Conditions: Carcinoma, Transitional Cell
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 809
Healthy volunteers: no

Brief summary:
This Phase III, open-label, randomized, multicenter study is to evaluate the efficacy and safety of adjuvant treatment with atezolizumab compared with observation in participants with muscle-invasive UC who are at high risk for recurrence following resection. Eligible participants were randomized by a 1:1 ratio into atezolizumab group or control group.

Detailed description:

Arms:
arm 1: Participants will receive intravenous (IV) atezolizumab on Day 1 of each 21-day cycle for 16 cycles (up to 1 year). arm 2: Participants will undergo observation starting on Day 1 for 16 cycles (up to 1 year).

Interventions: intervention 1: Atezolizumab
Intervention descriptions: intervention 1: Atezolizumab will be administered at a dose of 1200 milligrams (mg).

Protocol document:
Prot_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol WO29636, Version 10
PROTOCOL
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY OF ATEZOLIZUMAB 
(ANTI–PD-L1 ANTIBODY) VERSUS OBSERVATION 
AS ADJUVANT THERAPY IN PATIENTS WITH 
HIGH-RISK MUSCLE-INVASIVE UROTHELIAL 
CARCINOMA AFTER SURGICAL RESECTION
PROTOCOL NUMBER:
WO29636
VERSION NUMBER:
10
EUDRACT NUMBER:
2014-005603-25
IND NUMBER:
120827
NCT NUMBER:
NCT02450331
TEST PRODUCT:
Atezolizumab (MPDL3280A; RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  1 April 2015
DATES AMENDED:
Version 2:  2 June 2015
Version 3 (UK Only):  28 July 2015
Version 4:  24 September 2015
Version 5:  4 April 2016
Version 6:  14 July 2016
Version 7:  4 October 2017
Version 8:  19 November 2018
Version 9: 3 February 2020
Version 10:  See electronic date stamp below.
 
13-Apr-2020 22:30:49
Title
Approver's Name
Company Signatory
Date and Time (UTC)


At e z oli z u m a b — F. H off m a n n -L a R o c h e Lt d
2/ Pr ot o c ol W O 2 9 6 3 6, V er si o n 1 0
P R O T O C O L A M E N D M E N T, V E R SI O N 1 0 :
R A TI O N A L E
Pr ot o c ol W O 2 9 6 3 6 h a s b e e n a m e n d e d pri m aril y t o all o w m or e fl e xi bilit y o n t h e ti mi n g of 
di s e a s e a s s e s s m e nt vi sit s f oll o wi n g t h e pri m ar y a n al y si s. C h a n g e s t o t h e pr ot o c ol, 
al o n g wit h a r ati o n al e f or e a c h c h a n g e, ar e s u m m ari z e d b el o w:

F oll o wi n g t h e pri m ar y a n al y si s, p ati e nt s w h o ar e i n Y e ar s 1 3 or Y e ar s 2 3 , a s 
a p pli c a bl e, of t h e st u d y a n d ar e i n di s e a s e r e c urr e n c e f oll o w -u p m a y n o w b e 
a s s e s s e d f or r e c urr e n c e e v er y 2 4 w e e k s ( S e cti o n s 3. 1, 4. 5. 5, 4. 6. 1, a n d 
A p p e n di x 1).

T h e r e q uir e m e nt t o h a v e a c o nfir m at or y t u m or bi o p s y at t h e ti m e of di s e a s e 
r e c urr e n c e h a s b e e n m a d e o pti o n al ( S e cti o n s 3. 1, 3. 3. 8, 4. 5. 5, 4. 5. 7. 2, a n d 
A p p e n di x 1) .

E Q -5 D -5 L a s s e s s m e nt s ar e n o l o n g er r e q uir e d f or p ati e nt s w h o ar e i n di s e a s e 
r e c urr e n c e f oll o w-u p or f or p ati e nt s w h o h a v e h a d a D F S e v e nt ( S e cti o n 4. 5. 1 0 a n d 
A p p e n di x 1).

T h e s ur vi v al f oll o w -u p s c h e d ul e h a s b e e n u p d at e d t o f urt h er cl arif y t h at f oll o w-u p
a n d cli ni c vi sit s will b e a p pr o xi m at el y e v er y 3 m o nt h s
fr o m t h e c o m pl eti o n or 
di s c o nti n u ati o n of t h e tr e at m e nt/ o b s er v ati o n p eri o d , a n d t h at pati e nt s w h o h a v e 
c o m pl et e d t h e tr e at m e nt or o b s er v ati o n p h a s e a n d c o nti n u e i n di s e a s e r e c urr e n c e 
f oll o w-u p
e v er y 3 m o nt h s
( S e cti o n 4. 6. 4 a n d A p p e n di x 1).
A d diti o n al mi n or c h a n g e s h a v e b e e n m a d e t o i m pr o v e cl arit y a n d c o n si st e n c y.  
S u b st a nti v e n e w i nf or m ati o n a p p e ar s i n it ali c s.  T hi s a m e n d m e nt r e pr e s e nt s c u m ul ati v e 
c h a n g e s t o t h e ori gi n al pr ot o c ol.
s h o ul d h a v e s ur vi v al f oll o w- u p i n p ar all el a p pr o xi m at el y


Atezolizumab—F. Hoffmann-La Roche Ltd
3/Protocol WO29636, Version 10
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 26
1.1
Background on Muscle-Invasive Urothelial 
Carcinoma ............................................................................. 26
1.1.1
Neoadjuvant Treatment for MIBC.......................................... 27
1.1.2
Adjuvant Treatment for MIBC ................................................ 28
1.2
Background on Atezolizumab................................................ 29
1.2.1
Summary of Nonclinical Studies............................................ 30
1.2.2
Clinical Experience with Atezolizumab .................................. 30
1.2.2.1
Ongoing Clinical Studies........................................................ 30
1.2.2.2
Clinical Safety........................................................................ 31
1.2.2.3
Clinical Activity....................................................................... 35
1.2.2.4
Clinical Pharmacokinetics and Immunogenicity..................... 39
1.3
Study Rationale and Benefit-Risk Assessment...................... 39
2.
OBJECTIVES.............................................................................................. 41
2.1
Efficacy Objectives ................................................................ 41
2.2
Safety Objectives................................................................... 41
2.3
Pharmacokinetic Objective .................................................... 41
2.4
Patient-Reported Outcome Objective .................................... 41
2.5
Exploratory Objective............................................................. 41
3.
STUDY DESIGN......................................................................................... 42
3.1
Description of Study .............................................................. 42
3.1.1
Independent Data Monitoring Committee .............................. 45
3.2
End of Study.......................................................................... 45
3.3
Rationale for Study Design.................................................... 46
3.3.1
Rationale for Primary and Secondary Endpoints................... 46
3.3.2
Rationale for Inclusion of All Patients (All Levels 
of PD-L1 Expression by IHC) in the Study............................. 47
3.3.3
Rationale for Patient Population ............................................ 47


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3.3.4
Rationale for Observation Control Arm.................................. 48
3.3.5
Rationale for Stratification Factors......................................... 49
3.3.6
Rationale for Atezolizumab Dose and Schedule.................... 49
3.3.7
Rationale for Collection of Archival and/or Pre-
Treatment Tumor Specimens ................................................ 50
3.3.8
Rationale for Blood Sampling for Biomarkers and 
for Optional Collection of Tumor Specimens ......................... 51
3.4
Outcome Measures ............................................................... 51
3.4.1
Efficacy Outcome Measures.................................................. 51
3.4.1.1
Primary Efficacy Outcome Measure ...................................... 51
3.4.1.2
Secondary Efficacy Outcome Measures................................ 51
3.4.2
Safety Outcome Measures .................................................... 52
3.4.3
Pharmacokinetic Outcome Measures.................................... 52
3.4.4
Patient-Reported Outcome Measure ..................................... 52
3.4.5
Exploratory Outcome Measures ............................................ 52
4.
MATERIALS AND METHODS .................................................................... 52
4.1
Patients.................................................................................. 52
4.1.1
Inclusion Criteria.................................................................... 52
4.1.2
Exclusion Criteria................................................................... 56
4.2
Method of Treatment Assignment and Blinding..................... 59
4.3
Study Treatment.................................................................... 60
4.3.1
Formulation, Packaging, and Handling.................................. 60
4.3.1.1
Atezolizumab......................................................................... 60
4.3.2
Dosage, Administration, and Compliance.............................. 60
4.3.2.1
Atezolizumab......................................................................... 60
4.3.3
Investigational Medicinal Product Accountability ................... 61
4.3.4
Post-Trial Access to Atezolizumab ........................................ 62
4.4
Concomitant Therapy ............................................................ 62
4.4.1
Permitted Therapy with Atezolizumab ................................... 62
4.4.2
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 63
4.4.3
Prohibited Therapy ................................................................ 64
4.5
Study Assessments............................................................... 64
4.5.1
Informed Consent Forms and Screening Log........................ 64


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4.5.2
Medical History and Demographic Data ................................ 65
4.5.3
Physical Examinations........................................................... 65
4.5.4
Vital Signs.............................................................................. 65
4.5.5
Surveillance for UC Recurrence ............................................ 66
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 67
4.5.7
Resected Tumor Tissue Samples.......................................... 68
4.5.7.1
Resected Tumor Tissues for Screening................................. 69
4.5.7.2
Tumor Biopsy at the Time of Disease Recurrence ................ 69
4.5.7.3
Use and Storage of Remaining Samples from 
Study-Related Procedures..................................................... 70
4.5.8
Anti-Therapeutic Antibody Testing 
(Atezolizumab-Treated Patients Only)................................... 70
4.5.9
Electrocardiograms................................................................ 70
4.5.10
Patient-Reported Outcomes .................................................. 70
4.5.11
Age-Adjusted Charlson Comorbidity Index (ACCI)
.............................................................................................. 71
4.5.12
Optional Biopsies and Samples for Roche 
Clinical Repository (Optional Future Research)..................... 72
4.5.12.1
Overview of the Roche Clinical Repository............................ 72
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 72
4.5.12.3
Sample Collection.................................................................. 72
4.5.12.4
Confidentiality........................................................................ 73
4.5.12.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 74
4.5.12.6
Withdrawal from the Roche Clinical Repository..................... 74
4.5.12.7
Monitoring and Oversight....................................................... 75
4.5.13
Timing of Study Assessments ............................................... 75
4.5.13.1
Screening and Pre-Treatment Assessments ......................... 75
4.5.13.2
Assessments during Treatment/Observation......................... 75
4.5.13.3
Assessments at Treatment/Observation 
Discontinuation Visit .............................................................. 76
4.6
Follow-Up Assessments ........................................................ 77
4.6.1
Ongoing Imaging Assessments for Disease 
Recurrence............................................................................ 77


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4.6.2
Adverse Events ..................................................................... 77
4.6.3
Anti-Therapeutic Antibody and Pharmacokinetic 
Assessments ......................................................................... 77
4.6.4
Survival and Subsequent Anti-Cancer Therapy..................... 78
4.7
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 78
4.7.1
Patient Discontinuation.......................................................... 78
4.7.2
Discontinuation from Study Drug........................................... 79
4.7.3
Study and Site Discontinuation.............................................. 79
5.
ASSESSMENT OF SAFETY....................................................................... 79
5.1
Safety Plan ............................................................................ 80
5.1.1
Risks Associated with Atezolizumab ..................................... 80
5.1.2
General Plan to Manage Safety Concerns ............................ 80
5.1.2.1
Eligibility Criteria .................................................................... 80
5.1.2.2
Monitoring.............................................................................. 81
5.1.3
Atezolizumab Dose Modification............................................ 81
5.1.4
Management of Atezolizumab-Specific Adverse 
Events.................................................................................... 82
5.2
Safety Parameters and Definitions ........................................ 82
5.2.1
Adverse Events ..................................................................... 83
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 83
5.2.3
Adverse Events of Special Interest (Arm A Only; 
Immediately Reportable to the Sponsor) ............................... 84
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 85
5.3.1
Adverse Event Reporting Period ........................................... 85
5.3.2
Eliciting Adverse Event Information....................................... 86
5.3.3
Assessment of Severity of Adverse Events ........................... 86
5.3.4
Assessment of Causality of Adverse Events ......................... 86
5.3.5
Procedures for Recording Adverse Events............................ 87
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 87
5.3.5.2
Infusion-Related Reactions.................................................... 87
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 88


Atezolizumab—F. Hoffmann-La Roche Ltd
7/Protocol WO29636, Version 10
5.3.5.4
Persistent or Recurrent Adverse Events................................ 88
5.3.5.5
Abnormal Laboratory Values ................................................. 88
5.3.5.6
Abnormal Vital Sign Values ................................................... 89
5.3.5.7
Abnormal Liver Function Tests.............................................. 90
5.3.5.8
Deaths ................................................................................... 90
5.3.5.9
Preexisting Medical Conditions.............................................. 91
5.3.5.10
Recurrence of Urothelial Carcinoma (UC) ............................. 91
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 91
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 92
5.3.5.13
Patient-Reported Outcome Data ........................................... 92
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 92
5.4.1
Emergency Medical Contacts................................................ 93
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 93
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 93
5.4.2.2
Events That Occur after Study Drug Initiation........................ 93
5.4.3
Reporting Requirements for Pregnancies.............................. 94
5.4.3.1
Pregnancies in Female Patients............................................ 94
5.4.3.2
Abortions ............................................................................... 94
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 95
5.5
Follow-Up of Patients after Adverse Events .......................... 95
5.5.1
Investigator Follow-Up........................................................... 95
5.5.2
Sponsor Follow-Up ................................................................ 95
5.6
Adverse Events That Occur after THE Adverse 
Event Reporting Period.......................................................... 95
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 96
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 96
6.1
Determination of Sample Size ............................................... 96
6.1.1
Type I Error Control............................................................... 96
6.1.2
Primary Endpoint:  Disease-Free Survival............................. 97


Atezolizumab—F. Hoffmann-La Roche Ltd
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6.1.3
Secondary Endpoint:  Overall Survival .................................. 97
6.2
Summaries of Conduct of Study............................................ 98
6.3
Summaries of Treatment Group Comparability ..................... 98
6.4
Efficacy Analyses .................................................................. 98
6.4.1
Primary Efficacy Endpoint...................................................... 98
6.4.2
Secondary Efficacy Endpoints............................................... 99
6.4.2.1
Overall Survival ..................................................................... 99
6.4.2.2
Disease-Specific Survival ...................................................... 99
6.4.2.3
Distant Metastasis-Free Survival ......................................... 100
6.4.2.4
Non-urinary Tract Recurrence-Free Survival....................... 100
6.4.3
Handling of Missing Data..................................................... 100
6.5
Safety Analyses................................................................... 101
6.6
Pharmacokinetic Analyses................................................... 101
6.7
Patient-Reported Outcome Analyses .................................. 101
6.8
Exploratory Analyses........................................................... 101
6.8.1
Analyses at Landmark Timepoints....................................... 101
6.8.2
Subgroup Analyses ............................................................. 102
6.8.3
Biomarker Analyses............................................................. 102
6.9
Interim Analyses .................................................................. 102
6.9.1
Disease-Free Survival ......................................................... 102
6.9.2
Overall Survival ................................................................... 102
6.9.3
Optional Interim Analysis..................................................... 103
7.
DATA COLLECTION AND MANAGEMENT ............................................. 104
7.1
Data Quality Assurance....................................................... 104
7.2
Electronic Case Report Forms............................................. 104
7.3
Source Data Documentation................................................ 104
7.4
Use of Computerized Systems ............................................ 105
7.5
Retention of Records........................................................... 105
8.
ETHICAL CONSIDERATIONS.................................................................. 106
8.1
Compliance with Laws and Regulations .............................. 106
8.2
Informed Consent................................................................ 106
8.3
Institutional Review Board or Ethics Committee.................. 107


Atezolizumab—F. Hoffmann-La Roche Ltd
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8.4
Confidentiality...................................................................... 107
8.5
Financial Disclosure ............................................................ 108
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 108
9.1
Study Documentation .......................................................... 108
9.2
Protocol Deviations.............................................................. 108
9.3
Site Inspections ................................................................... 108
9.4
Administrative Structure....................................................... 109
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 109
9.6
Protocol Amendments ......................................................... 110
10. REFERENCES ......................................................................................... 111
LIST OF TABLES
Table 1
Adjuvant Chemotherapy:  Randomized Trials............................. 29
Table 2
Adverse Events Occurring in 10% of Urothelial Carcinoma 
Patients (n 79) in Study PCD4989g ......................................... 32
Table 3
Safety Profiles for Study IMvigor210:  Safety-Evaluable 
Population................................................................................... 33
Table 4
Objective Response Rate (per Investigator Assessment 
using RECIST v1.1) by PD-L1 Tumor Expression in Efficacy-
Evaluable UC Patients in Study PCD4989g................................ 36
Table 5
IRF-Assessed ORR and DOR per RECIST v1.1 in 
1L Patients with mUC:  Efficacy-Evaluable Population in 
IMvigor210 Cohort 1 ................................................................... 37
Table 6
IRF-Assessed ORR and DOR per RECIST v1.1 in 
2L+ Patients with mUC:  Efficacy-Evaluable Population in 
IMvigor210 Cohort 2 ................................................................... 38
Table 7
Administration of First and Subsequent Infusions 
of Atezolizumab .......................................................................... 61
Table 8
Adverse Event Severity Grading Scale ....................................... 86
LIST OF FIGURES
Figure 1
Overall Survival for All Cohort 1 Efficacy-Evaluable Patients...... 37
Figure 2
Overall Survival for All Cohort 2 Efficacy-Evaluable Patients...... 39
Figure 3
Study Schema............................................................................. 44


Atezolizumab—F. Hoffmann-La Roche Ltd
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LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 117
Appendix 2
Schedule of Pharmacodynamic and Pharmacokinetic 
Assessments............................................................................. 123
Appendix 3
Criteria for PD-L1 Diagnostic Assessment in Study 
WO29636.................................................................................. 124
Appendix 4
Age-Adjusted Charlson Comorbidity Index (ACCI) Worksheet . 125
Appendix 5
Preexisting Autoimmune Diseases ........................................... 127
Appendix 6
Anaphylaxis Precautions........................................................... 128
Appendix 7
Eastern Cooperative Oncology Group  Performance Status 
Scale......................................................................................... 129
Appendix 8
Patient-Reported Outcomes Instrument.................................... 130
Appendix 9
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 133


Atezolizumab—F. Hoffmann-La Roche Ltd
11/Protocol WO29636, Version 10
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY OF ATEZOLIZUMAB 
(ANTI–PD-L1 ANTIBODY) VERSUS OBSERVATION 
AS ADJUVANT THERAPY IN PATIENTS WITH, 
HIGH-RISK MUSCLE-INVASIVE UROTHELIAL 
CARCINOMA AFTER SURGICAL RESECTION
PROTOCOL NUMBER:
WO29636
VERSION NUMBER:
10
EUDRACT NUMBER:
2014-005603-25
IND NUMBER:
120827
NCT NUMBER:
NCT02450331
TEST PRODUCT:
Atezolizumab (MPDL3280A; RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please return a copy of the form to the Sponsor or their designee. Contact details will be 
provided to the investigator prior to the study start.  Please retain the original copy for 
your study files.


