10 mg/day oral prednisone or equivalent, 
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


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
168/Protocol MO29983, Version 15
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 based on an assessment of benefitrisk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as 
needed.
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.  The decision to re-
challenge patients with atezolizumab should be based on investigator's assessment 
of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
169/Protocol MO29983, Version 15
Table 9
Management Guidelines for Dermatologic Events (cont.)
Event
Management
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c
Stevens-Johnson 
syndrome or 
toxic epidermal 
necrolysis (any 
grade)
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis:

Withhold atezolizumab for suspected Stevens-Johnson 
syndrome or toxic epidermal necrolysis.

Confirm diagnosis by referring patient to a specialist 
(dermatologist, ophthalmologist or urologist as relevant) for 
evaluation and, if indicated, biopsy.

Follow the applicable treatment and management guidelines 
above.

If Stevens-Johnson syndrome or toxic epidermal necrolysis, 
permanently discontinue atezolizumab.
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 based on an assessment of benefitrisk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as 
needed.
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.  The decision to re-
challenge patients with atezolizumab should be based on investigator's assessment 
of benefitrisk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
170/Protocol MO29983, Version 15
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 work-up 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 and refer patient to neurologist.

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 

Refer patient to neurologist.

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 12 mg/kg/day oral or IV prednisone or 
equivalent.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
171/Protocol MO29983, Version 15
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 based on an assessment of benefitrisk by the investigator and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
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.  The decision to re-
challenge patients with atezolizumab should be based on investigator's assessment 
of benefitrisk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
172/Protocol MO29983, Version 15
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 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
173/Protocol MO29983, Version 15
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of 
atezolizumab.  Eligible patients must have adequate renal function, and 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.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
174/Protocol MO29983, Version 15
Table 12 Management Guidelines for Renal Events 
Event
Management
Renal event, 
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine and urine protein, 
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. c

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 based on an assessment of benefitrisk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as 
needed.
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.  The decision to
re-challenge patients with atezolizumab should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate 
delegate.  The Medical Monitor is available to advise as needed.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
175/Protocol MO29983, Version 15
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 possible myositis should be referred to a rheumatologist or neurologist.  
Patients with possible myositis should be monitored for signs of myocarditis.
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.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
176/Protocol MO29983, Version 15
Table 13 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-
mediated 
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-
mediated 
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on an assessment of benefitrisk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as 
needed.
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.  The decision to
re-challenge patients with atezolizumab should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed. 


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
177/Protocol MO29983, Version 15
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, permanently discontinue atezolizumab 
and contact Medical Monitor. c

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month..
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
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 based on an assessment of benefitrisk by the 
investigator and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator  The Medical Monitor is available 
to advise as needed.
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.  The decision 
to re-challenge patients with atezolizumab should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate 
delegate.  The Medical Monitor is available to advise as needed. 


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
178/Protocol MO29983, Version 15
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.
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
–
Platelet count 100109/L (100,000/L)
–
ANC 1.0109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard deviations 
above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
179/Protocol MO29983, Version 15
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14.
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 an immunosuppressive 
agent and/or anti-cytokine therapy.

If event does not respond to treatment within 24 hours, contact 
Medical Monitor and initiate treatment as appropriate according 
to published guidelines (La Rosée 2015; Schram and Berliner 
2015; La Rosée et al. 2019)..

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLHhemophagocytic lymphohistiocytosis; MASmacrophage activation syndrome.
REFERENCES
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024.
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906.
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577.
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538.
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.


Appendix 11: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
180/Protocol MO29983, Version 15
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562.
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.
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814.

SAP_001.pdf: 
 
Official Title: 
 
An Open Label, Single arm, Multicenter, Safety Study of Atezolizumab 
in Locally Advanced or Metastatic Urothelial or Non-Urothelial 
Carcinoma of the Urinary Tract 
NCT Number: NCT02928406 
Document Dates: SAP Version 3.0: 14-December-2022 
 
 
 


{Atezolizumab}—{Genentech, Inc.}{F. Hoffmann-La Roche Ltd} 
1/Statistical Analysis Plan { MO29983} 
STATISTICAL ANALYSIS PLAN 
TITLE: 
AN OPEN LABEL, SINGLE ARM, MULTICENTER, 
SAFETY STUDY OF ATEZOLIZUMAB IN LOCALLY 
ADVANCED OR METASTATIC UROTHELIAL OR 
NON-UROTHELIAL CARCINOMA OF THE 
URINARY TRACT 
PROTOCOL NUMBER: 
MO29983 
STUDY DRUG: 
Atezolizumab (MPDL3280A; RO5541267) 
VERSION NUMBER: 
3.0 
IND NUMBER: 
N/A 
EUDRACT NUMBER: 
2016-002625-11 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
 
DATE FINAL: 
14 December 2022 
Amendment: 
NA 
DATE AMENDED: 
NA 


Atezolizumab—F. Hoffmann-La Roche Ltd 
2/Statistical Analysis Plan MO29983 
 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 4 
2. 
STUDY DESIGN ........................................................................................... 4 
2.1 
Protocol Synopsis .................................................................... 5 
2.2 
outcome measures .................................................................. 5 
2.2.1 
Primary Efficacy Outcome Measures ...................................... 5 
2.2.2 
Secondary Efficacy Outcome Measures .................................. 5 
2.2.3 
Exploratory Efficacy Outcome Measures ................................. 6 
2.2.4 
Pharmacokinetic Efficacy Outcome Measures ........................ 6 
2.2.5 
Safety Outcome Measures ...................................................... 6 
2.3 
Determination of Sample Size ................................................. 6 
2.4 
Analysis Timing ....................................................................... 7 
3. 
STUDY CONDUCT ....................................................................................... 8 
3.1 
Randomization Issues ............................................................. 8 
3.2 
Independent Review Facility .................................................... 8 
3.3 
Data Monitoring ....................................................................... 8 
4. 
STATISTICAL METHODS ............................................................................ 8 
4.1 
Analysis Populations ............................................................. 10 
4.1.1 
Randomized Population......................................................... 10 
4.1.2 
Per Protocol Population ......................................................... 10 
4.1.3 
Pharmacokinetic-Evaluable Population ................................. 10 
4.1.4 
Safety Population .................................................................. 10 
4.1.5 
Intent-to-treat population ........................................................ 10 
4.2 
Analysis Of Study Conduct .................................................... 10 
4.3 
Analysis of BASELINE CHARACTERISTICS ........................ 11 
4.4 
Efficacy Analysis .................................................................... 15 
4.4.1 
Primary Efficacy Endpoint ...................................................... 15 
4.4.2 
Secondary Efficacy Endpoints ............................................... 16 
4.4.2.1 Overall Survival .................................................................... 16 
4.4.2.2 Progression-Free Survival .................................................... 17 
4.4.2.3 Overall Response ................................................................. 18 


Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan MO29983 
4.4.2.4 Duration of Response ........................................................... 19 
4.4.2.5 Disease Control .................................................................... 20 
4.4.2.6 QLQ-C30 questionnaire ....................................................... 21 
4.4.2.7 Utilities collected using the EQ-5D-5L for 
pharmacoeconomic models ................................................................ 22 
4.4.3 
Exploratory Efficacy Endpoints .............................................. 22 
4.4.4 
Sensitivity Analyses ............................................................... 22 
4.4.5 
Subgroup Analyses ............................................................... 22 
4.5 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 25 
4.6 
Safety Analyses ..................................................................... 25 
4.6.1 
Exposure of Study Medication ............................................... 25 
4.6.2 
Adverse Events ..................................................................... 26 
4.6.3 
Laboratory Data ..................................................................... 30 
4.6.4 
Vital Signs, Height and Weight .............................................. 31 
4.6.5 
Concomitant medications ...................................................... 31 
4.6.6 
Biomarker Endpoints ............................................................. 31 
4.7 
Missing Data .......................................................................... 31 
4.8 
Interim Analyses .................................................................... 32 
5. 
REFERENCES ........................................................................................... 33 
 
 
LIST OF TABLES 
Table 1 
Two-Sided Clopper-Pearson 95% Confidence Intervals for 
Adverse Event Rate Estimates ..................................................... 7 
Table 2 
Analysis Timing ............................................................................. 8 
 
 
LIST OF APPENDICES 
Appendix 1 
 Protocol Synopsis ...................................................................... 34 
Appendix 2 
 Schedule of Assessments .......................................................... 46 


Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Statistical Analysis Plan MO29983 
1. 
BACKGROUND 
Bladder cancer is the ninth most common cancer in the world (World Cancer Research 
Fund International 2016). In 2012, an estimated 14.1 million people worldwide had 
bladder cancer, of whom 330,380 were newly diagnosed; in the same year, 123,051 
deaths were attributable to the disease (International Agency for Research on Cancer 
2016; World Cancer Research Fund International 2016). In the United States, estimates 
are that 76,960 new cases of bladder cancer will be diagnosed in 2016 (about 58,950 in 
men and 18,010 in women), and 16,390 deaths will occur due to the disease (American 
Cancer Society 2016). 
This study is being conducted to evaluate the safety of atezolizumab as second-line 
treatment for locally advanced or metastatic urothelial or non-urothelial carcinoma of the 
urinary tract. The study will also evaluate treatment efficacy and explore potential tumor 
biomarkers related to atezolizumab. 
The aim of the Statistical Analysis Plan (SAP) for independent Data Monitoring 
Committee (iDMC) is to state the scope and extent of iDMC analyses. 
This SAP is based on the Study Protocol MO29983: 
• 
version 1.0, 21 Jul 2016  
• 
version 2.0, 25 Aug 2016  
• 
version 3.0, 23 Nov 2016  
• 
version 4.0, 31 Jan 2017 (Canada only) 
• 
version 5.0, 19 May 2017 
• 
 version 6.0, 06 Jul 2017 (Canada only) 
• 
version 7.0, 22 Feb 2018 
• 
version 8.0, 07 Mar 2018 (Canada only) 
• 
version 9.0, 08 Oct 2018 
• 
version 10.0, 08 Oct 2018 (Canada only) 
• 
version 11.0, 22 Oct 2019 
• 
version 12.0, 22 Oct 2019 (Canada only) 
• 
version 13.0, 03 Mar 2021 
• 
version 14.0, 04 Mar 2021 (Canada only) 
• 
version 15.0, 17 Dec 2021 
• 
version 16.0, 17 Dec 2021 (Canada only) 
 
2. 
STUDY DESIGN 
Study MO29983 is an open label, single-arm, multicenter study of the safety of 
atezolizumab as second-line treatment for patients with locally advanced or metastatic 
urothelial or non-urothelial carcinoma of the urinary tract.  The study includes evaluation 
of the efficacy of atezolizumab and potential tumor biomarkers associated with 
atezolizumab.   


Atezolizumab—F. Hoffmann-La Roche Ltd 
5/Statistical Analysis Plan MO29983 
Study screening will take place within 28 days prior to initiation of study treatment.  
Eligible patients will be enrolled and begin treatment with 1200 mg atezolizumab 
intravenous (IV) every 3 weeks.  The single agent study treatment will continue until 
investigator-assessed loss of clinical benefit, unacceptable toxicity, investigator or 
patient decision to withdraw from therapy, or death (whichever occurs first). 
During the study treatment period, patients will be followed for safety based on adverse 
event (AE) assessments including vital signs, physical findings and clinical laboratory 
test results.  Efficacy will be evaluated by the investigator according to both Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 and modified RECIST.  Exploratory 
biomarker analyses will be conducted based on primary tumor tissue or biopsied 
metastatic tumor tissue collected at baseline and an optional tumor sample collected at 
the second study treatment cycle.   
Following discontinuation of study treatment, safety assessments will be conducted 
30 days after the last study drug administration or until initiation of other anti-cancer 
therapy (whichever occurs first).  Thereafter, patients will be followed for disease 
progression (unless this has already occurred), serious adverse events (SAEs), AEs of 
special interest, anti-cancer therapy and survival.  Follow-up will continue for up to four 
years after the last patient is enrolled in the study. 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is provided in Appendix 1. For Appendix 1 additional details, see 
the Schedule of Assessments in Appendix 2. 
2.2 
OUTCOME MEASURES 
The primary objective of this study is to evaluate the safety of atezolizumab. The 
secondary objectives of the study include evaluation of the efficacy of atezolizumab. 
Additional secondary study objectives include the evaluation of efficacy of atezolizumab 
according to patient-reported outcomes (PROs). 
2.2.1 
Primary Efficacy Outcome Measures 
 
Not applicable for this study. 
2.2.2 
Secondary Efficacy Outcome Measures 
The following endpoints are defined to evaluate efficacy: 
• 
Overall survival (OS), defined as the time from initiation of study treatment to death 
from any cause. 
• 
Progression-free survival (PFS), defined as the time from initiation of study 
treatment to the first occurrence of disease progression or death from any cause, 
whichever occurs first. PFS will be calculated based on disease status evaluated by 


Atezolizumab—F. Hoffmann-La Roche Ltd 
6/Statistical Analysis Plan MO29983 
investigator according to RECIST v1.1 and also by disease status evaluated by the 
investigator according to modified RECIST  
• 
Overall response rate (ORR), defined as the proportion of patients with a best 
overall response of either complete response (CR) or partial response (PR). ORR 
will be calculated based on disease status evaluated by investigator according to 
RECIST v1.1 and also by disease status evaluated by the investigator according to 
modified RECIST 
• 
Disease control rate (DCR), defined as the sum of the CR, PR and stable disease 
(SD) rates. DCR will be calculated based on disease status evaluated by 
investigator according to RECIST v1.1 and also by disease status evaluated by the 
investigator according to modified RECIST 
• 
Duration of response (DoR), defined as the time from first occurrence of a 
documented response to disease progression or death from any cause, whichever 
occurs first. Duration of response will be calculated based on disease status 
evaluated by investigator according to RECIST v1.1 and also by disease status 
evaluated by the investigator according to modified RECIST 
Additional secondary study objectives include the evaluation of efficacy of atezolizumab 
to the following PROs: 
• 
Change from baseline in health-related quality of life (HRQoL), as assessed using 
the EORTC Quality-of-Life Questionnaire Core 30 (QLQ-C30). 
• 
EuroQol EQ-5D-5L-assessed utility. 
2.2.3 
Exploratory Efficacy Outcome Measures 
Not applicable for this study. 
 