Atezolizumab—F. Hoffmann-La Roche Ltd
12/Protocol WO29636, Version 10
PROTOCOL SYNOPSIS 
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED 
STUDY OF ATEZOLIZUMAB (ANTI–PD-L1 ANTIBODY) VERSUS 
OBSERVATION AS ADJUVANT THERAPY IN PATIENTS WITH 
HIGH-RISK MUSCLE-INVASIVE UROTHELIAL CARCINOMA 
AFTER SURGICAL RESECTION
PROTOCOL NUMBER:
WO29636
VERSION NUMBER:
10
EUDRACT NUMBER:
2014-005603-25
IND NUMBER:
120827
NCT NUMBER:
NCT02450331
TEST PRODUCT:
Atezolizumab (MPDL3280A; RO5541267)
PHASE:
III
INDICATION:
Muscle-invasive urothelial carcinoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives: 
The primary efficacy objective for this study is as follows: 

To evaluate the efficacy of adjuvant atezolizumab treatment in patients with 
muscle-invasive urothelial carcinoma (UC), as measured by disease-free survival (DFS)
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by overall 
survival (OS)

To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by 
disease-specific survival (DSS)

To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by distant 
metastasis-free survival (DMFS)

To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by non-urinary 
tract recurrence-free survival (NURFS)
Safety Objectives 
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of atezolizumab in the adjuvant setting

To evaluate the incidence of anti-therapeutic antibodies (ATAs) against atezolizumab and to 
explore the potential relationship of the immunogenicity response with pharmacokinetics, 
safety, and efficacy
Pharmacokinetic Objective 
The pharmacokinetic (PK) objective for this study is as follows:

To characterize the pharmacokinetics of atezolizumab


Atezolizumab—F. Hoffmann-La Roche Ltd
13/Protocol WO29636, Version 10
Patient-Reported Outcome Objective
The patient-reported outcome (PRO) objective for this study is as follows:

To assess health status as measured by the EuroQol 5-dimension, 5-level version 
(EQ-5D-5L) questionnaire
Exploratory Objective 
The exploratory objective for this study is as follows:

To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival 
and/or fresh tumor tissue and blood and their association with disease recurrence
Study Design
Description of Study 
Study WO29636 is a global Phase III, open-label, randomized, controlled trial designed to 
evaluate the efficacy and safety of adjuvant treatment with atezolizumab compared with 
observation in patients with muscle-invasive UC, who are at high risk for recurrence following 
resection. 
Male and female patients aged 18 years with Eastern Cooperative Oncology Group (ECOG)
performance status 2 who have histologically confirmed muscle-invasive UC (also termed 
TCC) of the bladder or upper urinary tract (i.e., renal pelvis or ureters) are eligible.  Patients with 
upper urinary tract urothelial carcinoma (UTUC) will be limited to no more than approximately 
10% of the study population.
Patients with bladder as the site of primary involvement must have undergone radical 
cystectomy with lymph node dissection.  Patients with UTUC as the site of primary involvement 
must have undergone radical nephroureterectomy (RNU) with excision of the bladder cuff 
regardless of the location of the tumor in the upper urinary tract.  RNU must include lymph node 
dissection.
Patients who have received prior neoadjuvant chemotherapy are eligible, but must have tumor 
staging of ypT24a or ypN+ (ypT2-4 or ypN+ for patients with UTUC) and M0 at pathological 
examination of the surgical resection specimen.  Patients who have not received prior 
neoadjuvant chemotherapy must be ineligible for or declined treatment with cisplatin-based 
adjuvant chemotherapy and have tumor staging of pT34a or pN+ (pT3-4 or pN+ for patients 
with muscle-invasive UTUC) and M0.
Tumor specimens from surgical resection (i.e., radical cystectomy, RNU, or lymph node 
dissection) from patients who have signed the Informed Consent Form will be evaluated for 
PD-L1 expression by IHC.  Only patients whose tumors have sufficient amounts of viable tumor 
and are evaluable for PD-L1 expression as confirmed by a central pathology laboratory prior to 
enrollment of the patient in the study will be eligible.
Patients will be randomized to one of the following arms in a 1:1 ratio:

Arm A (experimental arm):  atezolizumab 1200 mg q3w 

Arm B (control arm):  observation
Randomization will be stratified by the following factors:

Number of lymph nodes resected (10 vs. 10)

Nodal status (positive vs. negative)  

Tumor stage after surgical resection (pT2 vs. pT3/pT4)

PD-L1 IHC status (IHC score of IC0/1 vs. IHC score of IC2/3)

Prior neoadjuvant chemotherapy (yes vs. no) 
Randomization must occur within 14 weeks after surgical resection of the primary tumor and 
study drug administration should begin within 7 calendar days after randomization. 
For patients in Arm A, atezolizumab will be administered intravenously (IV) on Day 1 of each 
21-day cycle for 16 cycles (up to 1 year).  In Arm B, patients will continually undergo 
observation starting on Day 1 of each 21-day cycle for 16 cycles (up to 1 year).  
Treatment/observation will be discontinued in the event of disease recurrence, unacceptable 
toxicity, withdrawal of consent, or study termination by the Sponsor.


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To ensure the same frequency of study assessments between the treatment arms, including 
assessments for disease recurrence and safety, patients in Arm B will be required to undergo 
q3w medical contacts for assessments during the first year, which will consist of formal clinic 
visits alternating with clinical contacts (either via telephone call or formal outpatient clinic visit) 
for symptom and adverse event assessment.  
Patients in the control arm will not be allowed to cross over to receive atezolizumab treatment 
within this study.
All patients will undergo scheduled assessments for tumor recurrence at baseline and every 
12 weeks (approximately every 4 cycles) in the first year following randomization.  Upon 
completion of the treatment/observation period, surveillance for tumor recurrence will be 
performed every 12 weeks for Years 23; every 24 weeks for Years 45; and at Year 6 
(approximately 48 weeks after the last assessment in Year 5). After the primary analysis, 
patients in Years 23 of the study may be assessed for tumor recurrence every 24 weeks. In 
the absence of a DFS event (defined as any of the following:  local [pelvic] recurrence of UC; 
upper urinary tract or urethral recurrence of UC; distant metastasis of UC; or death from any 
cause), surveillance for tumor recurrence should continue regardless of whether patients start 
new anticancer therapy, until withdrawal of consent, loss to follow-up, or study termination by 
the Sponsor, whichever occurs first.  For patients with muscle-invasive bladder cancer (MIBC), 
surveillance for tumor recurrence will include physical examination, laboratory evaluation, and 
imaging studies of the chest, abdomen, upper urinary tracts, and pelvis.  Disease recurrence 
will be as determined by the investigator based on radiographic evidence (visual appearance of 
UC with histological confirmation is acceptable for recurrence in bladder).  For patients with 
UTUC, surveillance for tumor recurrence must include physical examination, cystoscopy, urine 
cytology and imaging studies of the chest, abdomen, and pelvis.  A confirmatory tumor biopsy is 
mandatory at the time of disease recurrence. Cases for which biopsy results definitively rule out 
recurrence of UC will not be considered as disease recurrence for this study. After the primary 
analysis, a confirmatory tumor biopsy is optional at the time of disease recurrence.
Safety assessments will include the incidence, nature, and severity of adverse events, changes 
in vital signs, and laboratory abnormalities graded per National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0.  Serum samples will be 
collected to monitor atezolizumab pharmacokinetics and to detect the presence of ATAs to 
atezolizumab.  A sample of archived tumor tissues, as well as serum and plasma samples, will 
be collected for future exploratory biomarker assessments.
An external independent Data Monitoring Committee (iDMC) will evaluate safety data according 
to policies and procedures detailed in an iDMC Charter.
Number of Patients 
Approximately 800 patients will be enrolled in the study.  
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Ability to comply with protocol

Age 18 years

Histologically confirmed muscle-invasive UC (also termed TCC) of the bladder or upper 
urinary tract (i.e., renal pelvis or ureters)
Patients with mixed histologies are required to have a dominant transitional cell pattern.

TNM classification (UICC/AJCC 7th edition) at pathological examination of surgical 
resection specimen as follows: 
For patients treated with prior neoadjuvant chemotherapy:  tumor stage of ypT2 -4a or 
ypN+ (ypT2-4 or ypN+ for patients with UTUC) and M0


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For patients who have not received prior neoadjuvant chemotherapy:  tumor stage of 
pT34a or pN+ (pT3-4 or pN+ for patients with UTUC) and M0

Surgical resection of muscle-invasive UC of the bladder, or UTUC upper tract
For patients with MIBC, radical cystectomy may be performed by the open, 
laparoscopic, or robotic approach.  Cystectomy must include bilateral lymph node 
dissection, the extent of which will be at the discretion of the treating surgeon but 
optimally should extend at a minimum from the mid common iliac artery proximally to 
Cooper's ligament distally, laterally to the genitofemoral nerve, and inferiorly to the 
obturator nerve.  The method of urinary diversion for patients undergoing cystectomy 
will be at the discretion of the surgeon and choice of the patient.
Patients with a negative surgical margin (i.e., R0 resection) or with carcinoma in 
situ (CIS) at the distal ureteral or urethral margin will be eligible.
Patients with a positive R2 margin (which is defined as a tumor identified at the 
inked perivesical fat margin surrounding the cystectomy specimen) or R1 margin 
(which is defined as evidence of microscopic disease identified at the tumor 
margin), except for CIS at the distal ureteral or urethral margin, will be excluded.
For patients with UTUC, RNU with excision of the bladder cuff is required and may be 
performed by the open or laparoscopic approach.  RNU must include lymph node 
dissection (LND), the extent of which will be at the discretion of the treating surgeon but 
optimally should include the para-aortic, paracaval or interaortocaval nodes from the 
renal hilum to the inferior mesenteric artery in renal pelvis and proximally ureteral 
tumors, or nodes from the renal hilum to the bifurcation of the common iliac artery and 
ipsilateral pelvic nodes in mid and lower ureteral tumors, respectively. 
Patients must have a negative surgical margin (i.e., R0 resection).  Patients with 
a positive R1 or R2 surgical margin will be excluded.

Patients who have not received prior platinum-based neoadjuvant chemotherapy, have 
refused, or are ineligible (“unfit”) for cisplatin-based adjuvant chemotherapy
Patients who have received at least two cycles of a platinum-containing regimen will be 
considered as those who have received prior neoadjuvant chemotherapy.
Cisplatin ineligibility is defined by any one of the following criteria:
Impaired renal function (glomerular filtration rate [GFR] 60 mL/min); GFR should be 
assessed by direct measurement (i.e., creatinine clearance or ethyldediaminetetra-
acetate) or, if not available, by calculation from serum/plasma creatinine 
(Cockcroft-Gault formula)
A hearing loss (measured by audiometry) of 25 dB at two contiguous frequencies
Grade 2 or greater peripheral neuropathy (i.e., sensory alteration or parasthesis 
including tingling)
ECOG performance status of 2 

Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens from surgical 
resection (i.e., radical cystectomy, nephroureterectomy, or lymph node dissection) in 
paraffin blocks (blocks preferred) or at least 15 unstained slides, with an associated 
pathology report, for central testing and determined to be evaluable for tumor PD-L1 
expression prior to study enrollment 
Patients with fewer than 15 unstained slides available at baseline (but no fewer than 10) 
may be eligible following discussion with Medical Monitor.
Tumor tissue should be of good quality based on total and viable tumor content.  
Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and 
lavage samples are not acceptable.  For core-needle biopsy specimens, at least three 
cores should be submitted for evaluation.


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Tumor tissue of bladder or upper tract should be of good quality based on total and 
viable tumor content and must contain a muscle invasive component (i.e., T2 or greater) 
of the tumor as verified by local pathology review.  Fine-needle aspiration, brushing, 
cell pellet from pleural effusion, bone metastases, and lavage samples are not 
acceptable.  For core-needle biopsy specimens, at least three cores should be 
submitted for evaluation.  In situations where multiple specimens were received from 
different sites or at different times, the score from the surgical resection of the primary 
tumor or lymph node dissection specimen will be used for both primary and secondary 
analyses.

Muscle-invasive UC with PD-L1 expression per IHC prospectively determined on the 
surgical resection or lymph node dissection tumor specimens by a central laboratory

Absence of residual disease and absence of metastasis, as confirmed by a negative 
baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan of the 
pelvis, abdomen, and chest no more than 4 weeks prior to randomization.
For patients with MIBC, imaging of the upper urinary tracts must include one or more of 
the following:  intravenous pyelogram (IVP), CT urography, renal ultrasound with 
retrograde pyelogram, ureteroscopy or MRI urogram, and must be completed no more 
than 4 weeks prior to randomization.
For patients with UTUC, cystoscopy and urine cytology must be completed no more 
than 4 weeks prior to randomization, however upper tract imaging is not needed.
Other examinations should be performed as clinically indicated.
For patients with both primary MIBC and primary UTUC, imaging of the upper urinary 
tracts, cystoscopy, and urine cytology is not required.

Full recovery from cystectomy or nephroureterectomy within 14 weeks following surgery

ECOG performance status of 2

Life expectancy 12 weeks

Adequate hematologic and end-organ function, as defined by the following laboratory 
results obtained within 14 days prior to the first study treatment:
ANC 1500 cells/L (without granulocyte colonystimulating factor support within 
2 weeks prior to Cycle 1, Day 1)
WBC counts 2500/L 
Lymphocyte count 300/L
Platelet count 100,000/L (without transfusion within 2 weeks prior to Cycle 1, Day 1)
Hemoglobin 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion.
AST, ALT, and alkaline phosphatase 2.5 the upper limit of normal (ULN)
Serum bilirubin 1.0 ULN
Patients with known Gilbert disease who have serum bilirubin level 3 ULN may 
be enrolled.
PTT/PT 1.5 ULN or INR 1.7 ULN
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be on a stable dose.
Calculated creatinine clearance 20 mL/min (Cockcroft-Gault formula)


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
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, and agreement to refrain from donating eggs during this same period
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of 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:
Cancer-Specific Exclusion Criteria:

Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 
3 weeks prior to initiation of study treatment
Hormone-replacement therapy or oral contraceptives are allowed.

Adjuvant chemotherapy or radiation therapy for UC following surgical resection
Patients who have received primary chemoradiation for bladder preservation before 
cystectomy are eligible and will be treated as the same as patients who have received 
prior neoadjuvant chemotherapy.
Postsurgical intrapelvic/intravesical chemotherapy or BCG is not allowed for patients 
with UTUC.

Treatment with any other investigational agent or participation in another clinical trial with 
therapeutic intent within 28 days or five half-lives of the drug, whichever is longer, prior to 
enrollment

Malignancies other than UC within 5 years prior to Cycle 1, Day 1
Patients with high risk UTUC (defined as tumor stage ypT24a or ypN+) within 5 years 
prior to Cycle 1 Day 1 will be ineligible after the UTUC limit of approximately 10% has 
been met. 
Patients with localized low risk prostate cancer (defined as Stage T2b, Gleason 
score7, and PSA at prostate cancer diagnosis 20 ng/mL [if measured]) treated with 
curative intent and without prostate-specific antigen (PSA) recurrence are eligible.
Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score 7and 
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 
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General Medical Exclusion Criteria:

Pregnancy or breastfeeding

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or 
any component of the atezolizumab formulation

History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone may be eligible for this study.
Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen 
may be eligible for this study.

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Serum albumin 2.5 g/dL

Positive test for HIV

Patients with active hepatitis B virus (HBV; chronic or acute; defined as having a positive 
hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C
Patients with past HBV infection or resolved HBV infection (defined as the presence of 
hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible.  HBV DNA 
must be obtained in these patients prior to Cycle 1, Day 1.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA.

Active tuberculosis

Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia
Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1

Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection 
or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction within the previous 3 months, unstable 
arrhythmias, or unstable angina
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, 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.

Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1 or 
anticipation of need for a major surgical procedure during the course of the study

Prior allogeneic stem cell or solid organ transplant


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
Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or 
anticipation that such a live, attenuated vaccine will be required during the study
Influenza vaccination should be given during influenza season only (approximately 
October through May in the Northern Hemisphere and approximately April through 
September in the Southern Hemisphere).  Patients must agree not to receive live, 
attenuated influenza vaccine (e.g., FluMist®) within 28 days prior to randomization, 
during treatment or within 5 months following the last dose of atezolizumab (for patients 
randomized to atezolizumab).

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications
Medication-Related Exclusion Criteria:

Prior treatment with CD137 agonists or immune checkpointblockade therapies, including 
anti-CD40, antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies

Treatment with systemic immunostimulatory agents (including but not limited to interferons, 
IL-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, 
Day 1

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 [anti-TNF] agents) within 2 weeks 
prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive 
medications during the trial
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea, multiple doses for 
contrast allergy) may be enrolled in the study. 
The use of inhaled or low-dose (e.g., ≤ 10 mg/day prednisone) corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, and mineralocorticoids 
(e.g., fludrocortisone for adrenal insufficiency) and low-dose corticosteroids for patients 
with orthostatic hypotension or adrenocortical insufficiency is allowed.
End of Study 
The end of the study as planned will occur when the required number of events for the final 
analysis of OS has occurred (projected to be approximately Month 95 from FPI).  However, the 
Sponsor may decide to terminate the study at any time.
Length of Study
The study is expected to last approximately 8 years after the first patient is randomized.
Outcome Measures
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is as follows: 

Investigator-assessed DFS, defined as the time from randomization to the time of first 
occurrence of a DFS event, defined as any of the following:
Local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes)
Urinary tract recurrence of UC (including all pathological stages and grades)
Distant metastasis of UC 
Death from any cause
The secondary efficacy outcome measures for this study are as follows: 

OS, defined as the time from randomization to the date of death from any cause

DSS, defined as the time from randomization to the date of death from UC per investigator 
assessment of cause of death


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
DMFS, defined as the time from randomization to the date of diagnosis of distant 
(i.e., non-locoregional) metastases or death from any cause

NURFS, defined as the time from randomization to the time of first occurrence of a NURFS 
event, defined as any of the following:
Local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes)
Distant metastasis of UC
Death from any cause
Safety Outcome Measures 
The safety outcome measures for this study are as follows:

Incidence, nature, and severity of adverse events graded according to NCI CTCAE v4.0

Changes in vital signs and clinical laboratory results

Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows:

Maximum observed serum atezolizumab concentration (Cmax) after infusion on Day 1 of 
Cycle 1

Minimum observed serum atezolizumab concentration (Cmin) prior to infusion on Day 1 of 
Cycles 1, 2, 3, and 4; every 8 cycles starting on Cycle 8; at treatment discontinuation; and 
at 120 days (30 days) after the last dose of atezolizumab
Patient-Reported Outcome Measure 
The PRO outcome measure for this study is as follows:

EQ-5D-5L as a measure of patient-reported health status
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows:

Status of tumor immune-related or disease type−related exploratory biomarkers in archival 
and/or freshly obtained tumor tissues and association with disease recurrence

Status of exploratory biomarkers in plasma, whole blood, or serum (including but not limited 
to cytokines such as IL-6) collected before or during treatment with atezolizumab or at 
recurrence and association with disease recurrence
Investigational Medicinal Products
Test Product (Investigational Drug) 
The dose level of atezolizumab to be tested in this study is 1200 mg (equivalent to an average 
body weightbased dose of 15 mg/kg) administered by IV infusion every 3 weeks (21 [3] days) 
for 16 cycles or 1 year (whichever occurs first). 
Statistical Methods
Primary Analysis 
The primary efficacy endpoint is investigator-assessed DFS, defined as the time from 
randomization to the time of first occurrence of a DFS event, defined as any of the following: 
local (pelvic) recurrence of UC; urinary tract recurrence of UC; distant metastasis of UC; or 
death from any cause.  Data for patients without a DFS event will be censored at the last date 
the patient was assessed to be alive and recurrence free as determined with radiographic 
evidence.  Data for patients with no post-baseline disease assessment will be censored at the 
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For United States registrational purposes, the primary efficacy endpoint of DFS will be defined 
as described above with an additional censoring rule for missed visits.  Data for patients with a 
DFS event who missed two or more scheduled assessments immediately prior to the DFS event 
will be censored at the last tumor assessment as determined with radiographic evidence prior to 
the missed visits.  Type I error control will be applied to this analysis of DFS.  
DFS will be analyzed in the ITT population.  The following analyses will be performed for both 
DFS endpoints described above.  DFS will be compared between treatment arms using the 
stratified log-rank test.  The hazard ratio (HR) for recurrence or death will be estimated using a 
stratified Cox proportional hazards model and the 95% CI for the HR will be provided.  The 
stratification factors will be the same as the randomization stratification factors; however, 
stratification factors may be combined for analysis purposes if necessary to minimize small 
stratum cell sizes.  Combination of stratification factors, if any, would be specified in the 
Statistical Analysis Plan (SAP) prior to analysis.  The stratification factors will be obtained from 
the IxRS at the time of randomization.  Results from an unstratified analysis will also be 
provided.  Kaplan-Meier methodology will be used to estimate median DFS for each treatment 
arm; Kaplan-Meier curves will be produced.  Brookmeyer-Crowley methodology will be used to 
construct the 95% CI for the median DFS for each treatment arm.  The DFS rate at various 
timepoints (i.e., every 6 months after randomization) will be estimated by Kaplan-Meier 
methodology for each treatment arm, and the 95% CI will be calculated using Greenwood’s 
formula.
The following additional analyses will be performed for both DFS endpoints described above:

Analyses at landmark timepoints

Subgroup analyses 
Determination of Sample Size 
Approximately 800 patients will be randomized in this study.
The type I error (alpha) for this study is 0.05 (two-sided).  Type I error will be controlled for the 
primary endpoint of DFS and the key secondary endpoint of OS.  To control the Type I error at 
alpha 0.05 (two-sided) for DFS and OS endpoints, the treatment arms will be compared in a 
hierarchical fashion as follows:  If the DFS analysis results (as defined for United States 
registrational purposes) are statistically significant at alpha 0.05 (two-sided), then the analysis 
of OS will be performed at alpha 0.05 (two-sided) and the interim analysis boundaries for OS 
will be calculated according to alpha 0.05 (two-sided).
The analysis of the primary endpoint of DFS will take place when approximately 377 DFS 
events have occurred and at least 12 months after the last patient is enrolled have elapsed.  
The estimated number of events required for the analysis is based on the following assumptions:

Two-sided log-rank test at the 0.05 significance level (two-sided)

80% power

1:1 randomization ratio

Median DFS for the control (observation) arm of 20 months and estimated median DFS in 
the atezolizumab arm of 26.7 months (corresponding to a HR of 0.75)

No interim analysis of DFS
Accrual of the planned 800 patients is projected to occur over 32 months, assuming a ramp-up 
period of 13 months to a projected accrual rate of 35 patients per month.  On the basis of these 
assumptions, and the projected probability of loss to follow-up for DFS of approximately 32% 
over 24 months after enrollment, the required number of DFS events is projected to occur at 
Month 50 from the time the first patient is randomized.  Also on the basis of these assumptions, 
it is projected that an observed HR of 0.82 or lower will result in a statistically significant 
difference between treatment arms (i.e., an HR of 0.82 will be the minimally detectable 
difference at the analysis; this corresponds to an improvement of 4.5 months in median DFS, 
from 20 months in the control [observation] arm to 24.5 months in the atezolizumab arm).
The final analysis of the secondary endpoint of OS will take place when approximately 
428 deaths have occurred on the basis of the following assumptions:

Two-sided log-rank test at the 0.05 significance level (two-sided)


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
80% power

1:1 randomization ratio

Median OS for the control (observation) arm of 34 months and estimated median OS in the 
atezolizumab arm of 44.7 months (corresponding to HR of 0.76)

Two interim analyses of OS
On the basis of these assumptions, the projected probability of loss to follow-up for OS of 
approximately 24% over 24 months after enrollment, and projected accrual, the required 
number of OS events for the final analysis of OS is projected to occur 95 months from the time 
the first patient is randomized.  It is projected that an observed HR of 0.82 or lower will result in 
a statistically significant difference between treatment arms (i.e., an HR of 0.82 will be the 
minimally detectable difference at the analysis; this corresponds to an improvement of 
7.4 months in median OS, from 34 months in the control [observation] arm to 41.4 months in the 
atezolizumab arm).
Two interim analyses of OS are planned.
Interim Analyses 
No interim efficacy analyses of DFS are planned for this study.
A total of three analyses of OS will be performed by the Sponsor (two interim analyses and one 
final analysis).  The final analysis of OS will be performed when approximately 428 deaths 
(54% of 800 patients) have occurred in the ITT population.  On the basis of accrual projections 
and projected median OS for each treatment arm, the final analysis of OS is projected to occur 
95 months from the time the first patient is randomized.  The interim analysis boundaries for 
statistical significance at each interim analysis will be determined on the basis of the 
Lan-DeMets implementation of the O’Brien-Fleming use function.  
The first interim analysis of OS will be performed at the time of the DFS analysis.  On the basis 
of the projected median OS for each treatment arm and the projected time of the final analysis 
of DFS, it is projected that approximately 280 deaths (35% of 800 patients) will have occurred at 
the first interim analysis of OS, which corresponds to approximately 65% of the 428 deaths 
required for the final analysis of OS.  It is projected that an observed HR of 0.74 or lower will 
result in a statistically significant difference between treatment arms at this analysis.
The second interim analysis of OS will be performed when approximately 342 deaths (43% of 
800 patients) have occurred, which corresponds to 80% of the 428 deaths required for the final 
analysis of OS.  The required number of OS events for the second interim analysis of OS is 
projected to occur 63 months from the time the first patient is randomized.  It is projected that an 
observed HR of 0.78 or lower will result in a statistically significant difference between treatment 
arms at this analysis.
The interim analyses of OS will be performed by the Sponsor.  The boundary for statistical 
significance at each interim analysis and the final analysis will be determined based on the 
Lan-DeMets implementation of the O’Brien-Fleming use function.  For example, with 0.05 
(two-sided) and using the two-sided log-rank test, if 280 deaths have occurred at the time of the 
first OS interim analysis, statistical significance will be declared p 0.011; if 342 deaths have 
occurred at the time of the second OS interim analysis, statistical significance will be declared if 
p 0.021; and if 428 deaths have occurred at the time of the final OS analysis, statistical 
significance will be declared if p 0.042.
An iDMC will be convened to evaluate safety results approximately every 6 months after 
enrollment of the first patient until the analysis of the primary endpoint (DFS). 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ACCI
age-adjusted Charlson comorbidity index
ATA
anti-therapeutic antibody
CL
clearance
Cmax
maximum observed serum concentration
Cmin
minimum observed serum concentration
CBC
complete blood count
CIS
carcinoma in situ
CMV
methotrexate, vinblastine, and cisplatin
CR
complete response
CT
computed tomography (scan)
CTCAE
Common Terminology Criteria for Adverse Events
DFS
disease-free survival
DLT
dose-limiting toxicity
DMFS
distant metastasis-free survival
DOR
duration of response
DSS
disease-specific survival
EAU
European Association of Urology
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EQ-5D-5L
EuroQol 5-dimension, 5-level version (questionnaire)
ESMO
European Society of Medical Oncology
FDA
U.S. Food and Drug Administration
FDG-PET
fludeoxyglucose (18F) positron emission tomography
FFPE
formalin-fixed paraffin-embedded
FPI
first patient in
GC
gemcitabine and cisplatin
GFR
glomerular filtration rate
HBc Ab
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
IC
tumor-infiltrating immune cell (score)


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Abbreviation
Definition
ICH
International Conference on Harmonisation
iDCC
independent data coordinating center
iDMC
independent Data Monitoring Committee
Ig
immunoglobulin
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IRF
independent review facility
IxRS
interactive voice/web response system
IV
intravenous
IVP
intravenous pyelogram
MIBC
muscle-invasive bladder cancer
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mUC
metastatic urothelial carcinoma
MVAC
methotrexate, vinblastine, doxorubicin, and cisplatin
NCCN
National Cancer Clinical Network
NCI
National Cancer Institute
NMIBC
nonmuscle-invasive bladder cancer
NSCLC
nonsmall cell lung cancer
NU
nephroureterectomy
NURFS
non-urinary tract recurrence-free survival
ORR
objective response rate
OS
overall survival
PBMCs
peripheral blood mononuclear cells
pCR
pathologic complete response
PD-1
programmed death-1
PD-L1
programmed death-ligand 1
PK
pharmacokinetic
PO
polyolefin
PR
partial response
PRO
patient-reported outcome
PSA
prostate-specific antigen
pTa
papillary urothelial carcinoma
PUNLMP
papillary urothelial neoplasm of low malignant potential
PVC
polyvinyl chloride


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Abbreviation
Definition
q3w
every 3 weeks
QoL
quality of life
QTcF
QT interval corrected using Fridericia’s formula
RCC
renal cell carcinoma
RCR
Roche Clinical Repository
RECIST
Response Evaluation Criteria in Solid Tumors
RFS
recurrence-free survival
RNU
radical nephroureterectomy
TCC
transitional cell carcinoma
TNF
tumor necrosis factor
TSH
thyroid-stimulating hormone
TURBT
transurethral resection of bladder tumor
UC
urothelial carcinoma
UBC
urothelial bladder cancer
ULN
upper limit of normal
UTUC
upper urinary tract urothelial cancer
VAS
visual analog scale
Vss
volume of distribution at steady state


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1.
BACKGROUND
1.1
BACKGROUND ON MUSCLE-INVASIVE UROTHELIAL 
CARCINOMA 
Urothelial carcinoma (UC, also termed transitional cell carcinoma [TCC] or urothelial 
bladder cancer [UBC]) is the most common cancer of the urinary system worldwide, with 
UC of the bladder being the predominant histologic type and location.  Although less 
common, UC may originate in the renal pelvis, ureter, or urethra.  
Globally, there were an estimated 429,793 new cases of bladder cancer and 
165,084 deaths in 2012 (GLOBOCAN 2012).  In 2012, it was estimated that there were 
151,297 new cases of bladder cancer and 52,411 deaths in Europe, including 
124,188 new cases and 40,635 deaths in the 28 member states of the European Union 
(EU).  In 2014, it was estimated that there would be 74,690 new cases of bladder cancer 
and 15,580 deaths in the United States (American Cancer Society 2014).  In 2012, it 
was estimated that there were 55,486 new cases of bladder cancer and 26,820 deaths 
in China (GLOBOCAN 2012).
The median age at diagnosis is 69 years in men and 71 years in women 
(Lynch and Cohen 1995; Scosyrev et al. 2009).  Multiple risk factors have been linked to 
the development of bladder cancer and include cigarette smoking, which is the most 
common risk factor, as well as various occupational exposures such as those 
experienced by metal workers; painters; electrical workers; miners; cement workers; 
transport operators; workers in the rubber, leather, and textile industries; and workers 
who manufacture plastics and industrial chemicals (Kogevinas et al. 2003; 
Gaertner et al. 2004; Smailyte et al. 2004).  High concentrations of arsenic in drinking 
water have been linked to bladder cancer (Tsai et al. 1998; Marshall et al. 2007).  
Other risk factors for the development of bladder cancer include chronic cystitis 
(Delnay et al. 1999) and human papillomavirus (HPV), especially HPV 16 
(Li et al. 2011).  Iatrogenic causes of bladder cancer include radiation therapy to the 
pelvic region and chemotherapy such as cyclophosphamide.
Bladder cancer presents as non-muscle-invasive (NMIBC), muscle-invasive (MIBC), or 
metastatic disease.  For patients with MIBC (pT2T4a, N0Nx, M0), radical cystectomy 
with bilateral pelvic lymphadenectomy forms the backbone of the management of MIBC.  
The surgery involves resection of the bladder, adjacent organs, and regional lymph 
nodes.  There are also gender-based differences in the surgical approach:  For men, the 
surgery includes removal of the prostate and seminal vesicles, and for women, the 
surgery includes removal of the uterus, cervix, ovaries, and anterior vagina.  Urinary 
diversion is required after removal of the bladder.  The perioperative mortality rate is 
approximately 2%3% when cystectomy is performed at centers of excellence 
(Stein et al. 2001; Madersbacher et al. 2003).  In spite of this surgery, many patients 
recur and present with pain (e.g., flank pain due to ureteral obstruction; abdominal or 
right upper quadrant pain due to liver metastasis or an abdominal lymph node; bone pain 


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secondary to bone metastases) or constitutional symptoms such as fatigue, weight loss, 
anorexia, and failure to thrive.  Approximately half of the patients with MIBC will develop 
a local and/or metastatic recurrence of their disease within 2 years of cystectomy and 
will eventually die from their disease (Raghavan et al. 1990; Stein et al. 2001; 
Stenzl et al. 2009).  For those with high-risk features (pT3T4a or pN+), the overall 
5-year survival ranges from 10%40% (Sternberg et al. 2007).
Because of the high risk of relapse with surgery alone, neoadjuvant and adjuvant 
treatment have been utilized in conjunction with radical cystectomy for MIBC.  
The rationale for perioperative chemotherapy is based on the response in patients with 
locally advanced or metastatic UC, in which cisplatin-based chemotherapy has 
demonstrated efficacy with a median survival of approximately 15 months with 
responses in 40%60% of patients (von der Maase et al. 2005).  However, there is an 
urgent need for effective regimens for patients with poor performance status, 
comorbidities, or renal insufficiency, for whom carboplatin-based regimens appear to 
generate suboptimal outcomes in both perioperative and advanced settings 
(De Santis et al. 2009; Abol-Enein et al. 1997).
1.1.1
Neoadjuvant Treatment for MIBC
Neoadjuvant chemotherapy has been shown to provide a small but statistically 
significant overall survival (OS) advantage.  The advantage of neoadjuvant 
chemotherapy is that it facilitates an assessment of the response of the primary cancer 
to chemotherapy as well as providing an indication as to the likelihood of long-term 
remission or survival.  The disadvantage of neoadjuvant chemotherapy is that definitive 
surgery management with a radical cystectomy is potentially delayed for those patients 
who do not have a major response to the neoadjuvant treatment.  In addition, certain 
low-risk (e.g., cT2N0) patients may be overtreated with neoadjuvant chemotherapy 
because it is difficult to identify low-risk patients reliably before cystectomy 
(Meeks et al. 2012).  It has been reported that 20% of patients who undergo radical 
cystectomy have received neoadjuvant chemotherapy prior to surgery (David et al. 2007; 
Miles et al. 2010; Porter et al. 2011; Raj et al. 2011).
A meta-analysis of data from 11 randomized trials has demonstrated that MIBC is most 
sensitive to cisplatin-based neoadjuvant chemotherapy, with a 5% net benefit in 5-year 
OS (Advanced Bladder Cancer Meta-analysis Collaboration 2003).  Commonly used 
cisplatin-based neoadjuvant chemotherapy regimens include MVAC (methotrexate, 
vinblastine, doxorubicin, and cisplatin), CMV (methotrexate, vinblastine, and cisplatin), 
and GC (gemcitabine and cisplatin).  European Society of Medical Oncology (ESMO), 
European Association of Urology (EAU) and National Cancer Clinical Network (NCCN) 
clinical practice guidelines recommend cisplatin-based neoadjuvant chemotherapy prior 
to cystectomy for MIBC patients (Bellmunt et al. 2014; Witjes et al. 2014).  Patients with 
MIBC who achieve a pathologic complete response (pCR; pT0N0M0 stage) or who are 
down-staged to non-muscle-invasive disease after neoadjuvant chemotherapy 