2.2.4 
Pharmacokinetic Efficacy Outcome Measures 
Not applicable for this study. 
2.2.5 
Safety Outcome Measures 
The following endpoints are defined to evaluate safety: 
• 
Nature, severity, duration, frequency and timing of AEs. 
• 
Changes in vital signs, physical findings, and clinical laboratory results during and 
following atezolizumab administration. 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
This is a single-arm safety study. There is no formal statistical hypothesis and all 
analyses will be descriptive. The results for the primary safety variables will be 
presented via percentages and corresponding 95% Clopper-Pearson confidence 
intervals (CIs). 


Atezolizumab—F. Hoffmann-La Roche Ltd 
7/Statistical Analysis Plan MO29983 
A sample size of approximately 1000 patients is planned for this study. The precision of 
(e.g., rare) AE incidence estimates presented by two-sided exact 95% Clopper-Pearson 
CIs are shown in Table 1. 
Table 1 
Two-Sided Clopper-Pearson 95% Confidence Intervals for Adverse 
Event Rate Estimates 
Number of Patients with at 
Least One Event (Expected) 
N=1000 
Expected 
Event Rate 
(%) 
Lower limit 
of CI 
(%) 
Upper limit 
of CI  
(%) 
12 
1.2 
0.62 
2.09 
10 
1.0 
0.48 
1.83 
8 
0.8 
0.35 
1.57 
6 
0.6 
0.22 
1.3 
5 
0.5 
0.16 
1.16 
4 
0.4 
0.11 
1.02 
3 
0.3 
0.06 
0.87 
2 
0.2 
0.02 
0.72 
1 
0.1 
0.00 
0.56 
CI = confidence interval. 
Therefore, for a sample size of 1000 patients and an expected AE incidence of 0.5%, 
based on the half-width of the Clopper-Pearson 95% CI, the true AE rate can be 
estimated with a precision of: ±(1.16% – 0.16%)/2 % = ±0.5 %. 
2.4 
ANALYSIS TIMING 
The primary analysis will occur 6 months after the last patient has been enrolled. 
The final analysis will occur at the end of the study, i.e., approximately 4 years after 
enrollment of the last study patient. 
In addition, iDMC interim safety reviews occurred 3 months after the first patient was 
enrolled and 3 months after 500 patients were enrolled and followed up for safety.  


Atezolizumab—F. Hoffmann-La Roche Ltd 
8/Statistical Analysis Plan MO29983 
Table 2 
Analysis Timing 
Analysis 
Timing of Analysis 
First iDMC review 
At least 3 months after enrollment of the first patient 
Second iDMC review 
 
After 500 patients who reach at least 3-month follow-
up 
 
Optional / additional iDMC 
reviews 
Defined by iDMC at any time during the study period 
Primary analysis 
6 months after the last patient has been enrolled  
Final analysis 
 
End of the study, i.e., approximately 4 (48 month) 
years after enrollment of the last study patient 
 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
Not applicable; study is not randomized. 
3.2 
INDEPENDENT REVIEW FACILITY 
No IRF will be included in this study. 
3.3 
DATA MONITORING 
The iDMC will share with the Sponsor the responsibility to monitor overall patient safety 
and/or efficacy of the Investigational Medicinal Product (IMP) with the objective to 
minimize patient exposure to unnecessary risk. The iDMC will notably review all AEs, 
SAEs and AEs of special interest and cumulative safety data including any death event 
during the scheduled interim analyses.  
The details of the data summaries that will be produced for iDMC are described in the 
SAP on hand (required data for review by iDMC is outlined in the iDMC Charter). 
4. 
STATISTICAL METHODS 
Categorical data will be summarized in terms of the number of patients providing data at 
the relevant time point, frequency counts and percentages; 95% exact Clopper-Pearson 
CI will also be provided when relevant. Missing data will be considered when calculating 
percentages. Therefore, the percentages will be based on the total number of patients in 
the corresponding population and not on the number of non-missing values.  
Unless otherwise specified, time periods are always calculated in months. If the duration 
is given in days, the number of days will be divided by 365.25 and multiplied by 12 to 
have the period shown in months. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
9/Statistical Analysis Plan MO29983 
Continuous data will be summarized using descriptive statistics. Missing data will not be 
imputed, unless otherwise stated. The number of observations being included as well as 
the number of missing observations will be given. Further the mean, standard deviation, 
median, lower (25%) and upper (75%) quartile, minimum and maximum will be used to 
describe the data. The minimum and maximum will be reported to the same number of 
decimal places as the raw data recorded in the database. The mean, median, lower and 
upper quartiles will be reported to one more decimal place than the raw data recorded in 
the database, and the standard deviation to two more decimal places.  
Time to event data will be estimated by the Kaplan-Meier approach with the 
corresponding 95% CIs. 
Two-sided 95% CIs for point estimates will be calculated and presented to one more 
decimal places than the raw data.  
All outputs (tables, listings, figures) will be produced using the statistical analysis 
software SAS®, version 9.3 or higher. The generated outputs will be incorporated into a 
Microsoft® Word 2010 document using portrait or landscape orientation, whatever is 
appropriate, and afterwards printed to PDF. 
Mapping of unscheduled visits:  
In case of an unscheduled assessment prior to the date of first study drug administration, 
the unscheduled assessment will be assigned to the baseline visit.  
In case of an unscheduled assessment after or on the date of first study drug 
administration, the unscheduled assessment will be assigned to the most recent visit 
performed. 
If a patient has more than one assessment assigned to a same visit, the latest value 
assigned to the visit will be used, when presenting data in summary tables by visit. In 
listings by patient by visit all assessments (scheduled and unscheduled) will be 
presented.  
Unscheduled visits will not be considered at all for tabulations of vital signs. In listings, 
these visits will appear as unscheduled without remapping. 
Mapping of progression visits: 
If the patient progresses, the visit where the first occurrence of tumor progression is 
recorded (earliest of the dates of the RECIST component indicating tumor progression) 
will be defined as the progression visit. 
 


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4.1 
ANALYSIS POPULATIONS 
In the study, two populations are distinguished: Safety Population and Intent-To-Treat 
(ITT) Population. The analysis for the iDMC will be provided based on the Safety 
Population.  
4.1.1 
Randomized Population 
Not applicable. 
4.1.2 
Per Protocol Population 
Not applicable for the analyses described in this SAP. 
4.1.3 
Pharmacokinetic-Evaluable Population 
Not applicable for the analyses described in this SAP. 
4.1.4 
Safety Population 
The analysis population for this study will include all enrolled patients who have received 
at least one dose of atezolizumab. The safety population will be used for all baseline and 
safety analyses, unless otherwise stated. 
4.1.5 
Intent-to-treat population  
The ITT population will include all patients who have signed informed consent and met 
all eligibility criteria. The ITT population will be used for all efficacy analyses, unless 
otherwise stated. (According to the Protocol, should the difference between the ITT and 
safety populations have been 5 or fewer patients – which was not the case –, all efficacy 
analyses would have been based only on the safety population). 
 
4.2 
ANALYSIS OF STUDY CONDUCT 
Disposition of patients 
Patients will be considered as having treatment discontinued when the “Study 
Completion/Early Discontinuation” has been captured for the treatment phase. 
Patients will be considered as having discontinued/completed the study when the “Study 
Completion/Early Discontinuation” has been captured for the follow-up phase or the 
treatment phase and it was indicated as the final study period. 
The disposition of patients will be summarized as follows: 
Enrolled patients: 
• 
Number of patients who signed informed consent and met all eligibility criteria, i.e. 
number of patients in the ITT Population 


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• 
Number and percentage of patients who have received at least one dose of 
atezolizumab, i.e. number and percentage of patients in the Safety Population (out 
of the ITT Population) 
• 
Number and percentages of patients who have permanently discontinued 
atezolizumab, overall and by reasons for discontinuation (out of the Safety 
Population) 
• 
Number and percentages of patients who have permanently discontinued 
atezolizumab by cycle and by reasons for discontinuation (out of the Safety 
Population). Discontinuations will be associated with the number of cycles the 
patient received, a cycle being counted when dose >0. A summary table and figure 
will be provided. 
• 
Number and percentages of patients who have discontinued the study, overall and 
by reasons for discontinuation (out of the ITT Population) 
• 
Number and percentages of patients by region, country and site number (out of the 
ITT population and Safety population) 
Following by-patient listing including site, patient identifier and relevant data will be 
provided: 
• 
Enrolled patients 
 
Protocol violations 
A by-patient listing of major protocol violations will be provided. 
 
4.3 
ANALYSIS OF BASELINE CHARACTERISTICS  
Demography and baseline characteristics will be summarized using descriptive statistics 
and frequency tables, respectively, based on the safety population at Baseline.  
A baseline value will be defined as the last available value before or on the date of first 
study drug administration, as follows:  
• 
Assessment with a date prior to the date of first study drug administration  
• 
Assessment with a date equal to the date of first study drug administration, if either 
o It is the screening/baseline visit  
o In case of assessments on the same date as the drug administration, it 
will be assumed that these were performed before the actual time of drug 
intake. 
Demography: 
• 
Descriptive statistics of age in years, age categories (<65, ≥65 -<85 and ≥85 years), 
age categories (<80 and ≥80 years)  
• 
Frequency tables of sex, ethnicity and race 


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Baseline characteristics  
• 
Non-cancer General Medical History  
o Number and percentages of patients with history of any medical condition 
overall and by status of medical condition and by System Organ Class (SOC) 
and Preferred Terms (PT) 
• 
History of Cancer 
o Descriptive statistics of time from primary diagnosis to start of study treatment, 
frequency tables of histological tumor type, non-urothelial tumors sub-type, 
squamous neoplasms sub-type, glandular neoplasms sub-type, 
neuroendocrine sub-type, histological grade, location, TNM classification and 
stage of tumor at primary diagnosis and at study entry, descriptive statistics 
of time from primary diagnosis to diagnosis of metastatic disease 
• 
Prior Tumor Surgery 
o Frequency of patients with prior tumor surgery before entering the study 
o Frequency tables of surgery setting and surgery purpose 
• 
Prior Cancer Radiotherapy  
o Frequency tables therapy setting and given boost 
• 
Prior Systemic Cancer Therapy 
o Frequency tables of therapy intent, highest line of therapy, and information 
regarding platinum treatment. Patients who received prior 
adjuvant/neoadjuvant chemotherapy will be considered as having 0 lines of 
treatment for metastatic disease (irrespective of the line(s) of therapy entered 
in eCRF). 
• 
General Surgery and Procedure History (Non-Cancer)  
o Number and percentages of patients with any relevant surgeries or procedures 
• 
Autoimmune disease  
o Number and percentages of patients who have any history of autoimmune 
disease 
o Number and percentages of patients with resolved diseases, ongoing diseases 
with treatment and ongoing diseases without treatment 
• 
Serology Local 
o HIV test 
▪ Number and percentages of patients with negative, positive and not 
done HIV tests 
▪ Number and percentages of patients with a final negative or positive 
HIV tests 
▪ Descriptive statistics of HIV Load for final positive HIV tests 
▪ Number and percentages of patients suffering from AIDS 


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o Hepatitis Testing 
▪ Number and percentages of patients with negative, positive and not 
done tests regarding Hepatitis B Surface Antigen 
▪ Number and percentages of patients with negative, positive and not 
done tests regarding Anti Hepatitis B Core Antibody 
▪ Number and percentages of patients with negative, positive and not 
done tests regarding Anti Hepatitis B Surface Antibody 
▪ Number and percentages of patients with negative, positive and not 
done tests regarding anti-HCV Antibody 
▪ Number and percentages of patients with negative, positive and not 
done tests regarding anti-HCV RNA 
▪ Number and percentages of patients with negative, positive and not 
done tests regarding anti-HBV DNA 
• 
Female Reproductive Status and Local Pregnancy Test 
o Frequency table of female reproductive status 
o Frequency table of sample type (urine, serum) 
o Frequency of patients with a final negative or positive test result 
• 
Tobacco Use History 
o Number and percentages of patients by tobacco use history and by sex (males 
vs females) 
o Descriptive statistics of smoking duration in years 
• 
Electrocardiogram (ECG) 
o Descriptive statistics of heart rate [beats/min], PQ (PR) duration [ms], QRS 
duration [ms], QT duration [ms], QTcF [ms] 
o Frequency table of ECG result 
• 
Eastern cooperative oncology group (ECOG) Performance Status 
o Frequency table of ECOG score 
• 
Age-adjusted Charlson Comorbidity Index (AACI) 
o Descriptive statistics of the calculated total score 
o Frequency table of the calculated total score 
• 
Brain magnetic resonance imaging/computed tomography (MRI/CT) status 
o Frequency of patients with knowledge, symptoms or suspicion of central 
nervous system (CNS) metastases  
o Frequency of patients with performed MRI/CT Scan 
o Frequency of patients with present metastasis 
o Descriptive statistics of number of metastasis 
• 
Renal impairment at baseline 


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o Descriptive statistics of creatinine clearance 
o Frequency of patients with/without renal impairment 
• 
PD-L1 expression 
o PD-L1 expression by IHC class (IC0 to IC3) 
o PD-L1 expression: IC0/1 or IC2/3 
 
Renal dialysis reported at baseline is defined as ‘No’ for all patients included with 
protocol version < 5 (regardless if any or no dialysis reported or no information given). 
For patients included with protocol version 5 or higher, if patient reports dialysis at 
Screening or Cycle 1 Day 1, then renal dialysis is set to ‘Yes’, otherwise if no dialysis is 
reported or if information is missing then renal dialysis is set to ‘No’. 
The time from diagnosis of primary disease to start of study treatment will be calculated 
in units of years as the difference between the date of start of study treatment and date 
of diagnosis of primary disease plus 1, divided by 365.25. For the calculation of the time 
from diagnosis of primary disease to start of study treatment, replacement rules will be 
applied in case the date of diagnosis of primary disease is incomplete. If day and month 
are missing, they will be imputed by June 30th to allow for time calculation, if only the 
day is missing, it will be imputed by 15. If after imputation, the date of diagnosis of 
primary disease is later than the start date of study treatment, then it will be set to the 
start date of study treatment. 
The time from diagnosis of primary disease to diagnosis of metastatic disease will be 
calculated in units of years as the difference between the date of occurrence of 
metastatic disease and date of diagnosis of primary disease plus 1, divided by 365,25. 
For the calculation of the time from diagnosis of primary disease to diagnosis of 
metastatic disease, replacement rules will be applied for both dates in case dates are 
incomplete. If day and month are missing, they will be imputed by June 30th, if only the 
day is missing, it will be imputed by 15. If after imputation, the date of diagnosis of 
primary disease is later than the date of diagnosis of metastatic disease, then it will be 
set to the date of diagnosis of metastatic disease. 
Creatinine clearance at baseline will be calculated using the Cockcroft-Gault formula:  
 








dL
mg
creatinine
serum
male
if
or
female
if
kg
weight
years
age
mL
clearance
Creatinine
/
72
)
0.1
85
.0
(
)
140
(
min
/



−
=
A patient will be defined as having renal impairment in case creatinine clearance at 
baseline is < 30 mL/min. 
By-patient listing of demographic and baseline characteristics as listed above will be 
provided based on the Safety Population. Prior intravesical therapy will also be listed. 


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For assessments listed above performed at baseline and post-baseline timepoints, the 
corresponding listings will include both baseline and post-baseline assessments. 
Derivations for selected prior platinum regimens are as follows (on regimens level): 
Selected prior platinum regimens 
  
Gemcitabine + Cisplatin 
If patient has at least at least one combination of 
(Gemcitabine or Gemcitabine hydrochloride) + 
Cisplatin within a prior systemic cancer therapy 
Gemcitabine + Carboplatin 
If patient has at least one combination of (Gemcitabine 
or Gemcitabine hydrochloride) + Carboplatin within a 
prior systemic cancer therapy 
Methotrexate + Vinblastine + Cisplatin + 
Adriamycin (MVAC) 
If patient has at least one combination of (Methotrexate 
or Methotrexate sodium) + Vinblastine + Cisplatin + 
(Adriamycin or Doxorubicin or Doxorubicin 
hydrochloride) within a prior systemic cancer therapy 
Methotrexate + Vinblastine + Cisplatin 
(MCV) 
If patient has at least one combination of (Methotrexate 
or Methotrexate sodium) + Vinblastine + Cisplatin, not 
together with (Adriamycin or Doxorubicin or 
Doxorubicin hydrochloride) nor (Epirubicin or Epirubicin 
hydrochloride), within a prior systemic cancer therapy 
Methotrexate + Vinblastine + Cisplatin + 
Epirubicin (MVEC) 
If patient has at least one combination of (Methotrexate 
or Methotrexate Sodium) + Vinblastine + Cisplatin + 
(Epirubicin or Epirubicin hydrochloride) within a prior 
systemic cancer therapy 
 
Derivations for selected regimens for patients who never had prior platinum are as 
follows (on patient-level) 
Patients who never had prior platinum 
regimens  
Number of patients  
Patients with Single-agent Gemcitabine 
If patient has at least one prior systemic cancer therapy 
with Gemcitabine or Gemcitabine Hydrochloride alone 
Patients with Single-agent Vinflunine 
If patient has at least one prior systemic cancer therapy 
with Vinflunine alone   
Patients with Other Regimens 
If patient has neither therapy with Gemcitabine or 
Gemcitabine Hydrochloride alone nor Vinflunine alone but 
any other non-platinum based prior systemic cancer 
therapy 
 
 
4.4 
EFFICACY ANALYSIS 
4.4.1 
Primary Efficacy Endpoint 
Not applicable for this study. 


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4.4.2 
Secondary Efficacy Endpoints 
4.4.2.1 
Overall Survival 
Overall survival (OS) is defined as date of death (due to any cause) or censoring minus 
date of start of study treatment + 1. Patients who never received treatment are censored 
with time equal to 1 day. 
 
Date of death is found either in the “Death Attributed to Progressive Disease” form, in 
the “Study Completion/Early Discontinuation” form (discontinuation date if death) or in 
the “Adverse Event” form. For patients not known to have died, the date of censoring is 
based on data from the Survival Follow-Up CRF or on data in the “Study 
Completion/Early Discontinuation” form: 
• “Date of contact” if “Survival status” is “Alive” 
• “Date last known to be alive” if “Survival status” is “Lost to Follow-up” 
• “Date withdrew consent for survival status” if “Survival status” is “Withdrew consent”.  
• Date of study discontinuation in case the patient discontinued the study 
The date of censoring will be the maximum of those dates. 
In case the patient withdrew consent or is lost to follow-up, but corresponding dates 
were not entered and only the date of contact is filled in on the Survival follow-up form, 
then the date of contact will be used instead. 
If the date of censoring is still missing, the last date where the patient is known to be 
still alive (from any CRF page) will be used. 
For patients known to have died but whose date of death is missing, the date will be 
imputed as the last date where the patient is known to be still alive (from any CRF 
page), but the imputed date will be marked as a death not a censoring. 
For patients known to have died but whose date of death is partial, take the latest of 
the last date where the patient is known to be still alive (from any CRF page) and a 
completion of the partial date where the missing components are taken as 1 for day 
and January for month.  The imputed date will be marked as a death not a censoring. 
 
Survival status up to the discontinuation date for OS analysis is summarized as number 
and percentage of patients who  
• died 
• were still in survival follow-up (still alive)  
• discontinued the survival follow-up (e.g., withdrew consent, lost to follow-up, 
discontinued study). 
A Kaplan-Meier (KM) curve for OS is presented including the  
• number of patients at risk for death (decreasing over time) 
• cumulative number of deceased patients (increasing over time) 
• cumulative number of patients censored for OS (increasing over time) 
every 6 months. 


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Two-sided 95% confidence intervals (CIs) for OS probabilities at 6 months timepoints 
are added to the KM curve. For calculating these CIs:  
• KM estimates are transformed to an unrestricted range by the log(-log(x)) function 
• calculation of CIs by applying normal approximation methods to the transformed 
scaled estimates of the survivor function 
• re-transformation of CIs to the original scale.  
This approach is triggered by option CONFTYPE=LOGLOG in SAS PROC LIFETEST. 
If applicable, median OS is estimated together with a two-sided 95% CI according to the 
method of Brookmeyer and Crowley 1982. 
4.4.2.2 
Progression-Free Survival 
Progression-free survival (PFS) is determined separately on disease status using 
RECIST v1.1 and modified RECIST, both evaluated by the investigator. 
The date of disease progression is derived based on scan/assessment or death dates, 
not on visit dates. RECIST assessments/scans contributing towards a particular visit 
may be performed on different dates.  
 
Progression-Free Survival based per RECIST v1.1 assessments: 
PFS is defined as date of first occurrence of tumor progression (earliest of the dates of 
the RECIST component indicating tumor progression) or date of death (in the absence of 
tumor progression) by any cause or date of censoring, whichever occurs first, minus 
date of start of study treatment + 1. 
For patients not known to have had a tumor progression or died, the date of censoring is 
the latest date of assessment from their last evaluable RECIST assessment or the date 
of start of subsequent cancer therapy whichever occurs first. Patients who never 
received treatment are censored with time equal to 1 day. 
If a patient has no evaluable post-screening RECIST assessments, the patient is 
censored at the day of study treatment initiation unless the patient dies within 18 weeks. 
In the latter case, the death date will be used as the date of disease progression. 
 
Progression-Free Survival based per modified RECIST assessments: 
PFS according to modified RECIST is defined as: 
- 
date of first occurrence of tumor progression after a modified confirmed response if 
the patient is a responder according to modified RECIST or 
- 
 date of first occurrence of tumor progression in case the patient is not a responder 
according to modified RECIST or 
- 
date of death (in the absence of tumor progression) by any cause or  
- 
date of censoring, whichever occurs first, minus date of start of study treatment + 1. 
For patients not known to have had a tumor progression or died after that modified 
response, the date of censoring is the latest date of assessment from their last evaluable 
RECIST assessment or the date of start of subsequent cancer therapy whichever occurs 
first. Patients who never received treatment are censored with time equal to 1 day. 


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If a patient has no evaluable post-screening RECIST assessments, the patient is 
censored with time equal to 1 day unless the patient dies within 18 weeks. In the latter 
case, the death date will be used as the date of disease progression. 
 
The analyses described below are performed separately for PFS based on disease 
status using RECIST v1.1 and for PFS based on disease status using modified RECIST, 
both evaluated by the investigator. 
Study treatment status at date of disease progression (for patients with disease 
progression) or at DCO date used for PFS analysis (for patients without disease 
progression) is summarized. This includes number and percentage of patients who 
• were on study treatment at date of disease progression 
• discontinued study treatment prior to disease progression 
• did not progress and were on study treatment at DCO date  
• did not progress and discontinued study treatment.  
 
A KM curve for PFS is presented including the  
• number of patients at risk for disease progression (decreasing over time) 
• cumulative number of patients with a disease progression (increasing over time) 
• cumulative number of patients censored for disease progression (increasing over time) 
every 6 months time. 
Two-sided 95% CIs for PFS probabilities at 6 months time points are added to the KM 
curve. For calculating these CIs:  
• KM estimates are transformed to an unrestricted range by the log(-log(x)) function 
• calculation of CIs by applying normal approximation methods to the transformed 
scaled 
• re-transformation of CIs to the original scale.  
This approach is triggered by option CONFTYPE=LOGLOG in SAS PROC LIFETEST. 
If applicable, median PFS is estimated together with a two-sided 95% CI according to 
the method of Brookmeyer and Crowley 1982. 
4.4.2.3 
Overall Response 
Overall response is determined separately on disease status using RECIST v1.1 and 
modified RECIST, both evaluated by the investigator. 
Best overall response will be derived differently for RECIST assessments and for 
modified RECIST assessments. 
 
Best overall response based on RECIST v1.1 assessments: 
The assessment of best overall response includes post-screening RECIST assessments 
obtained up to  
• disease progression 


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• death from any cause 
• last evaluable RECIST assessment in the absence of disease progression or death 
• start of a subsequent anti-cancer therapy   
whatever occurs first. 
 
A patient with complete response followed by complete response determined on two 
consecutive investigator assessments (>=4 weeks apart) has confirmed complete 
response as Best Overall Response. 
Otherwise, a patient with complete response followed by partial response or partial 
response followed by complete response or partial response followed by partial 
response determined on two consecutive investigator assessments (>=4 weeks apart) 
has confirmed partial response as Best Overall Response. 
Otherwise, if there exists at least an assessment of CR, PR or SD, then the patient has 
Stable disease as Best Overall Response.  
If the patient has confirmed complete or partial response, the patient is an overall 
responder, otherwise, the patient is an overall non-responder. Therefore, if best overall 
response is Stable Disease, Progressive Disease, Non-Evaluable disease or missing, 
the patient is an overall non-responder.  
Patients who never received treatment are considered as non-responder. 
 