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demonstrate longer OS than those who fail to achieve pCR or are not down-staged 
(Grossman et al. 2003; Petrelli et al. 2014).  For patients with residual muscle-invasive 
disease (pT24a) or lymph node-positive disease (pN+) at cystectomy, the median 
survival is only 3.4 and 2.4 years, respectively (Sonpavde et al. 2009). There is 
currently no standard active treatment for those patients in the adjuvant setting.
1.1.2
Adjuvant Treatment for MIBC
Many patients with MIBC choose to undergo definitive surgery (i.e., radical cystectomy) 
first and defer neoadjuvant chemotherapy; patients at a high risk for recurrence based 
on pathologic staging could consider adjuvant chemotherapy given its potential to 
eradicate micrometastatic disease.  However, unlike the benefits that have been shown 
with neoadjuvant chemotherapy, results from prospective studies of cisplatin-based 
adjuvant chemotherapy in patients with MIBC after a radical cystectomy are mixed.  Two 
clinical trials have shown a survival benefit (Skinner et al. 1991; Stöckle et al. 1992); 
however, these trials enrolled less than 100 patients and the small datasets impact the 
interpretability of the results.  A meta-analysis conducted in 2005 (Vale 2005) with data 
from 491 individual patients obtained from six adjuvant chemotherapy trials was 
inconclusive because of its small number and heterogeneity among the trials included.  
Meeks et al. (2012) performed a systematic review, which found no evidence that 
adjuvant chemotherapy improved survival outcomes, even in the highest-risk patients 
with pathologic extravesical and/or node-positive disease.  Four recent trials (by US 
Intergroup [Stadler et al. 2011], Italian Multicenter [Cognetti et al. 2012], SOGUG 
[Paz-Ares et al. 2010], and EORTC [Sternberg et al. 2015]), which were not included in 
the above mentioned meta-analysis, failed to meet their original accrual goals and were 
prematurely terminated.  As one of the largest randomized trials ever reported for 
adjuvant chemotherapy in patients with MIBC, the EORTC trial was closed after 
recruitment of 284 of the planned 660 patients.  In that study, 284 patients with pT3pT4 
or N+ M0 MIBC were randomized to receive either immediate versus deferred 
cisplatin-based combination chemotherapy after cystectomy.  Immediate treatment 
significantly prolonged progression-free survival compared with deferred treatment 
(HR 0.54; 95% CI: 0.40.73; p0.0001).  However, no significant improvement in OS 
was noted with immediate treatment when compared with deferred treatment (HR 0.78; 
95% CI: 0.561.08; p0.13).  Thus, the benefit and usefulness of cisplatin-based 
adjuvant chemotherapy remains highly controversial.
Only approximately 50% of patients are eligible for cisplatin-based adjuvant 
chemotherapy; factors rendering patients ineligible for cisplatin therapy include an 
Eastern Cooperative Oncology Group (ECOG) performance status of 2, impaired renal 
function, hearing loss, and neuropathy (Dash et al. 2006).  On the basis of current 
clinical guidelines, there is no standard adjuvant chemotherapy for patients who are 
ineligible for cisplatin-based therapy.  There is no evidence that non-cisplatin-based 
adjuvant regimens (e.g., carboplatin-based adjuvant chemotherapy) are as effective as 
cisplatin-based adjuvant chemotherapy.  


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Key adjuvant randomized trials are listed in Table 1.
Table 1
Adjuvant Chemotherapy:  Randomized Trials
Institution
No. of 
Patients
Regimen
Survival 
Benefit
Completed 
Accrual
University of Southern California 
(Skinner et al. 1991)
91
CISCA
Yes a
Yes
University of Mainz, Germany 
(Stöckle et al. 1995
49
MVAC/MVEC
Yes
Yes
Swiss Group for Clinical Cancer 
Research, Switzerland (Studer et 
al. 1994)
77
Cisplatin
No
Yes
Stanford University (Freiha et al. 
1996)
55
CMV
No
Yes
US Intergroup (Stadler et al. 
2011)
114
MVAC
No
No
Italian multicenter (Cognetti et al. 
2012)
194
GC
No
No
SOGUG (Paz-Ares et al. 2010)
142
PCG
Yes b
No
EORTC Trial (NCT00028756; 
Sternberg et al. 2015)
248
MVAC, GC, DD-
MVAC
No
No
CISCAcisplatin, doxorubicin; MVACmethotrexate, vinblastine, doxorubicin, cisplatin; 
MVECmethotrexate, vinblastine, epirubicin, cisplatin; CMVcisplatin, methotrexate, vinblastine; 
GCgemcitabine, cisplatin; PCG paclitaxel, gemcitabine, cisplatin; SOGUG Spanish Oncology 
Genitourinary Group; EORTCEuropean Organization for Research and Treatment of Cancer; 
DD-MVACdouble dense MVAC.
Note:  Adapted from Meeks et al. 2012.
a
Median survival timechemotherapy – 4.3 yrs; observation – 2.4 yrs (p0.0062).
b
PCG:  mOS not reported, 5 yr OS 60%; observation mOS 26 months, 5 yr OS 31% (p0.0009).
1.2
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab (MPDL3280A) is a humanized immunoglobulin (Ig) G1 monoclonal 
antibody consisting of two heavy chains (448 amino acids) and two light chains 
(214 amino acids) and is produced in Chinese hamster ovary cells.  Atezolizumab was 
engineered to eliminate Fc-effector function via a single amino acid substitution 
(asparagine to alanine) at position 298 on the heavy chain, which results in a 
non-glycosylated antibody that has minimal binding to Fc receptors and prevents 
Fc-effector function at expected concentrations in humans.  Atezolizumab targets human 
programmed death-ligand 1 (PD-L1) and inhibits its interaction with its receptors, 
programmed death-1 (PD-1) and B7.1 (CD80, B7-1).  Both of these interactions are 
reported to provide inhibitory signals to T cells.  


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1.2.1
Summary of Nonclinical Studies
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and 
in vivo activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an 
acceptable safety profile, and to identify a Phase I starting dose.  Comprehensive 
pharmacology, PK, and toxicology evaluations were thus undertaken with atezolizumab.
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in 
mice and cynomolgus monkeys to support intravenous (IV) administration and to aid 
in projecting the appropriate starting dose in humans.  Given the similar binding of 
atezolizumab for cynomolgus monkey and human PD-L1, the cynomolgus monkey was 
selected as the primary and relevant nonclinical model for understanding the safety, 
pharmacokinetics, and toxicokinetics of atezolizumab.
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab 
supported entry into clinical studies, including providing adequate safety factors for the 
proposed Phase I starting doses.  The results of the toxicology program were consistent 
with the anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway 
and supported entry into clinical trials in patients.
Refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical studies.
1.2.2
Clinical Experience with Atezolizumab
1.2.2.1
Ongoing Clinical Studies
Atezolizumab is currently being tested in multiple Phase I, II, and III studies, both as 
monotherapy and in combination with several anticancer therapies (see the 
Atezolizumab Investigator’s Brochure for study descriptions).  The majority of the safety 
and efficacy data summarized below are from the following two studies:  
1) Study PCD4989g, a Phase Ia, multicenter, first-in-human, open-label, dose-escalation 
trial evaluating the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of biologic activity of atezolizumab
administered as a single agent by IV infusion every 3 weeks (q3w) to patients with 
locally advanced or metastatic solid malignancies or hematologic malignancies; and 
2) Study IMvigor210, a single-arm Phase II study evaluating single-agent atezolizumab 
(1200 mg IV q3w) for the treatment of patients with metastatic urothelial carcinoma 
(mUC).  Patients in Study IMvigor210 were enrolled into two cohorts.  Cohort 1 
comprised patients who were treatment naive (1L) and cisplatin-ineligible (see 
Section 4.1.1 for definition of cisplatin-ineligibility).  Cohort 2 comprised patients who had 
disease progression following at least one platinum-containing regimen (2L+). Patients 
who had progressed within 12 months of treatment with a platinum-containing 
adjuvant/neoadjuvant regimen were also considered 2L patients. 
For the PCD4989g and IMvigor210 studies, an immunohistochemistry (IHC)-based
scoring criteria has been formulated to represent PD-L1 expression in tumor-infiltrating 
immune cells (IC) (see Appendix 3).  Any cutoff references are to a single IC score 


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(e.g., IC2), whereas patient population references include all IC subgroups within a 
particular cutoff (e.g., IC2/3 population from a selection at the IC2 cutoff).
1.2.2.2
Clinical Safety
The safety data for atezolizumab have been derived mainly from the treatment of 
patients in Study PCD4989g and Study IMvigor210.  As of 10 May 2014, the clinical 
database contained preliminary safety data from 412 patients in Study PCD4989g who 
have received any amount of atezolizumab at doses between 0.01 and 20 mg/kg across 
multiple tumor types.  No dose-limiting toxicities (DLTs) have been observed at any dose 
level and no maximum tolerated dose (MTD) was established.
As of 14 March 2016, 119 and 310 patients with mUC in Cohort 1 (treatment naive and 
cisplatin ineligible) and Cohort 2 (2L+), respectively, received atezolizumab as a single 
agent.  Despite the different patient populations in these two cohorts, the safety profile of 
atezolizumab in each cohort was consistent with the other (see Table 3).  Additionally, 
the safety profiles of these two cohorts were consistent with the UC cohort in Study 
PCD4989g (as of 10 May 2014), where 79 safety-evaluable patients with UC from all 
lines of therapy received atezolizumab monotherapy.
Refer to the Atezolizumab Investigator’s Brochure for further updated details on 
clinical safety.
Adverse Events
Of the 412 treated patients, 97% reported an adverse event regardless of attribution to 
atezolizumab.  Of these adverse events, 48.8% were Grade 1 or 2 in maximum severity 
based on the National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 4.0 (NCI CTCAE v4.0).  The most frequently observed adverse events 
(occurring in 10% of treated patients) included fatigue, nausea, decreased appetite, 
pyrexia, dyspnea, diarrhea, constipation, cough, headache, back pain, vomiting, anemia, 
arthralgia, rash, insomnia, asthenia, abdominal pain, chills, pruritus, generalized pain, 
and peripheral edema.  Treatment-related adverse events (per investigator assessment 
of causality) were reported in 72% of patients.
PCD4989g:  Adverse Events in Patients with 1L+ mUC
A total of 79 patients with bladder cancer received atezolizumab in Study PCD4989g as 
of the 10 May 2014 datacut.  Of these, 75 (94.9%) reported at least one adverse event.  
Grade 3 adverse events occurred in 45.6% of patients.  Seven bladder cancer patients 
(8.9%) experienced Grade 35 treatment-related adverse events.  The events included 
thrombocytopenia, asthenia, alanine aminotransferase increase, aspartate 
aminotransferase increased, blood creatinine increased, blood phosphorus decreased, 
and gamma-glutamyltransferase increased.  


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Table 2 summarizes adverse events regardless of attribution that occurred in10% of 
the bladder cancer patients and the investigator’s assessment of relatedness for 
these events.
Table 2
Adverse Events Occurring in 10% of Urothelial Carcinoma 
Patients (n79) in Study PCD4989g
Preferred Term
Adverse Event 
Regardless of Attribution
n (%)
Related Adverse Events
n (%)
Anemia
19 (24.1)
2 (2.5)
Nausea
12 (15.2)
8 (10.1)
Constipation 
11 (13.9)
0 (0.0)
Abdominal pain 
10 (12.7)
1 (1.3)
Vomiting
9 (11.4)
2 (2.5)
Fatigue
18 (22.8)
11 (13.9)
Pyrexia
15 (19.0)
8 (10.1)
Edema peripheral
8 (10.1)
0 (0.0)
Pain
8 (10.1)
2 (2.5)
Urinary tract infection
16 (20.3)
0 (0.0)
Blood creatinine increased
18 (22.8)
1 (1.3)
Blood alkaline phosphatase
8 (10.1)
1 (1.3)
Decreased appetite
16 (20.3)
8 (10.1)
Back pain
10 (12.7)
0 (0.0)
Cough
10 (12.7)
0 (0.0)
Dyspnea
8 (10.1)
0 (0.0)
IMvigor210 Cohort 1:  Adverse Events in Patients with 1L 
Cisplatin-Ineligible mUC
Of the 119 safety-evaluable Cohort 1 patients, 95.8% reported an adverse event 
(see Table 3).  The most frequently reported adverse events (20%) included fatigue 
(45.4%), decreased appetite (27.0%), nausea (21.8%), and diarrhea (21.0%).


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Table 3
Safety Profiles for Study IMvigor210:  Safety-Evaluable 
Population
Cohort 1 a, b
(n119)
Cohort 2 a, c
(n310)
Parameter
Any AE
114 (95.8%)
302 (97.4%)
Related AE
79 (66.4%)
218 (70.3%)
Grade 34
53 (44.5%)
177 (57.1%)
Related Grade 34
18 (15.1%)
51 (16.5%)
Grade 5 
4 (3.4%)
3 (1.0%)
Related Grade 5
1 (0.8%)
0
SAE
43 (36.1%)
143 (46.1%)
Related SAE
10 (8.4%)
36 (11.6%)
AEs leading to 
withdrawal from study 
treatment
7 (5.9%)
9 (2.9%)
AEadverse event; CCOD clinical cutoff date; mUCmetastatic urothelial carcinoma; 
SAEserious adverse event
a CCOD14 March 2016.
b Cohort 1 consisted of patients with mUC who were treatment naive and cisplatin ineligible.
c Cohort 2 consisted of 2Lpatients with mUC.
Fewer than half (44.5%) of the Cohort 1 patients had a Grade 34 adverse event 
(see Table 3).  The most commonly reported Grade 34 adverse events (2.5% or 
3 patients) were fatigue and anemia (5% each), hyponatremia and blood creatinine 
increases (3.4% each), small intestinal obstruction and urinary tract infection, decreased 
appetite, increased ALT, and hypotension (2.5% each).  Fatigue (3.4%) and increased 
ALT (2.5%) were the Grade 34 adverse events most commonly (2.5% or 3 patients) 
considered related to atezolizumab.
Four Cohort 1 patients (3.4%) had a Grade 5 adverse event (see Table 3).  These 
were cardiac arrest, myocardial infarction, sepsis (related to atezolizumab), and 
respiratory failure.
Approximately one-third of Cohort 1 patients (36.1%) had a serious adverse event 
(see Table 3).  Most of these serious adverse events were each reported in 1 patient. 
Ten patients (8.4%) had atezolizumab-related serious adverse events.  Renal failure and 
diarrhea were the only related serious adverse events occurring in 2 patients.
Cardiac arrest, myocardial infarction, autoimmune colitis, diarrhea, hypersensitivity, 
sepsis, and respiratory failure were the adverse events that led to 7 Cohort 1 patients 
(5.9%) terminating atezolizumab.


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IMvigor210 Cohort 2:  Adverse Events in Patients with 2L+ mUC
Of the 310 safety-evaluable patients in Cohort 2, 97.4% reported an adverse event of 
any grade (see Table 3).  The most frequently reported adverse events (20%) included 
fatigue (50.3%), decreased appetite (26.8%), nausea (26.1%), constipation (25.2%), 
urinary tract infection (23.5%), pyrexia (21.6%), and diarrhea (21.3%).
Slightly more than half of the Cohort 2 patients (57.1%) reported a Grade 34 adverse 
event (see Table 3), with the most common (2.3%) being anemia (9.4%), urinary tract 
infection (7.7%), fatigue (5.8%), hyponatremia (3.5%), dehydration and dyspnea 
(3.2% each), hematuria (2.9%), abdominal pain, back pain, and sepsis (2.6% each), and 
pain and pulmonary embolism (2.3% each).  The Grade 34 adverse events considered 
related to atezolizumab were generally reported in 1 patient.  Those reported in
2 patients (0.6%) were fatigue (1.6%), AST and ALT increased (1.3% each), and 
colitis, decreased appetite, dyspnea, pneumonitis, arthralgia, anemia, and hypotension 
(0.6% each).
Grade 5 adverse events of subileus, pulmonary sepsis, and cerebral hemorrhage 
occurred in 1 Cohort 2 patient each (see Table 3).  None of the events were considered 
related to atezolizumab.
Slightly fewer than half of the Cohort 2 patients (46.1%) reported a serious adverse 
event (see Table 3).  Urinary tract infection (7.1% or 22 patients) was the only serious 
adverse event that occurred in 5% of the patients.  Thirty-six (11.6%) patients had an 
atezolizumab-related serious adverse event, with the most common (0.6% 
or 2 patients) being pneumonitis and pulmonary embolism (1.0% each) and 
encephalopathy, colitis, and pyrexia (0.6% each).
Nine adverse events led to 9 patients being withdrawn from atezolizumab treatment 
(2.9%) in Cohort 2 (see Table 3):  pulmonary sepsis, retroperitoneal infection, sepsis, 
cerebral hemorrhage, posterior reversible encephalopathy syndrome, subileus, fatigue, 
acute kidney injury and pruritus.
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, as well as events of hepatitis/elevated liver function tests (LFTs) 
and influenza-like illness that are considered potential adverse drug reactions associated 
with atezolizumab.  There is also a potential for immune activation being associated with 
generalized systemic features (e.g., hypotension, respiratory failure, and other organ 
impairment).
Refer to the Atezolizumab Investigator’s Brochure for details regarding 
immune-mediated adverse events observed in patients treated with atezolizumab.  