Best overall response based on modified RECIST assessments: 
The assessment of best overall response includes post-screening RECIST assessments 
obtained up to  
• death from any cause 
• last evaluable RECIST assessment in the absence of death 
• start of a subsequent anti-cancer therapy   
whatever occurs first. 
For best overall response based on modified RECIST, all RECIST assessments are 
considered even after progression. 
The calculations of best overall response based on modified RECIST assessments is 
similar to the best overall response based on RECIST v1.1 assessments. 
In case there are more than one occurrence of CR (or PR in the absence of CR), the first 
occurrence of CR (respectively PR) will be considered. 
4.4.2.4 
Duration of Response 
Duration of response (DoR) is determined separately on disease status using RECIST 
v1.1 and modified RECIST, both evaluated by the investigator 
 
Duration of response based on RECIST v1.1 assessments: 


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For overall responders, DoR is defined as the time from the date of first occurrence of a 
confirmed response (CR or PR) to date of tumor progression or death from any cause or 
to censoring date:   
• end of response coincides with the date of tumor progression or death (in the 
absence of tumor progression) used for the PFS endpoint 
• for a patient without disease progression or death following a response, the censored 
end of response coincides with the PFS censoring date (that is latest RECIST 
assessment or start of subsequent cancer therapy whichever occurs first) 
• DoR is computed as date of PFS event or censoring minus date of first response + 1. 
DoR is not defined for overall non-responders. 
Duration of response based on modified RECIST assessments: 
For overall responders, DoR is defined as the time from the date of first occurrence of a 
confirmed response (CR or PR) to date of tumor progression following that confirmed 
response or death from any cause or to censoring date:   
• end of response will be the date of tumor progression after that confirmed response 
or death (in the absence of tumor progression)  
• for a patient without disease progression or death following a response, the censored 
end of response will be the latest RECIST assessment or start of subsequent cancer 
therapy whichever occurs first. 
DoR is not defined for overall non-responders. 
Therefore, in case of disease progression followed by a confirmed response of CR or PR 
(and no confirmed CR or PR before the disease progression), this confirmed response 
will be considered as Best overall response and the duration of response will start from 
this confirmed response until next disease progression or death or censoring. 
Additionally, a descriptive KM curve (including estimated median) for DoR is provided 
based on patients with an overall response.  
4.4.2.5 
Disease Control 
Disease control is determined separately on disease status using RECIST v1.1 and 
modified RECIST, both evaluated by the investigator.  
Disease control rate (DCR) is defined as the sum of the CR, PR and stable disease (SD) 
rates. 
A patient with complete response followed by complete response determined on two 
consecutive investigator assessments (>=4 weeks apart) has confirmed complete 
response as Best Overall Response. 
Otherwise, a patient with complete response followed by partial response or partial 
response followed by complete response or partial response followed by partial 
response determined on two consecutive investigator assessments (>=4 weeks apart) 
has confirmed partial response as Best Overall Response. 
Otherwise, if there exists at least an assessment of CR, PR or SD, then the patient has 
Stable disease as Best Overall Response.  
Patients who never received treatment are considered as non-responder. 


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4.4.2.6 
QLQ-C30 questionnaire 
In this study, health-related quality of life (HRQoL) are assessed using the EORTC 
Quality-of-Life Questionnaire Core 30 (QLQ-C30, European Organisation for Research 
and Treatment of Cancer 2016, Aaronson et al 1993). 
The EORTC QLQ-C30 consists of 30 questions, which are combined to produce 5 
functional scales (Physical, Role, Cognitive, Emotional, Social), 3 symptom scales 
(Fatigue, Pain, Nausea/vomiting), 6 individual symptom items (dyspnoea, insomnia, 
appetite loss, constipation, diarrhoea and financial difficulties) and a global health status.  
A score ranging from 0 to 100 is derived for each of the functional scales, symptom 
scales, symptom items and the global health status according to the EORTC QLQ-C30 
Scoring Manual, 3rd Edition (Fayers et al 2001). In particular:   
• higher scores on the global health status and functional scales indicate better health 
status/function 
• higher scores on the symptoms scales and symptom items indicate greater symptom 
burden. 
If at least half the components of a scale are present in a EORTC QLQ-C30 
questionnaire, the score is calculated. Otherwise, the score is set to missing. 
In addition, the change from baseline (post-baseline value minus baseline value) is 
calculated for each of the functional scales, symptom scales, symptom items and the 
global health status. 
 
EORTC QLQ-C30 questionnaire: compliance  
EORTC QLQ-C30 questionnaire compliance rate over time is calculated separately for 
each EORTC QLQ-C30 visit (Day 1 of first 3 study treatment cycles, then with tumor 
assessments) by using numbers of expected questionnaires as defined below:  
• the expected number of EORTC QLQ-C30 questionnaires at a specific EORTC QLQ-
C30 visit is either the 
o number of patients attending Day 1 visit of cycles 1, 2 or 3, respectively 
o number of patients attending a tumor assessment visit, respectively  
Number of patients with expected questionnaires, all questions completed, at least one 
question completed and no question at all completed are summarized at each scheduled 
EORTC QLQ-C30 visit. 
EORTC QLQ-C30 questionnaire: summaries by visits 
Summaries by visit, including changes from baseline, are provided for the EORTC QLQ-
C30 scores for 
• each of the 5 functional scales 
• each of the 3 symptom scales 
• each of the 6 individual symptom items 
• the global health status.   
EORTC QLQ-C30 questionnaire will not be presented for primary analysis. 


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4.4.2.7 
Utilities collected using the EQ-5D-5L for pharmacoeconomic 
models 
The EuroQol 5-Dimension Questionnaire (EQ-5D-5L) is a self-report health status 
questionnaire that consists of 6 questions used to calculate a health utility score for use 
in health economic analysis (Herdman et al 2011; Janssen et al 2013).  
There are two components to the EuroQol EQ-5D:  
• a five-item health state profile that assesses mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression,  
• a visual analogue scale (VAS) that measures health state.  
Overall scores range from 0 to 1, with low scores representing a higher level of 
dysfunction.  
Country-specific, published utility functions would allow for creation of a single summary 
score for health-economic modelling.  Such modelling is outside the scope of this SAP. 
EQ-5D questionnaire compliance rate over time is calculated separately for each EQ-5D 
visit (Day 1 of first 3 study treatment cycles, then with tumor assessments) by using 
numbers of expected questionnaires as defined below:  
• the expected number of EQ-5D questionnaires at a specific EQ-5D visit is either the 
o number of patients attending Day 1 visit of cycles 1, 2 or 3, respectively 
o number of patients attending a tumor assessment visit, respectively  
Number of patients with expected questionnaires, all questions completed, at least one 
question completed and no question at all completed are summarized at each scheduled 
EQ-5D visit. 
 
Summaries by visit, including changes from baseline, are provided for the EQ-D scores 
for 
• each of the 5 dimensions 
• the visual analogue scale 
EQ-5D questionnaire will not be presented for primary analysis. 
 
4.4.3 
Exploratory Efficacy Endpoints 
Not applicable for this study. 
4.4.4 
Sensitivity Analyses 
No formal sensitivity analyses are pre-planned. 
4.4.5 
Subgroup Analyses 
Secondary efficacy endpoints are also analyzed by the following subgroups: 
• ECOG Performance status: 0–1 vs. 2 
• Presence of CNS metastases at baseline: yes vs. no 


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• Renal impairment at study entry: yes vs. no 
• Creatine clearance at study entry (mL/min): 15-<30 vs 30-<60 vs >=60 
• Sex: female vs. male 
• HIV status: negative vs. positive 
• Patients aged ≥65 years: yes vs. no 
• Patients aged ≥70 years: yes vs. no 
• Patients aged ≥75 years: yes vs. no 
• Patients aged ≥80 years: yes vs. no 
• Patients aged 65-<75 vs 75-<80 vs >=80  
• History of autoimmune disease: yes vs. no 
• Progression on, or within 12 months of, prior platinum-based treatment: yes vs. no 
• Concomitant steroid treatment ongoing at baseline: yes vs. no 
• History of non-urothelial or mixed urinary tract carcinoma histology: yes vs. no 
• Tumor location: Ureter vs Renal Pelvis vs all UTUC (Ureter or Renal Pelvis) vs 
Bladder 
• Prior Lines of Treatment for Metastatic Disease (0 vs 1 vs. 2 vs. 3) 
• Age-adjusted Charlson comorbidity index (AACI): ≤ 11 vs. > 11 
• PD-L1 expression: IC2/3 vs. IC0/1 
• PD-L1 expression by IHC Class: IC0 to IC3 
• IMvigor211-like patients: yes vs. no 
• Region: Australia/Canada/Western Europe vs Eastern Europe vs Other regions 
 
All subgroup analyses are based on the same methods for statistical analyses of the 
respective secondary efficacy endpoint. Graphical displays such as forest plots are used 
to visualize the homo-/heterogeneity of secondary efficacy endpoint results across 
different levels of the subgroups defined above (proportions and 95% CI, or KM medians 
and corresponding 95% CI as applicable). 
 
The subgroup PD-L1 expression will be derived from the percentage of tumor area 
infiltrating immune cells as follows: 
IC=0 (<1%), IC=1 (≥1% - <5%), IC=2 (≥5% - <10%), IC=3 (≥10%). 
 
The subgroup “IMvigor211-like patients” is defined as follows: 
Patients with: 
• ECOG Performance status: 0–1 
• Presence of CNS metastases at baseline: no 
• Renal impairment at study entry: no 
• Patient with renal dialysis reported at baseline: no 
• HIV status: negative 
• History of autoimmune disease: no 


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• Progression on, or within 12 months of, prior platinum-based treatment: yes 
• Concomitant steroid treatment ongoing at baseline: no 
• History of non-urothelial or mixed urinary tract carcinoma histology: no 
• Prior Lines of Treatment for Metastatic Disease: 0 or 1 or 2  
• Patients aged ≥65 years: indifferent 
• Patients aged ≥70 years: indifferent 
• Patients aged ≥75 years: indifferent 
• Patients aged ≥80 years: indifferent 
• Age-adjusted Charlson comorbidity index (AACI): indifferent 
• PD-L1 expression: indifferent 
• Region: indifferent 
• Sex: indifferent 
 
All adverse events/deaths tables and RECIST based efficacy tables by subgroup PD-L1 
Expression IC2/3 vs IC0/1 will be further broken down by IMvigor211-like patients 
subgroup. 
All RECIST based efficacy tables by subgroup PD-L1 Expression IC0/1 will be further 
broken down by IMvigor211-like patients subgroup and by Prior Lines of Treatment for 
Metastatic Disease= 0. 
All RECIST based efficacy tables by subgroup PD-L1 Expression by IHC Class (IC0 to 
IC3) will be further broken down by IMvigor211-like patients subgroup. 
 
All adverse events/deaths tables and RECIST based efficacy tables by subgroup PD-L1 
Expression IC2/3 vs IC0/1 will be further broken down by Prior Lines of Treatment for 
Metastatic Disease: 0 to 3 subgroup. 
 
All RECIST based efficacy tables by subgroup ECOG will be further broken down by the 
following subgroups: 
• Patients aged ≥65 years: yes 
• Patients aged ≥70 years: yes 
• Patients aged ≥75 years: yes 
• Patients aged ≥80 years: yes 
 
Positive and negative associations between subgroups will also be tested pairwise and 
reported. An association between 2 subgroups is positive when lower limit of 80 % 
Clopper-Pearson Confidence interval of percentage of patients in subgroup 1 within 
subgroup 2 is higher than the percentage of patients in subgroup 1 in the whole 
population. An association between 2 subgroups is negative when upper limit of 80 % 
Clopper-Pearson Confidence interval of percentage of patients in subgroup 1 within 
subgroup 2 is lower than the percentage of patients in subgroup 1 in the whole 
population. 
Associations will be tested pairwise among the following 12 subgroups: ECOG 
Performance status =2, Progression on, or within 12 months of, prior platinum-based 


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treatment, Concomitant steroid treatment ongoing at baseline, History of non-urothelial 
or mixed urinary tract carcinoma histology, AACI: > 11, Renal impairment at study entry, 
female patients, male patients, HIV status positive, History of autoimmune disease, 
Presence of CNS metastases at baseline, Patients aged ≥ 65 years, Patients aged ≥ 70 
years; Patients aged ≥ 75 years, Patients aged ≥ 80 years and PD-L1 expression IC2/3. 
Only positive and negative associations will be reported in table. 
 
4.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not applicable for this study. 
 
4.6 
SAFETY ANALYSES 
The safety analyses will be conducted on the Safety Population. 
4.6.1 
Exposure of Study Medication 
Data of atezolizumab administration will be summarized using descriptive statistics and 
frequency tables, respectively, based on the Safety Population, considering all exposure 
data until the date of last study treatment, as reported for treatment phase on the Study 
Completion/Early Discontinuation page of the electronic case report form (eCRF). 
The duration of treatment will be calculated in units of days as the difference of the start 
date of treatment until the date of the most recent study treatment at data cut-off plus 1, 
converted into months as described in section 4. 
A treatment cycle is defined as 3 weeks (+/- 3 days) in duration. An atezolizumab 
treatment cycle will be counted as such if the first atezolizumab administration is given 
for this cycle.  
The relative dose intensity of atezolizumab will be calculated as the total dose 
administered between the first and the last administration of study treatment divided by 
the amount of planned dose for this period multiplied by 100.  
The total dose will be calculated as the sum of all doses that where administered during 
the time interval between the first and the last administration of study treatment, as 
entered on the eCRF.  
The planned dose will be calculated as the amount of drug which should have been 
received during the time interval between the first and the last administration of study 
treatment based on a dose level of 1200 mg every 3 weeks, accounting for the 
theoretical duration of the last cycle.  Consequently, the calculation of the planned dose 
will be performed as follows: 


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

21
1200
)
21
(

+
−
=
date
dose
first
date
dose
last
mg
dose
Planned
 
Time on treatment will be presented in two ways.  First, for the purposes of describing 
the exposure to atezolizumab at the time of analysis, it will be presented in standard 
summary form without taking account of censoring. Second, for the purposes of 
estimating the time spent on treatment phase by the end of the study, it will be analyzed 
using the Kaplan-Meier method. A patient with a recorded end of treatment phase before 
or on the cut-off date will be considered as having experienced an end of treatment 
event on the date of last dose. Patients with ongoing treatment at the cut-off date will be 
censored at the time of last dose before or on cut-off date. 
Duration of follow-up time will also be calculated using the reverse Kaplan-Meier method 
(that is, using the time variable for the Overall Survival (efficacy) analysis with the 
censoring flag reversed)  
Atezolizumab exposure will be summarized as follows:  
• 
Number of patients with infusion by cycle 
• 
Descriptive statistics for time on treatment [months] 
• 
Kaplan-Meier analysis of time on treatment and corresponding Kaplan-Meier plot 
• 
Number of treatment cycles per patient during study 
• 
Descriptive statistics for relative dose intensity 
• 
Frequency table of treatment cycles by dose (categorized in original, below and 
above dose [dose = 1200mg, dose < 1200mg, dose > 1200mg])  
• 
Number of patients with injection/infusion modified, overall and by reason for 
modification. 
• 
Number of patients with dose modification, overall and by reason for modification 
A by-patient listing of exposure data including site, patient identifier will be provided 
based on the Safety Population.  
Additionally, for responders, the number of subjects treated after response by the 
number of cycles of treatment after response and the number of subjects still ongoing 
treatment at cutoff date will be presented. For progressors, the number of subjects 
treated after progression by the number of cycles of treatment after progression and the 
number of subjects still ongoing treatment at cutoff date will be presented. This will be 
based on the ITT population. 
4.6.2 
Adverse Events 
Verbatim descriptions of AEs will be mapped to latest version of MedDRA thesaurus 
terms and graded according to the National Cancer Institute Common Terminology 
Criteria version 4.0 (NCI CTCAE v4.0).  


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Multiple occurrences of the same event will be counted once at the maximum severity. 
The following AEs will be initially considered as AEs of special interest: 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal Insufficiency, 
hypothyroidism/hyperthyroidism and hypophysitis 
• 
Hepatitis 
• 
Transaminitis Grade ≥ 2 (Aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) >3x ULN and bilirubin >2x ULN ) OR AST/ALT >10x ULN 
• 
Systemic lupus erythematosus 
• 
Neurological: Guillian-Barre Syndrome, myasthenic syndrome or myasthenia gravis, 
meningoencephalitis 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• 
Myositis 
• 
Myopathies, including rhabdomyolysis 
• 
Vasculitis 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release, 
HLH and MAS 
• 
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 of the protocol) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below:  
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 
a patient exposed to a medicinal product. This term applies only when a 
contamination of the study drug is suspected. 
• 
Cardiac toxicities of Grade ≥ 2 (e.g., atrial fibrillation, myocarditis, pericarditis) 
• 
Autoimmune flare of Grade ≥ 3 
Beside the listed AEs of special interest, Roche will provide a list of MedDRA Preferred 
Terms (basket) during the study to identify the AEs of special interest for the statistical 
analysis. 
Treatment-emergent AEs (TEAEs) will be defined as any AEs with an onset date after 
the start date and time of first administration of study treatment and up to 30 days after 


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the date of last administration of study treatment (For SAEs and AEs of special interest 
up to 90 days).    
AEs with onset on first dosing date, not recorded as starting before study treatment 
administration will be considered as TEAEs. Similarly, AEs with onset date prior first 
dosing date but worsening/change recorded on or after first dosing date will be 
considered as TEAEs. 
Only TEAEs will be included in summary tables. AEs which are not treatment-emergent 
will only be included in the AE listings. 
Patient rates for AEs will be presented and accompanied by the respective two-sided 
95% Pearson-Clopper CIs.  
In any AE summary tables, number and percentage of patients reporting at least one AE 
will be provided. In AE summary tables by SOC and PT, the number of reported events 
will be presented additionally.  
Every occurrence of an AE in any patient will be counted in the total number of events. 
In tables presenting frequency of AEs by worst grade, only the event with the highest 
grade will be counted when there are multiple occurrences of a same AE in one patient. 
A missing NCI CTCAE grade will be imputed as follows: for a fatal AE, as Grade 5; for a 
non-fatal AE, as Grade 4. 
 
A summary table will be provided presenting: 
• 
Number and percentage of patients with any TEAE 
• 
Number and percentage of patients with any Serious TEAE 
• 
Number and percentage of patients with any related TEAE 
• 
Number and percentage of patients with any related Serious TEAE 
• 
Number and percentage of patients with any TEAE leading to study drug 
discontinuation 
• 
Number and percentage of patients with any grade 3 to 4 TEAE 
• 
Number and percentage of patients with any grade 5 TEAE 
• 
Number and percentage of patients with any AESI 
• 
Number and percentage of patients with any grade 3 to 5 AESI 
• 
Number and percentage of deaths, overall and by reason 
• 
Number and percentage of deaths on study treatment (i.e. within 30 days post last 
study treatment administration), overall and by reason 
Following safety data will be summarized: 


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• 
TEAEs by SOC, PT and by worst grade 
• 
TEAEs of grade 3 to 5, by PT and by worst grade 
• 
TEAEs of grade 5, by PT  
• 
TEAEs leading to study drug discontinuation, by SOC and PT 
• 
TEAEs leading to study discontinuation, by SOC and PT 
• 
TEAEs related to study drug, by SOC, PT and worst grade 
• 
Serious TEAEs by SOC, PT and worst grade 
• 
Serious TEAEs related to study drug, by SOC and PT 
• 
AEs of special interest by category, PT and worst grade (with additional column for 
AESI of grade >=3) 
Death cases will be summarized as follows: 
• 
Number of death events, overall and by primary cause of deaths, occurrence of an 
autopsy, number of death events within 30 days/ later than 30 days to 90 days and 
later than 90 days after first study treatment administration, number of death events 
within 30 days/ later than 30 days to 90 days and later than 90 days after last study 
treatment administration 
• 
Number of death events by number of cycles started (1 cycle, 2 cycles, 3 cycles, 4 
cycles, 5 cycles or more and broken down by number of days since last dose: <=30 
days, >30-<=90 days or >90 days) and by primary cause of death and occurrence of 
an autopsy. A death event will be associated with the number of cycles the patient 
received, a cycle being counted when dose >0. A summary table and the 
corresponding figure will be provided. 
By-patient listings based on the safety population will be provided for the following types 
of AEs: 
• 
TEAEs and AEs who do not meet the criteria of TEAEs 
• 
AEs of special interest 
• 
AEs leading to permanent treatment discontinuation 
• 
SAEs 
• 
Fatal AEs (i.e. grade 5 AEs) 
In addition, a by-patient listing of death case will be provided based on the Safety 
Population. Deaths events will be categorized in days since first dose and days since 
last dose: ≤30 days, >30 - ≤90 days or >90days in this listing.  
In the above listings, information relative to the following subgroups of interest will be 
included: 
• 
ECOG Performance status: 0–1 vs. 2 (the category 2 includes patients who 
recorded status 2 at screening but 3 at baseline) 


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• 
Progression on, or within 12 months of, prior platinum-based treatment: yes vs. no 
• 
Concomitant steroid treatment ongoing at baseline: yes vs. no 
• 
History: non-urothelial or mixed urinary tract carcinoma histology vs urothelial 
• 
AACI: ≤ 11 vs. > 11 
• 
Renal impairment at study entry: yes vs. no 
• 
Sex: female vs. male 
• 
HIV status: negative vs. positive 
• 
History of autoimmune disease: yes vs. no 
• 
Presence of CNS metastases at baseline: yes vs. no 
• 
Patients: < 65 years vs. ≥ 65 years 
• 
Patients: < 70 years vs. ≥ 70 years 
• 
Patients: < 75 years vs. ≥ 75 years 
• 
Patients: < 80 years vs. ≥ 80 years 
• 
Prior Lines of Treatment for Metastatic Disease: 0 vs 1 vs. 2 vs. 3  
• 
PD-L1 expression: IC2/3 vs. IC0/1 
• 
PD-L1 expression: IC0 to IC3 
• 
IMvigor211-like patients: yes vs. no 
• 
Regions: Australia/Canada/Western Europe vs Eastern Europe vs Other regions 
In addition, the AE summary table described previously in this section will be repeated 
for each of the above subgroups.  
A by-patient listing of immune-related thyroid disorders on the safety population will also 
be provided. 
 
4.6.3 
Laboratory Data 
Assessments of laboratory parameters including hematology, chemistry, coagulation and 
thyroid panel will be performed as follows: 
• 
For parameters with corresponding NCI-CTCAE grading, shift tables will be 
provided displaying baseline versus worst NCI-CTCAE grade on treatment (last date 
of treatment + 21 days) 
• 
For parameters with no corresponding NCI-CTCAE grading, summary statistics will 
be provided for baseline values, actual values and the change from baseline values 
at post-baseline time points 
Additionally, by-patient listings of all laboratory data, including site and patient identifier 
will be generated based on the safety population. A by-patient listing of ALT, AST, 


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alkaline phosphatase (AP) and total bilirubin assessments for potential Hy´s law cases 
will also be provided. 
4.6.4 
Vital Signs, Height and Weight 
Summary statistics of vital signs including Systolic and Diastolic blood pressure, 
respiratory rate, pulse rate and temperature will be provided for baseline values, actual 
values and the change from baseline values at post-baseline time points. 
Baseline for vital signs will be defined as follows: 
• 
Select Vital signs at “Cycle 1 Day 1 - Within 60 min before Infusion” if (date/time 
of measurement and date/time of first treatment are both given and date/time of 
vital sign ≤ date/time of first treatment) OR if ((time of measurement or time of 
first treatment missing) and measurement and first treatment are on same date) 
• 
Otherwise select closest measurement before first treatment (i.e. last Screening 
measurement as we do not consider unscheduled visits). 
 
Vital signs information will be presented by a by-patient-by-visit listing, including site, 
patient identifier, date of assessment and study day, cycle, height, weight, Systolic and 
Diastolic blood pressure, respiratory rate, pulse rate as well as body temperature.  
4.6.5 
Concomitant medications 
Subsequent anti-cancer therapies will be summarized overall and by type of anti-cancer 
therapy on the Safety Population. 
By-patient listings including site and patient identifier will be provided for each of the 
following type of therapies based on the Safety Population:  
• 
Concomitant Medications (separately for corticosteroids, immunosuppressive 
medications and any other medications)  
• 
On-study Surgery and Procedure (Non-Cancer) 
• 
On-Study Cancer Radiotherapy 
• 
On-Study Tumor Surgery data.  
• 
Subsequent anti-cancer therapies  
4.6.6 
Biomarker Endpoints 
Not applicable for this study. 
 
4.7 
MISSING DATA 
Missing or partial dates of death are imputed as described in Section 4.4.2.1 for Overall 
Survival analysis. 


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Missing NCI CTCAE grade will be imputed as described in Section 4.6.2 for Adverse 
events. 
 