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Guidelines for the management of potential immune-mediated adverse events are 
described in Section 5.1.4.
1.2.2.3
Clinical Activity
Anti-tumor activity, including Response Evaluation Criteria in Solid Tumors 
(RECIST)based responses (i.e., RECIST [Version 1.1] responses), have been 
observed in patients with different tumor types, including nonsmall cell lung cancer 
(NSCLC), renal cell carcinoma (RCC), melanoma, gastric cancer, bladder cancer, 
colorectal cancer, head and neck cancer, breast cancer, and sarcoma treated with 
atezolizumab monotherapy in Study PCD4989g.
Among 345 evaluable patients treated by 21 October 2013 (data cutoff of 21 April 2014) 
with a median of 30.4 weeks of follow-up, 62 patients experienced objective responses 
per RECIST v1.1 with an objective response rate (ORR) of 18% (95% CI: 14.1%, 22.3%).  
Objective responses with atezolizumab monotherapy were observed in a broad range of 
malignancies, including NSCLC, RCC, melanoma, bladder cancer, colorectal cancer, 
head and neck cancer, gastric cancer, breast cancer, and sarcoma.  The median 
duration of response (DOR) was 77.6 weeks (range:  6.4to 97.9weeks, where “” 
denotes a censored value).  The majority of these responses have been durable, with 
72.6% of responses (45 of 62 patients) ongoing as of the clinical cutoff date.
Refer to the Atezolizumab Investigator’s Brochure for details on clinical activity in all 
patients treated to date, regardless of tumor type.
PCD4989g:  Clinical Activity in Patients with 1L+ mUC
As of the clinical cutoff of 21 April 2014, efficacy analyses were performed on the
70 patients with locally advanced or metastatic UC in Study PCD4989g who received 
atezolizumab treatment by 27 January 2014.  The median age of this population was 
65 years (range: 3689 years), and the group represented a heavily pre-treated 
patient population, with 44.3% of patients having received more than two prior 
systemic therapies (1L+).  The median duration on study treatment was 106 days 
(range: 1331 days).
Preliminary data show that patients with UC with a high level of PD-L1 expression in 
tumor-infiltrating immune cells (IC) per immunohistochemistry (IHC) demonstrated a 
greater response rate after treatment with atezolizumab compared with patients with a 
low level of PD-L1 expression.  When a diagnostic threshold of 5% PD-L1stained 
tumor-infiltrating immune cells (IHC score of IC2 or IC3) was used, IC2/3 patients (n 33) 
had an ORR per investigator assessment of 51.5% (95% CI: 33.8%, 69.2%) (see
Table 4).  When a higher diagnostic threshold of 10% PD-L1stained tumor-infiltrating 
immune cells (IHC score of IC3) was used, IC3 patients (n 10) had an ORR of 60.0% 
(95% CI: 26.7%, 85.0%).  In responding PD-L1 IC2/3 patients (n 17), the median time 
to first response was 43.0 days (range: 38.0248.0 days) and the median DOR has not 
been reached (range: 0.1to 42.3weeks). 


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For patients with a PD-L1 IHC score of IC0 or IC1, the ORR per investigator assessment 
was 13.9% (95% CI: 5.6%, 27.9%).  In responding patients (n 5), the median time to 
first response was 83.0 days (range: 38.085.0 days) and the median DOR has not 
been reached (range: 6.1to 19.1weeks).  
Table 4
Objective Response Rate (per Investigator Assessment using 
RECIST v1.1) by PD-L1 Tumor Expression in Efficacy-Evaluable 
UC Patients in Study PCD4989g
IHC Score
Objective Response Rate
(CR or PR a)
ORR (CR or PR) of Combined 
IHC Groups
IC3 (IC10%)
60.0% (6 of 10)
(95% CI: 26.7%, 85.0%)
51.5% (17 of 33)
(95% CI: 33.8%, 69.2%)
IC2 (10%IC5%)
47.8% (11 of 23)
(95% CI: 26.8%, 68.3%)
IC1 (5%IC1%)
16.7% (4 of 24)
(95% CI: 5.9%, 36.6%)
13.9% (5 of 36)
(95% CI: 5.6%, 27.9%)
IC0 (IC1%)
8.3% (1 of 12)
(95% CI: 0.4%, 34.9%)
CRcomplete response; Dx diagnostic; ICtumor-infiltrating immune cell; 
IHCimmunohistochemistry; ORRoverall response rate; PD-L1programmed deathligand 1; 
PRpartial response; RECIST Response Evaluation Criteria in Solid Tumors; UCurothelial 
carcinoma.
Note:  There is 1 UC efficacy-evaluable patient with unknown IHC score.
a As of 21 April 2014, 18 of the 22 responses have been confirmed per RECIST v1.1.
IMvigor210 Cohort 1:  Clinical Activity in Patients with 1L 
Cisplatin-Ineligible mUC
As of the clinical cutoff of 14 March 2016, efficacy analyses were performed on the 
119 patients in Cohort 1 of from Study IMvigor210.  The median age of this population 
was 73 years (range: 5192 years), and the group represented a cisplatin-ineligible 
patient population who were previously untreated in the metastatic setting.  The median 
duration on study treatment was 15 weeks.
With a median follow-up duration of 14.4 months, the cisplatin-ineligible mUC patients 
demonstrated clinically meaningful response rates (see Table 5) after first-line treatment 
with atezolizumab in all PDL1 IC subgroups:  IC0/1 patients had an ORR of 21.8% and 
IC2/3 patients had an ORR of 28.1%.  For patients with upper urinary tract urothelial 
carcinoma (UTUC) (n33), the ORR was 42.4%. 
As of 14 March 2016, the median duration of response (DOR) had not been reached 
in any of the IC subgroups (range: 3.716.6 months), with 21 patients with an 
ongoing response.


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The median OS for all patients was 14.8 months (95% CI: 10.1, NE), and over half of the 
patients (52.9%) remained event-free (Figure 1).
Table 5
IRF-Assessed ORR and DOR per RECIST v1.1 in 1LPatients with 
mUC:  Efficacy-Evaluable Population in IMvigor210 Cohort 1
IC0/1
(n 87)
IC2/3
(n 32)
All Patients
(n 119)
ORR (%)
19 (21.8)
9 (28.1)
28 (23.5)
95% CI
(13.7, 32.0)
(13.8, 46.8)
(16.2, 32.2)
Complete response
6
2
8
Partial response
13
7
20
Median DOR 
(months)
NE
NE
NE
95% CI
(12.8, NE)
(11.1, NE)
(12.8, NE)
Patients with event 
(%)
4 (21.1)
3 (33..3)
7 (25.0)
DORduration of response; ICtumor-infiltrating immune cell; IRF = independent review facility; 
mUCmetastatic urothelial carcinoma; ORRobjective response rate; RECIST v1.1Response 
Evaluation Criteria in Solid Tumors, Version 1.1.
Note:  The responses were confirmed responses.
The clinical cutoff date was 14 March 2016.
Figure 1
Overall Survival for All Cohort 1 Efficacy-Evaluable Patients
IMvigor210 Cohort 2:  Clinical Activity in Patients with 2L+ mUC
As of the clinical cutoff of 14 March 2016, efficacy analyses were performed on the 
310 Cohort 2 patients from Study IMvigor210.  The median age of this population was 
66 years (range: 3291 years), and the group represented a 2L+ mUC patient population 


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that was previously treated with at least one platinum-containing regimen.  The median 
duration on study treatment was 12 weeks.
With a median follow-up duration of 14.4 months, atezolizumab treatment for 2L+ mUC 
patients demonstrated clinical activity in in all PD-L1 IC subgroups with higher ORRs 
associated with higher PD-L1 scores:  The IC2/3 subgroup had a clinically meaningful 
ORR of 28.0% (15 CRs and 13 PRs) versus the 10% in the IC0/1 subgroup (6 CRs and 
16 PRs) (see Table 6).  The ORR for all patients was 15.8%.
The median duration of response (DOR) for all responders (n 49) has not been 
reached in any of the IC subgroups (range: 2.1to 19.2months), with 35 patients with 
an ongoing response.
With patient-event ratio at 70.3%, the median OS was 7.9 months (95% CI: 6.7, 9.3) for 
all patients (see Figure 2).
Table 6
IRF-Assessed ORR and DOR per RECIST v1.1 in 2L+ Patients 
with mUC:  Efficacy-Evaluable Population in IMvigor210 Cohort 2
IC0/1
(n 210)
IC2/3
(n 100)
All Patients
(n 310)
ORR (%)
21 (10.0)
28 (28.0)
49 (15.8)
95% CI
(6.4, 14.9)
(19.5, 37.9)
(11.9, 20.3)
Complete 
response
6
15
21
Partial 
response
16
13
28
Median DOR 
(months)
NE
NE
NE
95% CI
(10.6, NE)
NE
NE
Patients with 
event (%)
6 (28.6)
8 (28.6)
14 (28.6)
DORduration of response; ICtumor-infiltrating immune cell; IRF = independent review facility; 
mUCmetastatic urothelial carcinoma; ORRobjective response rate; RECIST v1.1Response 
Evaluation Criteria in Solid Tumors, Version 1.1.
Note:  The responses were confirmed responses.
The clinical cutoff date was 14 March 2016.


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Figure 2
Overall Survival for All Cohort 2 Efficacy-Evaluable Patients  
See the Atezolizumab Investigator’s Brochure for further information regarding efficacy 
data with atezolizumab.
1.2.2.4
Clinical Pharmacokinetics and Immunogenicity
On the basis of available preliminary PK data (0.0320 mg/kg), atezolizumab appeared 
to show linear pharmacokinetics at doses 1 mg/kg.  For the 1 mg/kg and 20 mg/kg 
dose groups, the mean apparent clearance (CL) and the mean volume of distribution at 
steady state (Vss) had a range of 3.20 to 4.43 mL/day/kg and 48.1 to 64.1 mL/kg, 
respectively, which is consistent with the expected profile of an IgG1 antibody in humans.
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in 
all dose cohorts and was associated with changes in pharmacokinetics for some patients 
in the lower dose cohorts (0.3, 1, and 3 mg/kg).  The development of detectable ATAs 
has not had a significant impact on pharmacokinetics for doses from 1020 mg/kg.  
Patients dosed at the 10, 15, and 20 mg/kg dose levels have maintained the expected 
target trough levels of drug despite the detection of ATAs.  To date, no clear 
relationship between the detection of ATAs and adverse events or infusion reactions has 
been observed.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies 
(Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012).


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PD-L1 is an extracellular protein that downregulates immune responses primarily in 
peripheral tissues through binding to its two receptors PD-1 and B7.1.  Many human 
tumors have been found to overexpress PD-L1, which acts to suppress anti-tumor 
immunity.  PD-1 is an inhibitory receptor expressed on T cells following T-cell activation, 
which is sustained in states of chronic stimulation such as in chronic infection or cancer 
(Blank et al. 2005; Keir et al. 2008).  Ligation of PD-L1 with PD-1 inhibits T-cell 
proliferation, cytokine production, and cytolytic activity, leading to the functional 
inactivation or exhaustion of T cells.  B7.1 is a molecule expressed on 
antigen-presenting cells and activated T cells.  PD-L1 binding to B7.1 on T cells and 
antigen-presenting cells can mediate downregulation of immune responses, 
including inhibition of T-cell activation and cytokine production (Butte et al. 2007; 
Yang et al. 2011).
Overexpression of PD-L1 on tumor cells has been reported to impede anti-tumor 
immunity, resulting in immune evasion (Blank and Mackensen 2007).  Therefore, 
interruption of the PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate 
tumor-specific T-cell immunity.
PD-L1 expression is prevalent in many human tumors, and elevated PD-L1 expression 
on tumor cells is associated with a poor prognosis in patients with UC 
(Nakanishi et al. 2007).
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed or refused standard-of-care therapies.  
In Study PCD4989g, a Phase Ia dose-escalation and expansion study, objective 
responses with atezolizumab monotherapy were observed in a broad range of 
malignancies including urothelial carcinoma (see Section 1.2.2.3).  More recent data 
from a pivotal Phase II IMvigor210 study demonstrated clinically meaningful response 
rates and a noteworthy median overall survival in both 1L, cisplatin-ineligible, and 
2L+ mUC patients treated with atezolizumab (see Section 1.2.2.3). 
Atezolizumab has been generally well tolerated (see Section 1.2.2.2).  Adverse events 
with potentially immune-mediated causes consistent with an immunotherapeutic agent, 
including rash, hypothyroidism, hepatitis/transaminitis, colitis, and myasthenia gravis, 
have been observed in Study PCD4989g.  To date, these events have been 
manageable with treatment.
Given the evidence of the clinical activity of atezolizumab in advanced and metastatic 
UC, treatment with atezolizumab offers the potential for clinical benefit in patients with 
high risk muscle-invasive UC of the bladder and upper tract.  Because most 
atezolizumab-related toxicities observed to date have been mild and transient in nature, 
it is anticipated that adjuvant treatment with atezolizumab will have a manageable safety 
profile and has an acceptable benefit-risk assessment for the conduct of the study.


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2.
OBJECTIVES
2.1
EFFICACY OBJECTIVES
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of adjuvant atezolizumab treatment in patients with 
muscle-invasive urothelial carcinoma (UC) as measured by disease-free 
survival (DFS)  
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by overall 
survival (OS)

To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by 
disease-specific survival (DSS)

To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by distant 
metastasis-free survival (DMFS)

To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by 
non-urinary tract recurrence-free survival (NURFS)
2.2
SAFETY OBJECTIVES
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of atezolizumab in the adjuvant setting

To evaluate the incidence of anti-therapeutic antibodies (ATAs) against 
atezolizumab and to explore the potential relationship of the immunogenicity 
response with pharmacokinetics, safety, and efficacy
2.3
PHARMACOKINETIC OBJECTIVE
The pharmacokinetic (PK) objective for this study is as follows:

To characterize the pharmacokinetics of atezolizumab
2.4
PATIENT-REPORTED OUTCOME OBJECTIVE
The PRO objective for this study is as follows:

To assess health status as measured by the EuroQol 5-dimension, 5-level version 
(EQ-5D-5L) questionnaire 
2.5
EXPLORATORY OBJECTIVE
The exploratory objective for this study is as follows:

To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in 
archival and/or fresh tumor tissue and blood and their association with disease 
recurrence


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3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
Study WO29636 is a global Phase III, open-label, randomized, controlled trial designed 
to evaluate the efficacy and safety of adjuvant treatment with atezolizumab compared 
with observation in patients with muscle-invasive UC, who are at high risk for recurrence 
following resection. 
Male and female patients aged 18 years with Eastern Cooperative Oncology Group 
(ECOG) performance status 2 who have histologically confirmed muscle-invasive UC
(also termed TCC) of the bladder or upper urinary tract (i.e., renal pelvis or ureters) are 
eligible.  Patients with upper urinary tract urothelial carcinoma (UTUC) will be limited to 
no more than approximately 10% of the study population.
Patients with bladder as the site of primary involvement must have undergone radical 
cystectomy with lymph node dissection.  Patients with UTUC as the site of primary 
involvement must have undergone radical nephroureterectomy (RNU) with excision of 
the bladder cuff regardless of the location of the tumor in the upper urinary tract.  
RNU must include lymph node dissection.
Patients who have received prior neoadjuvant chemotherapy are eligible, but must have 
tumor staging of ypT24a or ypN+ (ypT2-4 or ypN+ for patients with UTUC) and M0 at 
pathological examination of the surgical resection specimen.  Patients who have not 
received prior neoadjuvant chemotherapy must be ineligible for or declined treatment 
with cisplatin-based adjuvant chemotherapy and have tumor staging of pT34a or pN+
(pT3-4 or pN+ for patients with muscle-invasive UTUC) and M0.
Tumor specimens from surgical resection (i.e., radical cystectomy, RNU, or lymph node 
dissection) from patients who have signed the Informed Consent Form will be evaluated 
for PD-L1 expression by IHC (see Appendix 3).  Only patients whose tumors have 
sufficient amounts of viable tumor and are evaluable for PD-L1 expression as confirmed 
by a central pathology laboratory prior to enrollment of the patient in the study will be 
eligible.
Figure 3 shows the study schema.  
Approximately 800 patients globally will be randomized to one of the following arms in 
a 1:1 ratio:

Arm A (experimental arm):  Atezolizumab 1200 mg q3w 

Arm B (control arm):  Observation


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Randomization will be stratified by the following factors:

Number of lymph nodes resected (10 vs. 10)

Nodal status (positive vs. negative)  

Tumor stage after surgical resection (pT2 vs. pT3/pT4)

PD-L1 IHC status (IHC score of IC0/1 vs. IHC score of IC2/3)

Prior neoadjuvant chemotherapy (yes vs. no)
Randomization must occur within 14 weeks after surgical resection of the primary tumor, 
and study drug administration should begin within 7 calendar days after randomization. 
For patients in Arm A, atezolizumab will be administered intravenously (IV) on Day 1 of 
each 21-day cycle for 16 cycles (up to 1 year).  In Arm B, patients will continually 
undergo observation starting on Day 1 of each 21-day cycle for 16 cycles (up to 1 year).  
Treatment/observation will be discontinued in the event of disease recurrence, 
unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor.
To ensure the same frequency of study assessments between the treatment arms,
including assessments for disease recurrence and safety, patients in Arm B will be 
required to undergo q3w medical contacts for assessments during the first year, which 
will consist of formal clinic visits alternating with clinical contacts (either via telephone 
call or formal outpatient clinic visit) for symptom and adverse event assessment.  
Patients in the control arm will not be allowed to cross over to receive atezolizumab 
treatment within this study.




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(MIBC), surveillance for tumor recurrence will include physical examination, laboratory 
evaluation, and imaging studies of the chest, abdomen, upper urinary tracts, and pelvis.  
Disease recurrence will be determined by the investigator based on radiographic 
evidence (visual appearance of UC with histological confirmation is acceptable for 
recurrence in bladder).  For patients with UTUC, surveillance for tumor recurrence must 
include physical examination, cystoscopy, urine cytology and imaging studies of the 
chest, abdomen, and pelvis.  A confirmatory tumor biopsy is mandatory at the time of 
disease recurrence (see Section 4.5.5).  Cases for which biopsy results definitively rule 
out recurrence of UC will not be considered as disease recurrence for this study. After 
the primary analysis, a confirmatory tumor biopsy is optional at the time of disease 
recurrence.
Safety assessments will include the incidence, nature, and severity of adverse events, 
changes in vital signs, and laboratory abnormalities graded per National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0.  Serum 
samples will be collected to monitor atezolizumab pharmacokinetics and to detect the 
presence of ATAs to atezolizumab.  A sample of archived tumor tissues, as well as 
serum and plasma samples, will be collected for future exploratory biomarker 
assessments.
An external independent Data Monitoring Committee (iDMC) will evaluate safety data 
according to policies and procedures detailed in an iDMC Charter (see Section 3.1.1).
A schedule of assessments is provided in Appendix 1.
3.1.1
Independent Data Monitoring Committee
An iDMC will be convened to evaluate safety data until the analysis of the primary 
endpoint (DFS), after which iDMC review of the study data will be discontinued.  The 
iDMC will evaluate study safety data on a periodic basis, approximately every 6 months 
after enrollment of the first patient.  Members of the iDMC will be external to the Sponsor 
and will follow a charter that outlines their roles and responsibilities.  The Sponsor will 
remain blinded to the results until the analysis of the primary endpoint of DFS.
All summaries and analyses by treatment arm for the iDMC review will be prepared by 
an external independent data coordinating center (iDCC).  The safety data will include 
demographic data, adverse events, serious adverse events, and relevant laboratory data.  
Following their data review, the iDMC will provide a recommendation as to whether the 
study may continue, whether amendment(s) to the protocol should be implemented, or 
whether the study should be stopped; the final decision will rest with the Sponsor.
3.2
END OF STUDY
The end of the study as planned will occur when the required number of events for the 
final analysis of OS has occurred (projected to be approximately Month 95 from FPI; 


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see Section 6.1.3).  However, the Sponsor may decide to terminate the study at any time 
(see Section 4.7.3). 
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Primary and Secondary Endpoints
Improvement in DFS represents clinically meaningful benefit to MIBC patients.  Up to 65% 
of MIBC patients who relapsed after cystectomy had symptoms associated with disease 
recurrence (Volkmer et al. 2009).  The most frequent symptoms were pain, ileus, acute 
urinary retention, hydronephrosis with flank pain, hematuria, and neurological symptoms.  
After relapse, the current standard chemotherapy regimens given in the locally advanced 
and metastatic UC setting are associated with significant toxicity (e.g., anemia, 
thrombocytopenia, neutropenia, and mucositis).  An improvement in DFS would delay 
symptoms associated with recurrence and the initiation of toxic therapy and therefore 
reflects direct benefit to patients.  Further, DFS is not confounded by subsequent 
therapies.  Given the development of multiple agents (including atezolizumab) in the 
relapsed and metastatic settings, it is likely that the analysis of OS will be confounded in 
this patient population.
For MIBC, distant metastases or local recurrence typically develop in the first 2 years 
after cystectomy (Volkmer et al. 2009).  Retrospective analysis showed that DFS at 2 or 
3 years correlates with 5-year OS of MIBC patients post-cystectomy.  In 2724 selected 
MIBC patients with negative surgical margin, high agreement rates were observed 
between DFS at 2 and 3 years after cystectomy with OS at 5 years (79% and 81%, 
respectively; Sonpavde et al. 2011).  A strong correlation was observed in a separate 
study that revealed even higher overall agreements between DFS at 2 years (86.5%) 
and 3 years (90.1%) and OS at 5 years.  In addition to the previous findings, this 
association was demonstrated in patients with different tumor stages and both negative 
and positive surgical margins (Nuhn et al. 2012).
OS is included as an important secondary endpoint; since subsequent treatments after 
disease recurrence are evolving, the impact of adjuvant treatment on OS may be 
confounded. 
Additionally, DSS (also known as cancer-specific survival) is a secondary endpoint 
because non-bladder cancer mortality in this frail and elderly population can be quite 
significant and may be a competing cause of mortality.  After 20 years of post-operative 
follow-up, the probability of non-tumor-related death was 42% in patients with 
Stage pT2a/b disease, 40% in pT3a/b, 25% in pT4a/b, and 12% in pTall pN+ 
(Hautmann et al. 2012), and improvement in DSS in this population may not be reflected 
in an analysis of OS.
NURFS is included as a secondary endpoint because the impact of urinary tract 
recurrence on patient survival may be different from non-urinary tract recurrence. 
Most urinary tract recurrence could be managed by surgical resection (e.g., the majority 


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of MIBC patients who develop upper urinary tract recurrence can achieve prolonged 
disease-free survival when treated with radical nephroureterectomy) 
(Sanderson et al. 2007).
DMFS is also included as a secondary endpoint because distant recurrence is 
considered to be a major threat to patient survival.  Furthermore, this endpoint will be 
informative as to how atezolizumab adjuvant treatment might affect patterns of 
recurrence.  For MIBC patients post-cystectomy, distant recurrences have been 
observed to occur more frequently than locoregional recurrences (approximately 
20%50% vs. 5%15% of cases) (Stein et al. 2001; Shariat et al. 2006).
3.3.2
Rationale for Inclusion of All Patients (All Levels of PD-L1 
Expression by IHC) in the Study
This study will enroll patients with muscle-invasive UC of the bladder and upper tract 
whose tumor specimens are evaluable for PD-L1 expression by IHC as determined by a 
central laboratory (see Appendix 3). 
Recent data from the metastatic UC setting demonstrated a median overall survival in all 
PD-L1 IC subgroups that was noteworthy when compared to historical controls.  
The median OS of 14.8 (95% CI: 10.1, NE) months suggests that there may be a 
benefit that is independent of PD-L1 status in patients treated with atezolizumab 
(see Section 1.2.2.3).  The inclusion of patients with all levels of PD-L1 expression by 
IHC in this study will enable a robust evaluation of DFS in the overall population with 
atezolizumab treatment relative to observation treatment irrespective of PD-L1 status.  
It will also allow assessment of whether high level of PD-L1 expression is predictive for 
atezolizumab treatment or whether PD-L1 expression is prognostic for disease outcome 
in the adjuvant setting.
3.3.3
Rationale for Patient Population
The majority of urothelial tumors arise in the bladder, with TCC (also called UC) being 
the most common histologic subtype.  TCC accounts for 90% of all MIBC cases in the 
industrialized world (Chalasani et al. 2009).  For patients undergoing radical cystectomy 
alone, recurrence-free survival (RFS) and OS in male and female patients is reported as 
6668% and 5866% at 5 years and 6073% and 4349% at 10 years, respectively 
(Stein et al. 2001; Hautmann et al. 2003; Madersbacher et al. 2003).  In node-positive 
patients, 10-year DSS and OS rates decrease to 27.7% and 20.9%, respectively 
(Gschwend et al. 2002).
ESMO, EAU, and NCCN clinical practice guidelines recommend cisplatin-based 
neoadjuvant chemotherapy prior to cystectomy for MIBC patients based on a meta-
analysis which showed a 5% net benefit in 5-year OS (Sternberg et al. 2006).  Patients 
with pT0 or pT2N0 disease at cystectomy following neoadjuvant chemotherapy were 
associated with better median survival (13.6 and 12.5 years, respectively).  However, 
median survival (3.4 and 2.4 years, respectively) was very poor for patients with residual 


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muscle-invasive disease (pT24a) or lymph node-positive disease (pN+) following 
neoadjuvant chemotherapy; there is currently no standard of care for these patients 
(Sonpavde et al. 2009).  Study WO29636 includes MIBC patients with pathological 
staging of ypT24a or ypN+ at cystectomy following neoadjuvant chemotherapy in 
this trial because this segment of the MIBC patient population has a high unmet 
medical need.
Despite existing guidelines, the majority of MIBC patients do not receive neoadjuvant 
chemotherapy before cystectomy.  A recent study showed that neoadjuvant 
chemotherapy is used in only 12% of the approximately 5000 MIBC patients undergoing 
cystectomy annually in Europe who are being considered for neoadjuvant chemotherapy 
(Burger et al. 2012).  Post cystectomy, adjuvant chemotherapy for MIBC patients is 
advised only within clinical trials according to current EAU guidelines.  However, a recent 
meta-analysis indicated that cisplatin-based adjuvant chemotherapy is supported 
specifically in high-risk patients with extravesical or node-positive disease 
(Leow et al. 2014).  Unfortunately, only approximately 50% of patients are eligible for 
cisplatin-based adjuvant chemotherapy, and factors rendering patients ineligible for 
cisplatin therapy include ECOG performance status of 2, impaired renal function, hearing 
loss, and neuropathy (Dash et al. 2006).  On the basis of current clinical guidelines, 
there is no standard adjuvant chemotherapy for patients who are ineligible for cisplatin-
based therapy.  With radical cystectomy alone, patients with extravesical (pT3T4a) or 
lymph node-positive (pN+) disease are at high risk for relapse (40%67%) and 
associated with poor 5-year OS (25%30%) (Gschwend et al. 2002; Shariat et al. 2006).  
Thus, this population of MIBC patients (with pT34a or pN+ disease; who did not receive 
prior neoadjuvant chemotherapy and have declined or are ineligible for cisplatin-based 
adjuvant chemotherapy) represents another area of high unmet medical need and are 
included in this trial.
UTUC are less common and account for only 510% of urothelial tumors.  Given that 
UTUC have the same histology as UC of the bladder, the NCCN guidelines recommend 
that neoadjuvant and adjuvant chemotherapy be considered for selected patients with 
extensive UTUC based on extrapolation of data from bladder cancer series.  Thus, 
Study WO29636 includes high-risk patients of UTUC with similar staging to MIBC.
3.3.4
Rationale for Observation Control Arm 
Study WO29636 has an observation control arm.  There is no standard of care after 
surgical resection for patients with muscle-invasive UC of the bladder or upper tract who 
have declined or are ineligible for cisplatin-based adjuvant chemotherapy.  According to 
EAU guidelines (2014), there is no evidence that non-cisplatin-based adjuvant regimens 
(e.g., carboplatin-based adjuvant chemotherapy) are as effective as cisplatin-based 
adjuvant chemotherapy.  Use of adjuvant chemotherapy for cisplatin-ineligible patients is 
not listed in current EU and US guidelines. 


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For patients who have been treated with neoadjuvant chemotherapy and fail to achieve 
a pCR or downgrading to pT0-1, there is currently no standard active treatment for these 
patients in the adjuvant setting. 
Given the concerns of giving mock infusion q3w intravenously for up to 1 year to patients 
in the control arm, this study will not employ a placebo-controlled design.
3.3.5
Rationale for Stratification Factors
In order to balance the disease-related risk factors between the treatment arms, 
patients will be stratified at study entry.  A stratified permuted-block randomization 
scheme will be used to obtain a balanced assignment to each treatment within levels of 
the stratification factors.

Nodal involvement is considered to be a major prognostic factor for predicting 
disease recurrence and OS after cystectomy (Stein et al. 2001; 
Karakiewicz et al. 2006; Hautmann et al. 2012).  The number of lymph nodes 
removed during cystectomy is prognostic as well (Herr et al. 2004).

Pathological tumor stage is the most important independent prognostic variable for 
recurrence and OS for invasive bladder cancer.  Comprehensive pathologic staging 
could be performed after cystectomy (with lymphadenectomy) (Stein et al. 2001; 
Shariat et al. 2006).

Neoadjuvant chemotherapy has been added as a stratification factor to control for 
the potential differences in local standard care in major regions and for any 
differences in outcomes based upon the receipt of prior neoadjuvant chemotherapy.

The level of PD-L1 expression by IHC has been shown to correlate with recurrence 
or OS in patients with UC (McDaniel et al. 2016; Bellmunt et al. 2015).
3.3.6
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.
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 g/mL on the basis of several 
assumptions including the following:  1) 95% tumor-receptor saturation is needed for 
efficacy and 2) the tumor-interstitial concentration to plasma ratio is 0.30 based on tissue 
distribution data in tumor-bearing mice.
The atezolizumab dose was also informed by available clinical activity, safety, PK, and 
immunogenicity data.  Anti-tumor activity has been observed across doses from 
120 mg/kg in Study PCD4989g (see Section 1.2.2.3).  In Study PCD4989g, the MTD of 
atezolizumab was not reached, and no DLTs were observed at any dose levels.  


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Available preliminary PK data (0.0320 mg/kg) suggests that for doses 1 mg/kg, 
atezolizumab generally exhibits pharmacokinetics that are both linear and consistent 
with typical IgG1 antibodies (see Section 1.2.2.4).  Detectable ATAs were observed in 
patients at all dose levels but were associated with changes in pharmacokinetics for 
some patients in the lower dose cohorts only (0.3, 1, and 3 mg/kg).  It is unclear from 
currently available data in these lower dose cohorts whether administration of higher 
doses to patients with both detectable ATAs and reduced exposure would necessarily 
restore exposure to expected levels.  No clear relationship between the development of 
measurable ATAs and safety or efficacy has been observed.  Available data suggest 
that the development of detectable ATAs does not appear to have a significant impact 
on pharmacokinetics for doses from 10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 ATAs.  Currently available PK and ATA 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 g/mL and 
further minimize the potential of both interpatient variability and possible effect of ATAs 
leading 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 mg/kg atezolizumab q3w regimen does not appear to be 
warranted to maintain targeted Ctrough levels relative to the proposed 15 mg/kg 
atezolizumab q3w level.
Simulations using the methodology of Bai et al. (2012) do not suggest any clinically 
meaningful differences in exposure for atezolizumab following a fixed dose or dose 
adjusted for weight.  On the basis of this analysis, a fixed dose of 1200 mg (equivalent to 
a body weightbased dose of 15 mg/kg) was selected for ongoing and future studies of 
atezolizumab.
A 1-year period of adjuvant treatment has been selected because this is believed to 
balance the risks and tolerability of therapy with the expected benefit in the adjuvant 
setting on the basis of an assessment of benefit versus risk observed in the 
metastatic setting.
3.3.7
Rationale for Collection of Archival and/or Pre-Treatment 
Tumor Specimens
In this study, surgical resection or lymph node dissection tumor specimens from patients 
will be prospectively tested for PD-L1 expression by a central laboratory during the 
screening period and PD-L1 status (IHC score of IC0/1 vs. IC2/3) will be used as one of 
the stratification factors.  In addition to the assessment of PD-L1 status, other 
exploratory markers, such as potential predictive and prognostic markers related to the 
clinical benefit of atezolizumab, tumor immunobiology, mechanisms of resistance, or 
tumor type, may also be analyzed.


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Patients with additional pre-study tumor tissue samples (i.e., beyond those required to 
meet eligibility requirements) from procedures performed at different times during the 
course of their UC will be requested (but not required) to also submit these samples for 
central testing.  Tissue samples obtained at multiple times from individual patients will 
greatly contribute to an improved understanding of the dynamics of PD-L1 expression 
and relationship with intervening anti-cancer therapy.
3.3.8
Rationale for Blood Sampling for Biomarkers and for Optional 
Collection of Tumor Specimens
Changes in different blood biomarkers may provide evidence for biologic activity of 
atezolizumab in humans and may allow for the development of a blood-based biomarker 
to help predict which patients may benefit from atezolizumab.  An exploratory objective 
of this study is to evaluate changes in surrogate biomarkers in blood samples.
In addition, potential correlations of these pharmacodynamic markers with the dose, 
safety, and anti-tumor activity of atezolizumab will be explored.  
For this study, a confirmatory tumor biopsy is mandatory at the time of disease 
recurrence.  Analysis of biomarkers in the tumor samples may explain why UC 
recurs and help develop further treatment.  However, it is optional for patients to 
agree for their biopsy samples to be placed in the Roche Clinical Repository 
(RCR; see Section 4.5.12). After the primary analysis, a confirmatory tumor biopsy is 
optional at the time of disease recurrence.
3.4
OUTCOME MEASURES 
3.4.1
Efficacy Outcome Measures
3.4.1.1
Primary Efficacy Outcome Measure
The primary efficacy outcome measure for this study is as follows:

Investigator-assessed DFS, defined as the time from randomization to the time of 
first occurrence of a DFS event, defined as any of the following:
Local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes)
Urinary tract recurrence of UC (including all pathological stages and grades)
Distant metastasis of UC 
Death from any cause
3.4.1.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are as follows:

OS, defined as the time from randomization to the date of death from any cause

DSS, defined as the time from randomization to the date of death from UC per 
investigator assessment of cause of death

DMFS, defined as the time from randomization to the date of diagnosis of distant 
(i.e., non-locoregional) metastases or death from any cause


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
NURFS, defined as the time from randomization to the time of first occurrence of a 
NURFS event, defined as any of the following:
Local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes)
Distant metastasis of UC 
Death from any cause
3.4.2
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, nature, and severity of adverse events graded according to 
NCI CTCAE v4.0

Changes in vital signs and clinical laboratory results

Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters
3.4.3
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Maximum observed serum atezolizumab concentration (Cmax) after infusion on 
Day 1 of Cycle 1

Minimum observed serum atezolizumab concentration (Cmin) prior to infusion on 
Day 1 of Cycles 1, 2, 3, and 4; every 8 cycles starting on Cycle 8; at treatment 
discontinuation; and at 120 days (30 days) after the last dose of atezolizumab
3.4.4
Patient-Reported Outcome Measure
The PRO outcome measure for this study is as follows:

EQ-5D-5L as a measure of patient-reported health status
3.4.5
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Status of tumor immune-related or disease type−related exploratory biomarkers in 
archival and/or freshly obtained tumor tissues and association with disease 
recurrence

Status of exploratory biomarkers in plasma, whole blood, or serum (including but not 
limited to cytokines such as IL-6) collected before or during treatment with 
atezolizumab or at recurrence and association with disease recurrence
4.
MATERIALS AND METHODS
4.1
PATIENTS
4.1.1
Inclusion Criteria

Signed Informed Consent Form

Ability to comply with protocol

Age 18 years


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
Histologically confirmed muscle-invasive UC (also termed TCC) of the bladder or 
upper urinary tract (i.e., renal pelvis, or ureters)
Patients with mixed histologies are required to have a dominant transitional cell 
pattern.