4.8 
INTERIM ANALYSES 
There was no formal interim analysis in the study. However, regular safety data reviews 
were performed by iDMC. 
The iDMC interim safety reviews occurred 3 months after the first patient was enrolled 
and 3 months after 500 patients were enrolled and followed up for safety.  
Analysis 
Timing of Analysis 
First iDMC review 
Three months after enrollment of the first patient 
Second iDMC review 
After 500 patients who reach at least 3 months follow up 
Optional iDMC reviews 
Defined by iDMC at any time during the study period 


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5. 
REFERENCES 
Aaronson NK, Ahmedzai S, et al. The European Organisation for Research and 
Treatment of Cancer. QLQ-C30: a quality-of-life instrument for use in international 
clinical trials in oncology. J Natl Cancer Inst 1993;85:365-376. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 
1982;38:29-41. 
European Organisation for Research and Treatment of Cancer. EORTC QLQC30. 2016. 
Retrieved April 2016 from http://groups.eortc.be/qol/eortc-qlq-c30. 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of 
the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). 
Published by: European Organisation for Research and Treatment of Cancer, Brussels 
2001. 
Herdman M, Gudex C, et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:1727-1736. 
Janssen MF, Pickard AS, et al. Measurement properties of the EQ-5D-5L compared to 
the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life Res 
2013;22:1717-1727. 
 


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Appendix 1 
PROTOCOL SYNOPSIS 
TITLE: 
AN OPEN LABEL, SINGLE ARM, MULTICENTRE, SAFETY STUDY 
OF ATEZOLIZUMAB IN LOCALLY ADVANCED OR METASTATIC 
UROTHELIAL OR NON-UROTHELIAL CARCINOMA OF THE 
URINARY TRACT 
PROTOCOL NUMBER: 
MO29983 
VERSION NUMBER: 
9 
EUDRACT NUMBER: 
2016-002625-11 
IND NUMBER: 
120827 
TEST PRODUCT: 
Atezolizumab (MPDL3280A; RO5541267) 
PHASE: 
IIIB 
INDICATION: 
Advanced or metastatic urothelial or non-urothelial carcinoma of the 
urinary tract 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study is being conducted to evaluate the safety of atezolizumab as second-line treatment 
for locally advanced or metastatic urothelial or non-urothelial carcinoma of the urinary tract.  The 
study will also evaluate treatment efficacy and explore potential tumor biomarkers related to 
atezolizumab.  Specific objectives and corresponding endpoints for the study are outlined below. 
 
Primary Objective 
The primary objective of this study is to evaluate the safety of atezolizumab based on the 
following endpoints: 
• 
Nature, severity, duration, frequency and timing of adverse events (AEs) 
• 
Changes in vital signs, physical findings, and clinical laboratory results during and following 
atezolizumab administration 
 
Secondary Objectives 
The secondary objectives of the study include evaluation of the efficacy of atezolizumab based 
on the following disease response endpoints: 
• 
Overall survival (OS), defined as the time from initiation of study treatment to death from 
any cause 
• 
Progression-free survival (PFS), defined as the time from initiation of study treatment to the 
first occurrence of disease progression or death from any cause, whichever occurs first.  
PFS will be calculated based on disease status evaluated by the investigator according to 
RECIST v1.1, and also by disease status evaluated by the investigator according to 
modified RECIST 
• 
Overall response rate (ORR), defined as the proportion of patients with a best overall 
response of either complete response (CR) or partial response (PR).  ORR will be 
calculated based on disease status evaluated by the investigator according to RECIST v1.1, 
and also by disease status evaluated by the investigator according to modified RECIST 


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• 
Disease control rate (DCR), defined as the sum of the CR, PR and stable disease (SD) 
rates.  DCR will be calculated based on disease status evaluated by the investigator 
according to RECIST v1.1, and also by disease status evaluated by the investigator 
according to modified RECIST 
• 
Duration of response (DoR), defined as the time from first occurrence of a documented 
response to disease progression or death from any cause, whichever occurs first.  Duration 
of response will be calculated based on disease status evaluated by the investigator 
according to RECIST v1.1, and also by disease status evaluated by the investigator 
according to modified RECIST 
 
Additional secondary study objectives include the evaluation of efficacy of atezolizumab 
according to the following patient-reported outcomes (PROs; Appendix 4): 
• 
Change from baseline in health-related quality of life (HRQoL), as assessed using the 
EORTC Quality-of-Life Questionnaire Core 30 (QLQ-C30) 
• 
EuroQol EQ-5D-5L-assessed utility 
 
Exploratory Objectives 
Exploratory study objectives may include evaluations of atezolizumab efficacy according to 
additional efficacy endpoints. 
 
Biomarker Objectives 
The biomarker objectives of the study are as follows: 
• 
To evaluate PD-L1 prevalence based on retrospective evaluation of PD-L1 expression in 
tumor tissue measured by IHC.  PD-L1 testing may be conducted on a subset of samples at 
local laboratories for inter-laboratory concordance evaluation  
• 
The study also includes exploratory biomarker objectives to examine centrally assessed 
biomarkers and biomarker profiles in tumor tissue, and to correlate these with safety and/or 
efficacy outcomes.  Biomarkers and biomarker profiles may be assessed using various 
methodologies including, but not limited to, IHC (single and multiplex, e.g., PD-L1 
expression and immune cell infiltration analyses), RNA and DNA analysis (e.g., mutation 
and expression analyses) 
 
Study Design 
Description of Study 
Study MO29983 is an open label, single-arm, multicenter study of the safety of atezolizumab as 
second-line treatment for patients with locally advanced or metastatic urothelial or non-urothelial 
carcinoma of the urinary tract.  The study includes evaluation of the efficacy of atezolizumab 
and potential tumor biomarkers associated with atezolizumab.  An overview of study design is 
shown in the Synopsis Figure. 
Study screening will take place within 28 days prior to initiation of study treatment.  Eligible 
patients will be enrolled and begin treatment with 1200 mg atezolizumab IV every 3 weeks.  The 
single agent study treatment will continue until investigator-assessed loss of clinical benefit, 
unacceptable toxicity, investigator or patient decision to withdraw from therapy, or death 
(whichever occurs first). 
During the study treatment period, patients will be followed for safety based on AE assessments 
including vital signs, physical findings and clinical laboratory test results.  Efficacy will be 
evaluated by the investigator according to both RECIST v1.1 (Appendix 3) and modified 
RECIST (Appendix 2).  Exploratory biomarker analyses will be conducted based on primary 
tumor tissue or biopsied metastatic tumor tissue collected at baseline and an optional tumor 
sample collected at the second study treatment cycle.   
Following discontinuation of study treatment, safety assessments will be conducted 30 days 
after the last study drug administration or until initiation of other anti-cancer therapy (whichever 
occurs first).  Thereafter, patients will be followed for disease progression (unless this has 


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already occurred), SAEs, AEs of special interest, anti-cancer therapy and survival.  Follow-up 
will continue for up to four years after the last patient is enrolled in the study. 
An iDMC established for the study reviewed all AEs, SAEs and AEs of special interest and 
cumulative safety data. 
 
Synopsis Figure. Study Schema 
 
 
 
ECOG PS, Eastern Cooperative Oncology Group performance status; MVAC, methotrexate, 
vinblastine, doxorubicin, and cisplatin; GC, gemcitabine and cisplatin. 
 
 
Number of Patients 
Approximately 1000 patients with locally advanced or metastatic urothelial or non-urothelial 
carcinoma of the urinary tract who progressed on one to three prior combination lines of 
systemic therapy for inoperable, locally advanced or metastatic urothelial or non-urothelial 
carcinoma of the urinary tract will be enrolled in this study.  Patients who discontinue the study 
prior to study treatment initiation will not be replaced. 
 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Signed informed consent form 
2. Age ≥ 18 years 
3. Is, according to the investigator’s judgment, able to comply with the study protocol  
4. Histologically documented locally advanced (T4b, any N; or any T, N 2−3) or metastatic (M1, 
Stage IV) urothelial or non-urothelial carcinoma of the urinary tract 
– 
Urinary tract carcinoma includes carcinoma of the bladder, ureter, urethra, and renal 
pelvis 
– 
Primary non-urothelial carcinoma includes all sub-types listed in the WHO classification 
(see Appendix 8) 
Bellini collecting duct tumors are allowed if independently reviewed by two expert 
pathologists from different sites 
 
– 
Lymphoma, sarcoma, and renal cell carcinoma are excluded 
 
5. Patients with measurable and/or non-measurable disease according to RECIST v1.1 are 
allowed 


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6. Must have progressed during or following treatment with at least one (and not more than 3) 
prior treatments for inoperable, locally advanced or metastatic urothelial or non-urothelial 
carcinoma of the urinary tract 
– 
Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed 
within 12 months of treatment will be considered as having a first line of treatment for 
metastatic disease 
– 
Patients who were intolerant to prior systemic treatment are allowed as long as they 
had received at least 2 treatment cycles 
– 
Platinum- or non-platinum-based chemotherapy regimens are allowed 
– 
Low-dose chemotherapy given as radiosensitizer for curative treatment of localized 
disease does not count as a line of systemic chemotherapy 
 
7. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimen block available 
for submission  
– 
Only tissue from core needle (with ≥ 3 cores), punch, incisional, excisional, or forceps 
biopsies will be accepted.  Fine-needle aspiration, brushing, bone tissue, and lavage 
samples are not acceptable 
– 
If an appropriate tumor specimen is not available, a sample will be collected by biopsy 
during the study screening period 
– 
ONLY at sites where local laws and regulations prohibit the sending of tumor specimen 
blocks to an outside central laboratory, specimen slides are acceptable.  A minimum of 
15 unstained serially-cut sections must be prepared and sent per tumor sample.  For 
details, please refer to the Sample Handling Manual 
 
8. Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1 or 2 
9. Life expectancy ≥ 12 weeks 
10. Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 2 weeks prior to the first study treatment: 
– 
Absolute neutrophil count ≥ 1500 cells/µL (without granulocyte colony-stimulating 
factor support within 2 weeks prior to the first study treatment) 
– 
White blood cell count > 2500/µL 
– 
Lymphocyte count ≥ 500/µL 
– 
Platelet count ≥ 100,000/µL (without transfusion within 2 weeks prior to the first study 
treatment) 
– 
Hemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic treatment 
to meet this criterion) 
– 
Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase 
≤ 2.5 times the upper limit of normal (ULN), with the following exceptions: 
Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN 
Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 × 
ULN 
 
– 
Serum bilirubin ≤ 1.5 ×ULN. Patients with known Gilbert disease who have serum 
bilirubin level ≤ 3 × ULN may be enrolled 
– 
Calculated creatinine clearance ≥ 15 mL/min (Cockcroft-Gault formula) 
– 
International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 
1.5 ×ULN.  This applies only to patients who are not receiving therapeutic 
anticoagulation; patients receiving therapeutic anticoagulation must be on a stable 
dose 
 
11. Patients with treated, asymptomatic central nervous system (CNS) metastases are eligible, 
provided they meet all of the following criteria:  
– 
Evaluable disease outside the CNS  


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38/Statistical Analysis Plan MO29983 
– 
No history of intracranial or spinal cord hemorrhage  
– 
No evidence of significant vasogenic edema  
– 
No stereotactic radiation within 7 days or whole-brain radiation or neurosurgical 
resection within 2 weeks before the start of study treatment  
– 
Have had a screening CNS radiography ≥ 2 weeks since completion of radiotherapy or 
surgical resection  
– 
Radiographic demonstration of interim stability (i.e. no progression) between the 
completion of CNS-directed therapy and the screening radiographic study  
 
Note: Patients on stable doses of anticonvulsants or on prednisone doses (or dose 
equivalents) of ≤ 20 mg/day are allowed  
 
12. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of   1% 
per year during the treatment period and for at least 5 months after the last dose of 
atezolizumab 
– 
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 
(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 trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
13. Treatment with more than three prior lines of systemic therapy for inoperable, locally 
advanced or metastatic urothelial or non-urothelial carcinoma of the urinary tract 
14. Treatment with any other investigational agent or participation in another clinical trial with 
therapeutic intent within 4 weeks prior to study treatment initiation 
– 
Patients who were in another clinical trial with therapeutic intent within 4 weeks of 
study treatment initiation but were not on active drug in that prior trial are eligible 
– 
Patients who were in another clinical trial with therapeutic intent within 4 weeks of 
study treatment initiation but were in the follow-up phase of that prior trial and had 
stopped receiving active drug 4 or more weeks before study treatment initiation are 
eligible 
 
15. Treatment with chemotherapy within 2 weeks prior to study treatment initiation 
16. Treatment with radiotherapy ongoing at the time of study entry (for CNS-directed 
radiotherapy, please refer to Inclusion Criterion 11)  
17. Pregnant or lactating, or intending to become pregnant during the study 
– 
Women who are not postmenopausal (postmenopausal defined as ≥ 12 months of 
non-therapy-induced amenorrhea) or surgically sterile must have a negative serum 
pregnancy test result within 2 weeks prior to initiation of study drug 
 
18. Evidence of significant uncontrolled concomitant disease that could affect compliance with 
the protocol, including significant liver disease (such as cirrhosis, uncontrolled major seizure 
disorder, or superior vena cava syndrome) 


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19. Malignancies other than the one studied in this protocol within 5 years prior to 
Cycle 1, Day 1 
– 
Patients with localized low risk prostate cancer (defined as Stage ≤ pT2b, Gleason 
score ≤ 7, and prostate-specific antigen [PSA] at prostate cancer diagnosis ≤ 20 ng/mL) 
treated with curative intent and without PSA recurrence are eligible 
– 
Patients with pre-existing low risk prostate cancer (defined as Stage T1/T2a, Gleason 
score ≤ 6, and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active 
surveillance are eligible 
– 
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of 
metastasis or death < 5% at 5 years) are eligible provided they meet all of the following 
criteria: 
Malignancy treated with expected curative intent (such as adequately treated 
carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal 
carcinoma in situ treated surgically with curative intent) 
No evidence of recurrence or metastasis by follow-up imaging and any disease-
specific tumor markers 
 
20. Significant cardiovascular disease, such as New York Heart Association cardiac disease 
≥ Class III, myocardial infarction within 3 months, unstable arrhythmias, or unstable angina 
– 
Patients with known coronary artery disease or left ventricular ejection fraction < 50% 
must be on a stable medical regimen that is optimized in the opinion of the treating 
physician, in consultation with a cardiologist if appropriate 
 
21. Significant renal disorder indicating a need for renal transplant 
22. Signs or symptoms of severe infection within 2 weeks prior to initiation of study treatment, 
including but not limited to, hospitalization for complications of infection, bacteremia, or 
severe pneumonia 
23. Major surgical procedure within 4 weeks prior to study treatment initiation or anticipation of 
need for a major surgical procedure during the course of the study other than for diagnosis 
24. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
25. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation 
26. History of autoimmune disease (Appendix 5) are allowed if controlled and on stable 
treatment (i.e., same treatment, same dose) for the last 12 weeks, with the exception of: 
– 
Patients taking concurrent abatacept or belatacept treatment, unless therapy has been 
withdrawn for > 8 weeks 
– 
Patients with a history of serious or life threatening immune-related events 
– 
No more than 1 concomitant autoimmune disease at the time of study entry is allowed 
unless one of them is:  
Autoimmune-related hypothyroidism on a stable dose of thyroid replacement 
hormone  
Controlled Type I diabetes mellitus on a stable dose of insulin regimen 
A medical history of such entities as atopic disease or childhood arthralgias, 
where the clinical suspicion of autoimmune disease is low.  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) 
Vitiligo 
 
27. Prior allogeneic stem cell or solid organ transplantation 
28. History of idiopathic pulmonary fibrosis (including pneumonitis, drug-induced pneumonitis, 
organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest computed tomography (CT) scan 


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– 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted 
 
29. Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen 
[HBsAg] test at screening) or hepatitis C 
– 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as having a negative HBsAg test and a positive antibody to hepatitis B core antigen 
[anti-HBc] antibody test) are eligible 
– 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV RNA 
 
30. Active tuberculosis 
31. Administration of a live, attenuated vaccine within 4 weeks prior to study treatment initiation 
– 
Influenza vaccination should be given during influenza season only (e.g., 
approximately October to March in the Northern Hemisphere and April through 
September in the Southern Hemisphere) and must not be a live, attenuated vaccine.  
– 
Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 
weeks prior to study treatment initiation or at any time during the study treatment, and 
so for 5 months thereafter 
 
32. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
anti−CTLA-4, anti−PD-1, and anti−PD-L1 therapeutic antibodies 
– 
Patients who have received prior treatment with anti-CTLA-4 may be enrolled provided 
at least 5 half-lives (approximately 75 days) have elapsed from the last dose of 
anti−CTLA-4 to the first dose of atezolizumab and there was no history of severe 
immune-related adverse effects from anti-CTLA-4 (NCI CTCAE Grade 3 or 4) 
 
33. Treatment with systemic immunostimulatory agents (including, but not limited to, interferons 
or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to 
initiation of study treatment 
– 
Prior cancer vaccines and cellular immunotherapy are permitted 
 
34. Specifically for patients without autoimmune disease: treatment with systemic 
corticosteroids or other systemic immunosuppressive medications (including, but not limited 
to, prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, 
thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to study treatment 
initiation or anticipated requirement for systemic immunosuppressive medications during 
the study treatment period 
– 
For patients with CNS metastases, use of prednisone at a dose (or dose equivalent) of 
≤ 20 mg/day is acceptable  
– 
Chronic use of prednisone or equivalent should be discussed with the Medical Monitor 
– 
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and 
low-dose supplemental corticosteroids for adrenocortical insufficiency and topical 
steroids for cutaneous diseases are allowed. 
 
Note: For patients with autoimmune disease, immunosuppressive medications are 
permitted if the patient has controlled autoimmune disease and stable treatment (i.e., same 
treatment, same dose) for the previous 12 weeks. 
 
 
End of Study 
The end of study will occur when all patients enrolled have either died, withdrawn consent, are 
lost to follow up, or have been followed for 48 months since the last study patient is enrolled, 
whichever occurs first. 
 


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Length of Study 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 6 years. 
 
Investigational Medicinal Product 
The investigational medicinal product (IMP) for this study is atezolizumab. 
 
Formulation, Packaging, and Handling 
The atezolizumab drug product will be provided in a single-use, 20-cc USP/Ph. Eur. Type 1 
glass vial as a colorless to slightly yellow, sterile, preservative-free clear liquid solution intended 
for IV administration.  The vial is designed to deliver 20.0 mL (1200 mg) of atezolizumab 
solution, but may contain more than the stated volume to enable delivery of the entire 20.0 mL 
volume.  The atezolizumab drug product is formulated as 60 mg/mL atezolizumab in 20 mM 
histidine acetate, 120 mM sucrose, 0.04% polysorbate 20, pH 5.8. 
Atezolizumab must be refrigerated at 2°C–8°C (36°F–46°F) upon receipt until use.  
Atezolizumab vials should not be used beyond the expiration date provided by the manufacturer.  
No preservative is used in the atezolizumab drug product; therefore, each vial is intended for 
single use only.  Vial contents should not be frozen or shaken and should be protected from 
direct sunlight. 
For further details, see the Atezolizumab Pharmacy Manual and Investigator’s Brochure. 
Dosage, Administration, and Compliance 
The dose of atezolizumab in this study will be 1200 mg administered by intravenous infusion 
every 3 weeks (21 [± 3] days).  No dilution of the vial contents is required. 
Administration of atezolizumab will be performed in a setting with emergency medical facilities 
and staff who are trained to monitor for and respond to medical emergencies. 
For more detailed information on drug preparation, storage and administration, refer to the 
Atezolizumab Investigator’s Brochure and Pharmacy Manual. 
The initial dose of atezolizumab will be delivered over 60 (± 15) minutes.  If the first infusion is 
tolerated without infusion-associated AEs, the second infusion may be delivered over 30 (± 10) 
minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered 
over 30 (± 10) minutes.  For the first infusion, the patient’s vital signs (heart rate, respiratory rate, 
blood pressures, and temperature) should be determined within 60 minutes before, during 
(every 15 [± 5] minutes), and 30 (± 10) minutes after the infusion.  For subsequent infusions, 
vital signs will be collected within 60 minutes before the infusion, during the infusion if clinically 
indicated, and within 30 (± 10) minutes after the infusion.   
Patients will be informed about the possibility of delayed post-infusion symptoms and instructed 
to contact their study physician if they develop such symptoms. 
No premedication will be allowed for the first dose of atezolizumab.  Premedication may be 
administered for Cycles ≥ 2 at the discretion of the treating physician.  The management of 
infusion-related reactions will be according to severity as follows: 
• 
In the event that a patient experiences a mild (NCI CTCAE Grade 1) infusion-related event, 
the infusion rate should be reduced to half the rate being given at the time of event onset.  
Once the event has resolved, the investigator should continue to deliver the infusion at the 
reduced rate for 30 (± 10) minutes.  If tolerated, the infusion rate may then be increased to 
the original rate 
• 
In the event that a patient experiences a moderate infusion-related event (NCI CTCAE 
Grade 2) or flushing, fever, or throat pain, the patient should have his or her infusion 
immediately interrupted and should receive aggressive symptomatic treatment.  The 
infusion should be restarted only after the symptoms have adequately resolved to baseline 
grade.  The infusion rate at restart should be half of the infusion rate that was in progress at 
the time of the onset of the infusion-related event 


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• 
For severe or life-threatening infusion-related events (NCI CTCAE Grade 3 or 4), the 
infusion should be stopped immediately, and aggressive resuscitation and supportive 
measures should be initiated.  Patients experiencing severe or life-threatening infusion-
related events will not receive further infusion and will be further managed as clinically 
indicated until the event resolves 
 
For anaphylaxis precautions, see Appendix 6. 
Guidelines for dosage modification, treatment interruption or discontinuation, and the 
management of specific adverse events are provided in Section 5.1.2. 
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  AEs associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF. 
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, storage and 
administration. 
 
Concomitant Therapy 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient between the 7 days preceding the screening evaluation and the treatment 
discontinuation visit.  All such medications should be reported to the investigator and recorded 
on the Concomitant Medications eCRF.  
 
Permitted Therapy  
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine and/or famotidine or another H2 receptor 
antagonist, as per standard practice (equivalent medications may be substituted per local 
practice).  Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation or respiratory distress should be 
managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and β2-
adrenergic agonists; see Appendix 6). 
Systemic corticosteroids and tumor necrosis factor−α inhibitors may attenuate potential 
beneficial immunologic effects of treatment with atezolizumab, but may be administered at the 
discretion of the treating physician after consultation with the Medical Monitor (see Exclusion 
Criterion 23 [Section 4.1.2]).  If feasible, alternatives to corticosteroids should be considered.  
Premedication may be administered for cycles ≥ 2 at the discretion of the treating physician 
after consultation with the Medical Monitor.  The use of inhaled corticosteroids for COPD and 
mineralocorticoids (e.g., fludrocortisone) and low-dose corticosteroids for patients with 
orthostatic hypotension or adrenocortical insufficiency is allowed.  Megestrol administered as an 
appetite stimulant is acceptable while the patient is enrolled in the study. 
Colony-stimulating factors, such as granulocyte colony-stimulating factor and erythropoietin, 
should only be used according to manufacturers’ labels and the ASCO and ASCO/ASH 
guidelines (Smith et al. 2006; Rizzo et al. 2010).   
Influenza vaccination should be given during influenza season only (approximately October to 
March in the Northern Hemisphere) and must not be a live, attenuated vaccine.  Patients must 
not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to study 
treatment initiation or at any time during the study treatment, and for 5 months thereafter. 
Patients who use hormonal therapy with gonadotropin-releasing hormone agonists or 
antagonists for prostate cancer, oral contraceptives, hormone-replacement therapy, 
prophylactic or therapeutic anticoagulation therapy (such as low molecular weight heparin or 
warfarin at a stable dose level), or other allowed maintenance therapy (see Section 4.1.2) 
should continue their use. 
All concomitant medications should be reported to the investigator and recorded on the 
appropriate eCRF. 
 


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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: 
• 
Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, or investigational agents 
(except for maintenance therapies outlined in Section 4.1.1 and 4.1.2) 
– 
After completion of Cycle 1, certain forms of radiotherapy may be considered for 
palliation if patients are deriving benefit (e.g., treatment of known bone metastases or 
symptomatic hematuria)  
 
• 
Traditional herbal medicines are not recommended 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 
• 
Patients who are receiving a receptor activator of nuclear factor kappa B ligand inhibitor 
(denosumab) prior to enrollment must be willing and eligible to receive a bisphosphonate 
instead while on study; denosumab could potentially alter the activity and the safety of 
atezolizumab 
• 
Patients should not receive abatacept or belatacept treatment (those who were receiving it 
must stop it > 8 weeks before study entry) 
 
Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to initiation of study 
treatment, during atezolizumab treatment, and for 5 months after the discontinuation of 
atezolizumab. 
Patients are not allowed to receive immunostimulatory agents, including but not limited to 
interferon (IFN)-α, IFN-γ, or IL-2, during the entire study.  These agents, in combination with 
atezolizumab, could potentially increase the risk for autoimmune conditions. 
With the exception of autoimmune disease patients, patients should not receive 
immunosuppressive medications, including but not limited to cyclophosphamide, azathioprine, 
methotrexate, and thalidomide.  These agents could potentially alter the activity and the safety 
of atezolizumab.   
Systemic corticosteroids, immunosuppressive medications, and TNF-  inhibitors may attenuate 
potential beneficial immunologic effects of treatment with atezolizumab. Therefore, in situations in 
which systemic corticosteroids, immunosuppressive medications, or TNF-  inhibitors would be 
routinely administered, alternatives, including antihistamines, should be considered. If the 
alternatives are not feasible, systemic corticosteroids, immunosuppressive medications, and 
TNF-  inhibitors may be administered at the discretion of the investigator after consultation with 
the Medical Monitor. If feasible, alternatives to these agents should be considered.  
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy. 
 
Patients with CNS metastases are allowed to receive anticonvulsants and steroid treatments if 
the dose of prednisone is ≤ 20 mg / day (or equivalent).  
In addition, all patients (including those who discontinue the study early) should not receive 
other immunostimulatory agents for 10 weeks after the last dose of atezolizumab. 
The above list of medications is not necessarily comprehensive.  The investigator should 
consult the prescribing information for any concomitant medication and contact the Medical 
Monitor if questions arise regarding medications not listed above. 
 