TNM classification (UICC/AJCC 7th edition) at pathological examination of surgical 
resection specimen as follows: 
For patients treated with prior neoadjuvant chemotherapy:  tumor stage of 
ypT24a or ypN+ (ypT2-4 or ypN+ for patients with UTUC) and M0
For patients who have not received prior neoadjuvant chemotherapy:  tumor 
stage of pT34a or pN+ (pT3-4 or pN+ for patients with UTUC) and M0

Surgical resection of muscle-invasive UC of the bladder, or UTUC upper tract
For patients with MIBC, radical cystectomy may be performed by the open, 
laparoscopic, or robotic approach.  Cystectomy must include bilateral lymph 
node dissection, the extent of which will be at the discretion of the treating 
surgeon but optimally should extend at a minimum from the mid common iliac 
artery proximally to Cooper's ligament distally, laterally to the genitofemoral 
nerve, and inferiorly to the obturator nerve.  The method of urinary diversion for 
patients undergoing cystectomy will be at the discretion of the surgeon and 
choice of the patient.
Patients with a negative surgical margin (i.e., R0 resection) or with 
carcinoma in situ (CIS) at the distal ureteral or urethral margin will 
be eligible.
Patients with a positive R2 margin (which is defined as a tumor identified at 
the inked perivesical fat margin surrounding the cystectomy specimen) or 
R1 margin (which is defined as evidence of microscopic disease identified 
at the tumor margin), except for CIS at distal ureteral or urethral margin, will 
be excluded.
For patients with UTUC, RNU, with excision of the bladder cuff is required and 
may be performed by the open or laparoscopic approach.  RNU must include 
lymph node dissection (LND), the extent of which will be at the discretion of the 
treating surgeon but optimally should include the para-aortic, paracaval or 
interaortocaval nodes from the renal hilum to the inferior mesenteric artery in 
renal pelvis and proximally ureteral tumors, or nodes from the renal hilum to the 
bifurcation of the common iliac artery and ipsilateral pelvic nodes in mid and 
lower ureteral tumors, respectively.
Patients must have a negative surgical margin (i.e., R0 resection).  Patients 
with a positive R1 or R2 surgical margin will be excluded.  

Patients who have not received prior platinum-based neoadjuvant chemotherapy, 
have refused or are ineligible (“unfit”) for cisplatin-based adjuvant chemotherapy 
Patients who have received at least two cycles of a platinum-containing 
regimen will be considered as those who have received prior neoadjuvant 
chemotherapy. 


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Cisplatin ineligibility is defined by any one of the following criteria:
Impaired renal function (glomerular filtration rate [GFR]60 mL/min); GFR 
should be assessed by direct measurement (i.e., creatinine clearance or 
ethyldediaminetetra-acetate) or, if not available, by calculation from 
serum/plasma creatinine (Cockcroft-Gault formula)
A hearing loss (measured by audiometry) of 25 dB at two contiguous 
frequencies
Grade 2 or greater peripheral neuropathy (i.e., sensory alteration or 
parasthesis including tingling)
ECOG performance status of 2 (see Appendix 7)

Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens from 
surgical resection (i.e., radical cystectomy, nephroureterectomy, or lymph node 
dissection) in paraffin blocks (blocks preferred) or at least 15 unstained slides, with 
an associated pathology report, for central testing and determined to be evaluable 
for tumor PD-L1 expression prior to study enrollment 
Patients with fewer than 15 unstained slides available at baseline (but no fewer 
than 10) may be eligible following discussion with Medical Monitor.
Tumor tissue of bladder or upper tract should be of good quality based on total 
and viable tumor content and must contain a muscle invasive component 
(i.e., T2 or greater) of the tumor as verified by local pathology review.  
Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone 
metastases, and lavage samples are not acceptable.  For core-needle biopsy 
specimens, at least three cores should be submitted for evaluation.
Patients having additional tissue samples from procedures performed at 
different times during the course of their muscle-invasive UC (e.g., a specimen 
from a prior transurethral resection of bladder tumor [TURBT]) or having lymph 
node involvement identified at lymph node dissection will be requested (but not 
required) to also submit these samples for central testing.  Tissue samples 
obtained at multiple times or anatomical sites for individual patients will greatly 
contribute to an improved understanding of the dynamics of PD-L1 expression 
and relationship with intervening anti-cancer therapy.  
In situations where multiple specimens were received from different sites or at 
different times, the score from the surgical resection of the primary tumor or 
lymph node dissection specimen will be used for both primary and secondary 
analyses.

Muscle-invasive UC with PD-L1 expression per IHC (see Appendix 3) prospectively 
determined on the surgical resection or lymph node dissection tumor specimens by 
a central laboratory


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
Absence of residual disease and absence of metastasis, as confirmed by a negative 
baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan of 
the pelvis, abdomen, and chest no more than 4 weeks prior to randomization.
For patients with MIBC, imaging of the upper urinary tracts must include one or 
more of the following:  intravenous pyelogram (IVP), CT urography, renal 
ultrasound with retrograde pyelogram, ureteroscopy or MRI urogram, and must 
be completed no more than 4 weeks prior to randomization.
For patients with UTUC, cystoscopy and urine cytology must be completed no 
more than 4 weeks prior to randomization, however upper tract imaging is 
not needed.
Other examinations should be performed as clinically indicated.
For patients with both primary MIBC and primary UTUC, imaging of the upper 
urinary tracts, cystoscopy, and urine cytology is not required.  

Full recovery from cystectomy or nephroureterectomy within 14 weeks following 
surgery

ECOG performance status of 2 (see Appendix 7)

Life expectancy 12 weeks

Adequate hematologic and end-organ function, as defined by the following 
laboratory results obtained within 14 days prior to the first study treatment:
ANC 1500 cells/L (without granulocyte colonystimulating factor support 
within 2 weeks prior to Cycle 1, Day 1)
WBC counts 2500/L 
Lymphocyte count 300/L
Platelet count 100,000/L (without transfusion within 2 weeks prior to Cycle 1, 
Day 1)
Hemoglobin 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion.
AST, ALT, and alkaline phosphatase 2.5the upper limit of normal (ULN)
Serum bilirubin 1.0ULN
Patients with known Gilbert disease who have serum bilirubin level 
3ULN may be enrolled.
PTT/PT 1.5 ULN or INR 1.7 ULN
This applies only to patients who are not receiving therapeutic 
anticoagulation; patients receiving therapeutic anticoagulation should be on 
a stable dose.
Calculated creatinine clearance 20 mL/min (Cockcroft-Gault formula)


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
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, and agreement to refrain from donating eggs during this 
same period
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of 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:
Cancer-Specific Exclusion Criteria

Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy 
within 3 weeks prior to initiation of study treatment
Hormone-replacement therapy or oral contraceptives are allowed.

Adjuvant chemotherapy or radiation therapy for UC following surgical resection
Patients who have received primary chemoradiation for bladder preservation 
before cystectomy are eligible and will be treated as the same as patients who 
have received prior neoadjuvant chemotherapy.
Post-surgical intrapelvic/intravesical chemotherapy or BCG is not allowed for 
patients with UTUC.

Treatment with any other investigational agent or participation in another clinical trial 
with therapeutic intent within 28 days or five half-lives of the drug, whichever is 
longer, prior to enrollment

Malignancies other than UC within 5 years prior to Cycle 1, Day 1:
Patients with high risk UTUC (defined as tumor stage ypT24a or ypN+) within 
5 years prior to Cycle 1 Day 1 will be ineligible after the UTUC limit of 
approximately 10% has been met. 


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Patients with localized low risk prostate cancer (defined as Stage T2b, 
Gleason score 7, and PSA at prostate cancer diagnosis 20 ng/mL
[if measured]) treated with curative intent and without prostate-specific antigen 
(PSA) recurrence are eligible. 
Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason 
score 7 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
General Medical Exclusion Criteria

Pregnancy or breastfeeding

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation

History of autoimmune disease, including, but not limited to, myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 5 for a 
more comprehensive list of autoimmune diseases)
Patients with a history of autoimmune-related hypothyroidism on a stable dose 
of thyroid replacement hormone may be eligible for this study.
Patients with controlled Type I diabetes mellitus on a stable dose of insulin 
regimen may be eligible for this study.

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Serum albumin 2.5 g/dL

Positive test for HIV


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
Patients with active hepatitis B virus (HBV; chronic or acute; defined as having a 
positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C
Patients with past HBV infection or resolved HBV infection (defined as the 
presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are 
eligible.  HBV DNA must be obtained in these patients prior to Cycle 1, Day 1.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA.

Active tuberculosis

Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1

Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) 
are eligible.

Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction within the previous 3 months, 
unstable arrhythmias, or unstable angina
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, 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.

Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, 
Day 1 or anticipation of need for a major surgical procedure during the course of 
the study

Prior allogeneic stem cell or solid organ transplant

Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or 
anticipation that such a live, attenuated vaccine will be required during the study
Influenza vaccination should be given during influenza season only 
(approximately October through May in the Northern Hemisphere and 
approximately April through September in the Southern Hemisphere).  Patients 
must agree not to receive live, attenuated influenza vaccine (e.g., FluMist®) 
within 28 days prior to randomization, during treatment or within 5 months 
following the last dose of atezolizumab (for patients randomized to 
atezolizumab).

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment 
complications


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Medication-Related Exclusion Criteria

Prior treatment with CD137 agonists or immune checkpointblockade therapies, 
including anti-CD40, antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic 
antibodies

Treatment with systemic immunostimulatory agents (including but not limited to 
interferons, IL-2) within 6 weeks or five half-lives of the drug, whichever is shorter, 
prior to Cycle 1, Day 1

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 [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1, or 
anticipated requirement for systemic immunosuppressive medications during 
the trial
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea, multiple 
doses for contrast allergy) may be enrolled in the study.
The use of inhaled or low-dose (e.g., ≤10 mg/day prednisone) corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, 
mineralocorticoids (e.g., fludrocortisone for adrenal insufficiency) and low-dose 
corticosteroids for patients with orthostatic hypotension or adrenocortical 
insufficiency is allowed.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study.  The investigator and patient will not be blinded to treatment 
assignment.
After written informed consent has been obtained and eligibility has been established, 
the study site will obtain the patient’s identification number and treatment assignment 
from the Interactive Voice/Web Response System (IxRS).   
Patients will be randomized to one of the following two treatment arms in a 1:1 ratio:

Arm A (experimental arm):  Atezolizumab 1200 mg q3w for 16 cycles or 1 year 
(whichever occurs first)

Arm B (control arm):  Observation q3w for 16 cycles or 1 year (whichever 
occurs first)
Randomization will be stratified by the following factors:

Number of lymph nodes resected (10 vs. 10)

Nodal status (positive vs. negative)  

Tumor stage after surgical resection (pT2 vs. pT3/pT4)

PD-L1 status (IC0/1 vs. IC2/3)

Prior neoadjuvant chemotherapy (yes vs. no)


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A stratified permuted-block randomization method will be implemented in order to obtain 
a balanced assignment to each treatment within levels of the stratification factors.
4.3
STUDY TREATMENT 
Atezolizumab is considered the investigational medicinal product (IMP) in this study.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab
Atezolizumab will be supplied by the Sponsor as sterile liquid in 20-mL glass vials.  
The vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution, but may 
contain more than the stated volume to enable delivery of the entire 20 mL volume.   
For information on the formulation and handling of atezolizumab, refer to the 
Investigator's Brochure and Pharmacy Manual.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Atezolizumab
The dose level of atezolizumab to be tested in this study is 1200 mg (equivalent to an 
average body weightbased dose of 15 mg/kg) administered by IV infusion q3w 
(21 [3] days)16 cycles or 1 year (whichever occurs 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. 
For further details, see the Atezolizumab Pharmacy Manual and Investigator’s Brochure.
Atezolizumab infusions will be administered per the instructions outlined in Table 7.


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Table 7
Administration of First and Subsequent Infusions 
of Atezolizumab
First Infusion
Subsequent Infusions

No pre-medication is allowed.

Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before 
starting infusion.

Infuse atezolizumab (one vial in 250 mL 
NaCl) over 60 (15) minutes.

Record patient’s vital signs during the 
infusion and/or 30 minutes (10) after the 
infusion if clinically indicated.

Patients will be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.

If patient experienced infusion-related 
reaction during any previous infusion, 
pre-medication with antihistamines may 
be administered for Cycles 2 at the 
discretion of the treating physician.

If the patient tolerated the first infusion 
well without infusion-associated adverse 
events, the second infusion may be 
delivered over 30 (10 minutes) minutes.

If the patient had an infusion-related 
reaction during the previous infusion, the 
subsequent infusion must be delivered 
over 60 (15) minutes.

If clinically indicated or patient 
experienced symptoms during the 
previous infusion, record patient’s vital 
signs (heart rate, respiratory rate, blood 
pressure, and temperature) within 
60 minutes before starting infusion, during 
the infusion and/or 30 minutes (10) after 
the infusion.

If no reaction occurs, continue 
subsequent infusions over 
30 (10) minutes with same schedule for 
recording vital signs.
NaClsodium chloride.
For anaphylaxis precautions, see Appendix 6.
Guidelines for dosage modification and treatment interruption or discontinuation and the 
management of specific adverse events are provided in Sections 5.1.3, 5.1.4 and 
Appendix 9.
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF (see Section 5.3.5.12).
See the Atezolizumab Investigator’s Brochure and Pharmacy Manual for detailed 
instructions on drug preparation, storage, and administration.
4.3.3
Investigational Medicinal Product Accountability
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, and triple-negative breast cancer.  The investigational 
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provided by the Sponsor where required by local health authority regulations.  The study 
site will acknowledge receipt of IMPs using the IxRS to confirm the shipment condition 
and content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor or the Sponsor’s delegated 
representative with the appropriate documentation.  The site's method of IMP destruction 
must be agreed to by the Sponsor.  The site must obtain written authorization from the 
Sponsor before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Trial Access to Atezolizumab
Currently, the Sponsor does not have any plans to provide atezolizumab or any other 
study treatments or interventions to patients who have completed the study.  The 
Sponsor will evaluate whether to continue providing atezolizumab in accordance with the 
Roche Global Policy on Continued Access to Investigational Medicinal Product, available 
at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
4.4.1
Permitted Therapy with Atezolizumab
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to written informed consent until the treatment/observation discontinuation 
visit.  All such medications should be reported to the investigator.
Premedication with antihistamines may be administered for any atezolizumab infusions 
after Cycle 1.
The following therapies should continue while patients are in the study:

Oral contraceptives

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as lowmolecular weight 
heparin or warfarin at a stable dose level)

Inactive influenza vaccinations during influenza season ONLY

Megestrol administered as an appetite stimulant 

Inhaled or low-dose corticosteroids for COPD, or asthma

Mineralocorticoids (e.g., fludrocortisone)


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
Low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical 
insufficiency
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, as per local standards.  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 (for sites outside the United States, 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 2-adrenergic agonists; see Appendix 6.
All medications must be recorded on the Concomitant Medications eCRF.
4.4.2
Cautionary Therapy for Atezolizumab-Treated Patients
Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations where 
systemic corticosteroids or TNF-inhibitors would be routinely administered, alternatives 
(including antihistamines) should be considered first by the treating physician.  If the 
alternatives are not feasible, systemic corticosteroids and TNF-inhibitors may be 
administered at the discretion of the treating physician, including use of corticosteroids to 
premedicate patients for whom CT scans with contrast are contraindicated (i.e., patients 
with contrast allergy or impaired renal clearance). 
Systemic corticosteroids are recommended and permitted for management of 
gastrointestinal, dermatologic, endocrine, pulmonary toxicity, hepatotoxicity, potential 
pancreatic or eye toxicity and other immune-mediated adverse events when associated 
with atezolizumab therapy, at the discretion of the treating physician (see the 
Atezolizumab Investigator’s Brochure for details; see Appendix 6 for precautions for 
anaphylaxis).
The concomitant use of herbal therapies is not recommended as their pharmacokinetics, 
safety profiles, and potential drug-drug interactions are generally unknown.  However, 
their use for patients on study is allowed at the discretion of the investigator.