Statistical Methods 
All qualitative data will be presented in contingency tables, using absolute and relative 
frequencies, unless otherwise stated.  Percentages will be rounded to the first decimal place, 
and therefore may not always add up to 100%.  When applicable, 95% confidence intervals (CI) 
will be presented with estimates of proportions.  


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All quantitative data will be summarized via relevant descriptive statistics, such as number of 
observations with available measurements, mean, standard deviation, median, first and third 
quartiles (Q1 and Q3) when applicable, and minimum and maximum.  
Time to event data will be summarized via Kaplan-Meier (KM) estimates/curves and median 
with corresponding 95% CI. 
All analyses will be performed in SAS, version 9.3. 
Primary Analysis 
The primary endpoint of the study is the incidence of treatment-emergent AEs.  Verbatim 
descriptions of AEs will be mapped to MedDRA thesaurus terms and graded according to the 
National Cancer Institute Common Terminology Criteria version 4.0.  Multiple occurrences of 
the same event will be counted once at the maximum severity. 
Other safety variables will include: 
• 
Drug exposure (treatment duration, number of doses, dose intensity and dose 
modifications/discontinuations, with reasons) 
• 
All AEs 
• 
SAEs 
• 
AEs (grade 3–5) 
• 
AEs of special interest 
• 
AEs leading to study drug discontinuation or interruption 
• 
Changes in vital signs from baseline 
• 
Changes in physical findings from baseline 
• 
Changes in selected laboratory parameters from baseline 
• 
Deaths and cause of death 
• 
Concomitant medications 
 
The incidence of AEs will be summarized by frequency tables.  Corresponding 95% Clopper-
Pearson confidence intervals (CIs) will be presented, as applicable.  Time to first incidence of 
selected event types will also be estimated and presented graphically using the Kaplan-Meier 
method. 
Treatment exposure, discontinuation rate, and cause of death will be analyzed by frequency 
tables.  When appropriate, median time on treatment will be estimated by the Kaplan-Meier 
approach or univariate statistics, presenting mean, median, quartiles, minimum, maximum and 
standard deviation. 
Changes in vital signs and physical findings from baseline will be tabulated and presented 
graphically when applicable. 
Worst grades for laboratory parameters and newly occurring Grade 3 and 4 laboratory values 
during treatment will be summarized by frequency tables.  
Concomitant medications recorded during the study will be summarized by frequency tables. 
Determination of Sample Size   
This is a single-arm safety study.  There is no formal statistical hypothesis and all analyses will 
be descriptive.  The results for the primary safety variables will be presented via percentages 
and corresponding 95% Clopper-Pearson CIs. 
A sample size of approximately 1000 patients is planned for this study.  The precision of rare 
AE incidence estimates presented by two-sided exact 95% Clopper-Pearson CIs are shown in 
the Synopsis Table. 
 


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Synopsis Table. Two-Sided Clopper-Pearson 95% Confidence Intervals for Adverse 
Event Rate Estimates 
 
Number of Patients with at 
Least One Event (Expected) 
N=1000 
Expected 
Event Rate 
(%) 
Lower limit 
of CI 
(%) 
Upper limit 
of CI  
(%) 
12 
1.2 
0.62 
2.09 
10 
1.0 
0.48 
1.83 
8 
0.8 
0.35 
1.57 
6 
0.6 
0.22 
1.3 
5 
0.5 
0.16 
1.16 
4 
0.4 
0.11 
1.02 
3 
0.3 
0.06 
0.87 
2 
0.2 
0.02 
0.72 
1 
0.1 
0.00 
0.56 
CI = confidence interval. 
 
Therefore, for a sample size of 1000 patients and an expected AE incidence of 0.5%, based on 
the half-width of the Clopper-Pearson 95% confidence interval, the true AE rate can be 
estimated with a precision of:  ±(1.16% – 0.16%)/2 % = ±0.5 %. 
 
Interim Analyses 
An Independent Data Monitoring Committee (iDMC) conducted interim reviews of accumulated 
safety data.  The first review was performed three months after enrollment of the first patient.  
The iDMC performed another overall safety review after 500 patients have been followed up for 
3 months.   






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Abbreviations: aPTT: activated partial thromboplastin time; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EORTC: 
European Organisation for Research and Treatment of Cancer; INR: international normalized ratio; PD: progressive disease. 
Note: Unless otherwise indicated, assessments scheduled on the study treatment days should be performed prior to initiation of study treatment 
infusion. 
a. Written informed consent is required for performing any study-specific tests or procedures.  Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent and within 28 days prior to study entry (except where otherwise specified) may be used for 
screening assessments rather than repeating such tests.  
b. Medical history includes surgical and cancer histories.  Cancer history includes stage, date of diagnosis, and prior anti-cancer treatment.  
Reproductive status and smoking history should also be captured.  Demographic information includes age, sex, and self-reported 
race/ethnicity.  
c. ECG recordings will be obtained during screening and when clinically indicated.  Patients should be resting and in a supine position for at least 
10 minutes prior to each ECG collection.  
d. A representative formalin-fixed paraffin-embedded (FFPE) archival tumor block must be submitted.  If an archival tumor block is not available, a 
tumor FFPE block obtained by biopsy during screening must be submitted.  Only tissue from core needle (with ≥ 3 cores), will be accepted.  
Cytological samples (such as, for example, from fine-needle aspirations) and bone tissue are not acceptable.  ONLY at sites where local laws 
and regulations prohibit the sending of tumor specimen blocks to an outside central laboratory, slides (≥15) are acceptable.  
Only for patients eligible for the study and who submitted archival tissue, an optional tumor biopsy may be taken during screening.    
e. For patients who underwent screening biopsy, an optional tumor sample ideally from the same lesion may be taken at Cycle 2, Day 1 (± 1 
week), if feasible. 
f. 
A complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF.  At subsequent visits (or as clinically indicated), limited, 
symptom-directed physical examinations should be performed.  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. 
g. ECOG Performance Status, limited physical examination, and local laboratory assessments may be obtained ≤ 96 hours before Day 1 of each 
cycle.  It is not necessary to repeat these assessments again prior to Cycle 1 if they have been conducted for screening within this time period. 
h. Vital signs include respiratory rate, heart rate, systolic and diastolic blood pressures while the patient is in a seated position, and temperature.  
Treatment cycle Day 1 vital sign assessments will be done prior to study treatment.  
i. 
HIV testing will be performed in accordance with national and/or institutional guidelines.  HBV serology includes HBsAg testing. HCV serology 
includes anti-HCV antibody testing and, if indicated due to anti-HCV antibody positivity, PCR testing for HCV RNA. See Section 4.5.7. 
j. 
Hematology consists of CBC (including RBC count), hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils, and other cells), and platelet count.  A manual differential may be done if clinically indicated. 
k. Serum chemistry includes glucose, BUN or urea, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, phosphorus, total bilirubin, 
ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.  


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l. 
Urinalysis includes specific gravity, pH, glucose, protein, ketones, and blood. 
m. A serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and 
documented as negative within 14 days prior to Day 1.  On-study pregnancy tests performed every treatment cycle can be conducted with 
serum or urine. 
n. The same radiographic procedure should be used throughout the study for each patient.  A CT (with contrast) or MRI of the head must be 
included in screening tumor assessments for patients with known or suspected CNS disease.  Results must be reviewed by the investigator 
before dosing at the next cycle.  Patients who continue treatment beyond radiographic disease progression assessed per RECIST v1.1 should 
be monitored with a follow-up scan at the next scheduled tumor assessment when the scan frequency is every 9 weeks.  If the scan frequency 
is every 12 weeks, a follow-up scan is recommended at 9 weeks (± 2 weeks) as an unscheduled tumor assessment or earlier if clinically 
indicated.  Investigators may perform additional scans or more frequent assessments if clinically indicated. 
o. Concomitant medications include any prescription medications, over-the-counter medications, or herbal remedies.  At screening, any 
medications the patient has used within the 7 days prior to the screening visit should be documented.  At subsequent visits, changes to current 
medications or medications used since the last documentation of medications will be recorded. 
p. After informed consent has been obtained, but prior to initiation of study drug, only SAEs caused by a protocol-mandated intervention should 
be reported.  After initiation of study drug, all SAEs and AEs of special interest, regardless of relationship to study drug, will be reported until 90 
days after the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  All other AEs, regardless of relationship to 
study drug, will be reported until 30 days after the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  After 
this period, the investigator should report any SAEs or AEs of special interest believed to be related to prior study drug treatment.  The 
investigator should follow each AE 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 SAEs considered to be related to 
study drug or study-related procedures until a final outcome can be reported. 
q. Survival and new anti-cancer therapy follow-up information will be collected via telephone contact, patient medical records, and/or clinic visits 
approximately every 3 months until death, loss to follow-up, end of study, patient withdrawal or study termination by the Sponsor, whichever 
occurs first. 
 
 








Guidelines for the use of the DocuSign electronic signing system 
within F. Hoffmann-La Roche and companies of the Roche Group  
  
LEGAL DISCLOSURE 
By placing my electronic signature on this document, I expressly consent to use and rely on Electronic and Digital 
Signatures and I understand my signature will have the same binding effect as if I was providing a handwritten 
signature. 
I also confirm the email address that I am using as a valid one to be notified and identified electronically, for 
example through the DocuSign System, and/or to identify me as the signer of the document. I should inform Roche 
in the case that the email address changes. 
CONSUMER DISCLOSURE 
From time to time, F. Hoffmann-La Roche and companies of the Roche Group (hereinafter referred to as we, us or 
Company) may be required by law to provide to you certain written notices or disclosures. Described below are the 
terms and conditions for providing to you such notices and disclosures electronically through the DocuSign, Inc. 
(DocuSign) electronic signing system. Please read the information below carefully and thoroughly, and if you can 
access this information electronically to your satisfaction and agree to these terms and conditions, please confirm 
your consent by clicking the ‘I agree’ button at the bottom of this document. 
Consequences of changing your mind 
To indicate to us that you are changing your mind, you must withdraw your consent using the DocuSign ‘Withdraw 
Consent’ form on the signing page of a DocuSign envelope instead of signing it. This will indicate to us that you 
have withdrawn your consent to receive required notices and disclosures electronically from us and you will no 
longer be able to use the DocuSign system to receive required notices and consents electronically from us or to sign 
electronically documents from us. 
All notices and disclosures will be sent to you electronically 
Unless you tell us otherwise in accordance with the procedures described herein, we will provide electronically to 
you through the DocuSign system all required notices, disclosures, authorizations, acknowledgements, and other 
documents that are required to be provided or made available to you during the course of our relationship with you. 
To reduce the chance of you inadvertently not receiving any notice or disclosure, we prefer to provide all of the 
required notices and disclosures to you by the same method and to the same address that you have given us. If you 
do not agree with this process, please let us know as described below. Please also see the paragraph immediately 
above that describes the consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
How to contact us 
You may contact us to let us know of your changes as to how we may contact you electronically, to request certain 
information from us and to withdraw your prior consent to receive notices and disclosures electronically. To do so 
contact the sender of the envelope. 
To advise us of your new email address  
Electronic Record and Signature Disclosure created on: 2/13/2019 7:14:34 PM
Parties agreed to: 


To let us know of a change in your email address where we should send notices and disclosures electronically to 
you, you must send an email message to the sender of the envelope and in the body of such request you must state: 
your previous email address, your new email address.  We do not require any other information from you to change 
your email address. In addition, you must notify DocuSign, Inc. to arrange for your new email address to be 
reflected in your DocuSign account by following the process for changing email in the DocuSign system. 
To withdraw your consent 
To inform us that you no longer want to receive future notices and disclosures in electronic format you may decline 
to sign a document from within your DocuSign session, and on the subsequent page, select the check-box indicating 
you wish to withdraw your consent. 
  
  
  
Acknowledging your access and consent to receive materials electronically 
To confirm to us that you can access this information electronically, which will be similar to other electronic notices 
and disclosures that we will provide to you, please verify that you were able to read this electronic disclosure and 
that you also were able to print on paper or electronically save this page for your future reference and access or that 
you were able to email this disclosure and consent to an address where you will be able to print on paper or save it 
for your future reference and access. Further, if you consent to receiving notices and disclosures exclusively in 
electronic format on the terms and conditions described above, please let us know by clicking the ‘I agree’ button 
below. 
By checking the ‘I agree’ box, I confirm that: 
●        I can access and read this Electronic CONSENT TO ELECTRONIC RECEIPT OF ELECTRONIC 
CONSUMER DISCLOSURES document; and 
●        I can print on paper the disclosure or save or send the disclosure to a place where I can print it, for future 
reference and access; and 
●        Until or unless I notify the account owner as described above, I consent to receive from exclusively 
through electronic means all notices, disclosures, authorizations, acknowledgements, and other documents 
that are required to be provided or made available to me by the account owner during the course of my 
relationship with you.  
●        I acknowledge the information included in the DocuSign Privacy Policy