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4.4.3
Prohibited Therapy
Any concomitant therapy intended for the treatment of cancer, whether 
health authorityapproved or experimental, is prohibited for various time periods prior to 
starting study treatment (depending on the anticancer agent; see Section 4.1.2) and 
during study treatment until disease recurrence is documented and patient has 
discontinued study treatment.  This includes but is not limited to the following:

Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, intravesical 
therapy, or investigational agents
UTUC patients with bladder recurrence of papillary urothelial neoplasm of low 
malignant potential (PUNLMP) or low-grade papillary urothelial carcinoma 
(pTa), requiring local resection may still be eligible to continue study 
treatment, at the discretion of the investigator.
The following medications are prohibited for patients randomized to atezolizumab during 
study treatment, unless otherwise noted:

Any live, attenuated vaccine (e.g., FluMist) within 28 days prior to randomization, 
during treatment or within 5 months following the last dose of atezolizumab 
(for patients randomized to atezolizumab)

Immunomodulatory agents, including but not limited to interferons or IL-2, during the 
entire study; these agents could potentially increase the risk for autoimmune 
conditions when received in combination with atezolizumab

Immunosuppressive medications, including but not limited to cyclophosphamide, 
azathioprine, methotrexate, and thalidomide; these agents could potentially alter the 
activity and the safety of atezolizumab
4.5
STUDY ASSESSMENTS 
Refer to Appendix 1 for the schedule of assessments performed during the study.  
Patients will be closely monitored for safety and tolerability throughout the study.  
All assessments must be performed and documented for each patient.
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
If the timing of a protocol-mandated study visit coincides with a holiday and/or 
weekend that preclude the visit, the visit should be scheduled on the nearest following 
feasible date.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.


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Prior to signing the main consent form for the study, patients may specifically allow for 
the collection and testing of archival or fresh tumor tissue by signing the prescreening 
Informed Consent Form.  
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  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, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 7 days prior 
to written informed consent.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
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.
4.5.4
Vital Signs
Vital signs will include the measurements of respiratory rate, heart rate, systolic and 
diastolic blood pressures while the patient is in a seated position, and temperature.
For patients assigned to atezolizumab treatment (Arm A), at first infusion, vital signs 
(heart rate, respiratory rate, blood pressures, and temperature) should be determined 
within 60 minutes before the infusion.  Additional vital signs will be recorded at the first or 
following infusions only if clinically indicated (see Table 7).  Patients will be informed 
about the possibility of delayed post-infusion symptoms and instructed to contact their 
study physician if they develop such symptoms.
Vital signs will be performed as standard of care if clinically indicated for patients 
randomized to the observation arm (Arm B).  


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4.5.5
Surveillance for UC Recurrence
Patients will be assessed for tumor recurrence every 12 weeks for Years 13, every 
24 weeks for Years 45, and at Year 6 (approximately 48 weeks after the last 
assessment in Year 5) until occurrence of a DFS event, loss to follow-up, withdrawal of 
consent, or study termination, whichever occurs first, regardless of length of 
treatment/observation. After the primary analysis, patients in Years 13 of the study 
may be assessed for tumor recurrence every 24 weeks.
For patients with MIBC, surveillance for tumor recurrence must include physical 
examination, and imaging studies of the chest, abdomen, upper urinary tracts, and pelvis.  
Imaging of the upper urinary tracts is required and may include one or more of the 
following:  IVP, CT urography, renal ultrasound with retrograde pyelogram, ureteroscopy, 
or MRI urogram. However, separate imaging of the upper urinary tracts during 
surveillance via one of these modalities is not required if the upper tracts are covered in 
the imaging of the abdomen and pelvis. Other examinations such as laboratory 
evaluation (e.g., to monitor tumor recurrence in liver or bone), urine cytology or bone 
scan should be performed as clinically indicated.
For patients with UTUC, surveillance for tumor recurrence must include physical 
examination, cystoscopy, urine cytology and imaging studies of the chest, abdomen, and 
pelvis, however upper tract imaging is not needed.  Other examinations such as 
laboratory evaluation (e.g., to monitor tumor recurrence in liver or bone) or bone scans 
should be performed as clinically indicated.
For patients with primary MIBC and primary UTUC, imaging of the upper urinary tracts, 
cystoscopy, and urine cytology are not required. 
All eligible patients will undergo a contrast-enhanced CT or MRI of the chest, abdomen, 
and pelvis at screening (no more than 4 weeks prior to randomization). In patients for 
whom CT scans with contrast are contraindicated (i.e., patients with contrast allergy or 
impaired renal clearance), MRIs of the abdomen and pelvis with a non-contrast CT scan 
of the chest may be used. For MIBC patients with renal impairment or contrast allergy,
upper tract imaging is still required. For patients with renal impairment, CT urography 
with a reduced contrast agent or a non-contrasted MRI is recommended. For patients 
with a contrast allergy, non-contrasted MRI urogram or ureteroscopy is recommended.
If a CT scan for tumor assessment is performed in a positron emission tomography/CT 
scanner, the CT acquisition must be consistent with the standards for a full-contrast 
diagnostic CT scan. 


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Surveillance imaging studies should use the same imaging modality that was used at 
screening and be performed at the timepoints specified in Appendix 1, regardless of 
drug delays or interruptions.
If recurrent disease or occurrence of a new primary tumor is suspected on clinical 
grounds, imaging studies must be performed expeditiously, even if not mandated in the 
schedule of assessments. 
All patients who present with findings suspicious for disease recurrence must undergo a 
confirmatory biopsy for histopathologic confirmation.  Biopsy can only be waived for 
patients who have no lesions amenable for biopsy at disease recurrence, following 
discussion with and approval by the Medical Monitor. After the primary analysis, a 
confirmatory tumor biopsy is optional at the time of disease recurrence.
Disease recurrence will be determined by the investigator based on radiographic 
evidence.  For patients with UTUC, disease recurrence determined by visual 
appearance of UC in bladder is acceptable with histopathologic confirmation.  Cases for 
which biopsy results definitively rule out recurrence of UC will not be considered as 
disease recurrence for this study. After the primary analysis, a confirmatory tumor 
biopsy is optional at the time of disease recurrence.
4.5.6
Laboratory, Biomarker, and Other Biological Samples 
Samples for hematology, serum chemistries, coagulation, urinalysis, and the pregnancy 
test will be analyzed at the study site’s local laboratory.  Central laboratories will 
coordinate the collection of archival tumor, fresh tumor, and leftover tumor tissue and 
blood samples for the assessment of atezolizumab pharmacokinetics and 
pharmacodynamic biomarkers, ATA assays, and auto-antibody testing.  Instruction 
manuals and supply kits will be provided for all central laboratory assessments.
Local laboratory assessments will include the following:

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, chloride, bicarbonate, calcium, phosphorus, total bilirubin, ALT, AST, 
alkaline phosphatase, LDH, total protein, and albumin)

Coagulation (aPTT and INR)

Serum pregnancy test during screening and serum or urine pregnancy tests during 
the study (for women of childbearing potential, including 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)


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
All patients will be tested for HIV prior to the inclusion into the study, and 
HIV-positive patients will be excluded from the clinical trial.

HBV serology (HBsAg, antibody to HBsAg [anti-HBs], anti-HBc)
HBV DNA is required on or before Cycle 1, Day 1 if patient has negative 
serology for HBsAg and positive serology for anti-HBc. 

HCV serology (anti-HCV)
Instruction manuals and supply kits will be provided for all central laboratory 
assessments.  The following assessments will be performed at a central laboratory or by 
the Sponsor:

ATA assays (patients assigned to atezolizumab only) 
Serum samples will be assayed for the presence of ATAs to atezolizumab with 
use of validated immunoassays.

PK assays (patients assigned to atezolizumab only)
Serum samples will be assayed for atezolizumab concentration with use of a 
validated immunoassay.
Residual PK and ATA samples will be retained for further method development, 
validation and characterization.  Samples will be stored for 5 years after the 
study results have been reported. 

Auto-antibody testing (patients assigned to atezolizumab only); baseline sample to 
be collected on Cycle 1, Day 1 prior to the first dose of study drug.  For patients who 
show evidence of immune-mediated toxicity, additional samples may be collected 
and all samples will be analyzed centrally.
Anti-nuclear antibody
Antidouble-stranded DNA
Circulating anti-neutrophil cytoplasmic antibody
Perinuclear anti-neutrophil cytoplasmic antibody

Biomarker assays 
Blood samples will be obtained for biomarker evaluation (including but not 
limited to biomarkers that are related to bladder or tumor immune biology) from 
all eligible patients according to the schedule in Appendix 2.  Samples will be 
processed to obtain plasma and serum for the determination of changes in 
blood-based biomarkers.  Whole blood samples may be processed to obtain 
peripheral blood mononuclear cells (PBMCs) and their derivatives (e.g., RNA).
4.5.7
Resected Tumor Tissue Samples 
A central laboratory will coordinate the sample collection of resected tumor tissue 
samples for research-related testing at central laboratories or at the Sponsor.  Instruction 
manuals and supply kits will be provided for all central laboratory assessments.
See the Laboratory Manual for additional details on tissue sample handling.


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4.5.7.1
Resected Tumor Tissues for Screening
Representative FFPE tumor specimens in paraffin blocks (blocks preferred) or at least 
15 unstained slides, with an associated pathology report, must be submitted for central 
testing for determination of sufficient viable tumor content prior to study enrollment; 
tumor specimens will be evaluated for PD-L1 expression.
Tumor tissue should be of good quality based on total and viable tumor content 
(sites will be informed if the quality of the submitted specimen is inadequate to determine 
tumor PD-L1 status).  Fine-needle aspiration, brushing, cell pellets from pleural effusion, 
and lavage samples are not acceptable.  For core-needle biopsy specimens, at least 
three cores should be submitted for evaluation.
Patients having additional tissue samples from procedures performed at different times 
during the course of their UC will be requested (but not required) to also submit these 
samples for central testing.  Tissue samples obtained at multiple times for individual 
patients will greatly contribute to an improved understanding of the dynamics of PD-L1 
expression and relationship with intervening anti-cancer therapy.
The status of immune-related and tumor typerelated and other exploratory biomarkers 
(including but not limited to T-cell markers and tumor mutation status) in archival and 
fresh tumor tissue samples of enrolled patients may be evaluated.
For archival samples, the remaining tumor tissue block for all patients enrolled will be 
returned to the site upon request or 18 months after final closure of the study database, 
whichever is sooner.  Tissue samples from patients who are not eligible to enroll in the 
study will be returned no later than 6 weeks after eligibility determination.
4.5.7.2
Tumor Biopsy at the Time of Disease Recurrence
Biopsy at the time of first radiographic confirmation of disease recurrence is mandatory 
for all randomized patients (in both Arms A and B).  Biopsy can only be waived for 
patients who have no lesions amenable for biopsy at disease recurrence, following 
discussion with and approval by the Medical Monitor. After the primary analysis, a 
confirmatory tumor biopsy is optional at the time of disease recurrence.
Acceptable samples include resections; core needle biopsies for deep tumor tissue or 
lymph nodes; or excisional, incisional, punch, or forceps biopsies for cutaneous, 
subcutaneous, or mucosal lesions.  For core needle biopsy specimens, at least three 
cores should be submitted for evaluation.
The status of immune-related and tumor typerelated, and other exploratory biomarkers 
(including but not limited to T-cell markers and tumor mutation status) in tumor tissue 
samples of enrolled patients may be evaluated.
Next-Generation Sequencing (NGS) may be performed by Foundation Medicine.  
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samples collected at the time of disease recurrence in the form of an NGS report, which 
is available upon request directly from Foundation Medicine.  The investigator may share 
and discuss the results with the patient, unless the patient chooses otherwise.  
The Foundation Medicine NGS assay has not been cleared or approved by health 
authorities.  The NGS report is generated for research purposes and is not provided for 
the purpose of guiding future treatment decisions.
4.5.7.3
Use and Storage of Remaining Samples from Study-Related 
Procedures
The remaining samples obtained for study-related procedures will be destroyed no later 
than 5 years after the end of the study or earlier depending on local regulations.  If the 
patient provides optional consent for storing samples into the RCR for future research 
(see Section 4.5.12), the samples will be destroyed no later than 15 years after the date 
of final closure of the clinical database.
4.5.8
Anti-Therapeutic Antibody Testing (Atezolizumab-Treated 
Patients Only)
Atezolizumab may elicit an immune response.  Patients with signs of any potential 
immune response to atezolizumab will be closely monitored.  Validated screening and 
confirmatory assays will be employed to detect ATAs at multiple timepoints before, 
during, and after treatment with atezolizumab (see Appendix 2 for the schedule).  
The immunogenicity evaluation will utilize a risk-based immunogenicity strategy 
(Rosenberg et al. 2004; Koren et al. 2008) to characterize ATA responses to 
atezolizumab in support of the clinical development program.  This tiered strategy will 
include an assessment of whether ATA responses correlate with relevant clinical 
endpoints.  Implementation of ATA characterization assays will depend on the safety 
profile and clinical immunogenicity data.
4.5.9
Electrocardiograms
A twelve-lead ECG is required at screening and when clinically indicated during study.  
ECGs for each patient should be obtained from the same machine wherever possible.  
ECG recordings must be performed after the patient has been resting in a supine 
position for at least 10 minutes.
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.
4.5.10
Patient-Reported Outcomes
The EQ-5D-5L is a generic preference-based HRQoL questionnaire that provides a 
single index value for health status (see Appendix 8) and is used to inform 
pharmacoeconomic evaluations and to measure general health status.  The EQ-5D-5L 
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health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  
From these five items, a utility measure is obtained for each patient.  The second part, 
consisting of a visual analog scale (VAS), allows the patient to indicate, on a scale of 
0100, how his or her health is on the day of assessment, with 100 being the “best 
imaginable health state” and 0 being the “worst imaginable health state.”  The VAS score 
will be used as a measure of overall health status. 
The EQ-5D-5L will be administered every 6 weeks during study treatment/observation. 
After discontinuation of the treatment/observation period, for patients who have not 
experienced disease recurrence, the EQ-5D-5L will be administered at the same 
schedule as the assessments for disease recurrence (see Section 4.5.5).  The 
EQ-5D-5L will also be recorded (in both study arms) at 6, 12, and 24 weeks after 
occurrence of a DFS event. After the primary analysis, the EQ-5D-5L assessments are 
no longer required for patients who are in disease recurrence follow-up or who have had 
a DFS event. 
During study treatment/observation, the EQ-5D-5L will be administered at the study sites.  
The PRO questionnaires, translated as required in the local language, will be distributed 
by the investigator’s staff and completed in their entirety by the patient.  To ensure 
instrument validity and that data standards meet health authority requirements, PRO 
questionnaires filled out at the study sites should be self-administered at the 
investigational site prior to the completion of other study assessments and the 
administration of study treatment.  Study personnel should review all questionnaires for 
completeness before the patient leaves the investigational site.  Hard copy originals of 
the questionnaires must be maintained as part of the patient’s medical record at the site 
for source data verification.  These originals should have the respondent’s initials on 
each page in compliance with good clinical practices.
Assessments of the EQ-5D-5L at 6, 12, and 24 weeks after a DFS event will be 
administered by telephone.  Interviews will be conducted by trained site staff and in 
compliance with best practices and recommendations by EuroQol.  Study personnel will 
record patient responses on a paper copy of the EQ-5D-5L during the telephone 
interview as record of source documentation. After the primary analysis, the 
EQ-5D-5L assessments are no longer required for patients who have had a DFS event. 
4.5.11
Age-Adjusted Charlson Comorbidity Index (ACCI)
ACCI (see Appendix 4) is a significant independent predictor for OS and for 
cancer-specific mortality following radical cystectomy in multivariate analysis that 
included other clinicopathologic features (Koppie et al. 2008; Mayr et al. 2012).  
A baseline ACCI should be determined for every patient.


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4.5.12
Optional Biopsies and Samples for Roche Clinical Repository 
(Optional Future Research)
4.5.12.1
Overview of the Roche Clinical Repository
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
recurrence

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
4.5.12.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (Section 4.5.12) will not be 
applicable at that site.
4.5.12.3
Sample Collection
The following samples will be collected for research purposes, including but not limited 
to research on dynamic (non-inherited) biomarkers:

Remaining blood derivatives (serum, plasma, PBMCs and their derivatives) after 
study-related tests have been performed

Remaining FFPE tissue (with the exception of archival FFPE blocks, which will be 
returned to sites) after study-related tests have been performed

Optional tissue samples collected for biopsy during the study (preferably at the time 
of disease recurrence)
The following samples will be collected for research purposes, including but not limited 
to research on genetic (inherited) biomarkers:

Whole blood sample for DNA isolation 


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This sample will be collected from patients who have consented to optional 
RCR sampling at baseline as shown in the schedule of assessments in 
Appendix 1.  If, however, the RCR genetic blood sample is not collected during 
the scheduled visit, it may be collected as soon as possible (after randomization) 
during the conduct of the clinical study.  Collection of whole blood will enable 
the evaluation of single nucleotide polymorphisms in genes associated with 
immune biology including but not restricted to the target and pathway 
associated genes such as PD-L1, PD-1, and B7.1 as well as IL-8, IL-6, and 
related cytokines.  The sample may be processed using techniques such as 
kinetic PCR and DNA sequencing.
For all samples, dates of consent should be recorded on the associated RCR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the laboratory manual.
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.  
4.5.12.4
Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 


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authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
4.5.12.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
4.5.12.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  After withdrawal of consent, any 
remaining samples will be destroyed or will no longer be linked to the patient.  If a patient 
wishes to withdraw consent to the testing of his or her specimens, the investigator must 
inform the Medical Monitor in writing of the patient's wishes through use of the RCR 
Subject Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on 
the RCR Research Sample Withdrawal of Informed Consent eCRF.  If a patient wishes 
to withdraw consent to the testing of his or her RCR samples after closure of the site, the 
investigator must inform the Sponsor by emailing the study number and patient number 
to the following email address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from Study WO29636 does not, by itself, constitute withdrawal of 
specimens from the RCR.  Likewise, a patient's withdrawal from the RCR does not 
constitute withdrawal from Study WO29636.


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4.5.12.7
Monitoring and Oversight
RCR specimens 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.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
4.5.13
Timing of Study Assessments
Flowcharts of scheduled study assessments are provided in Appendix 1 and Appendix 2.  
Patients will be closely monitored for safety and tolerability throughout the study.  All 
assessments must be performed and documented for each patient.  Patients should be 
assessed for toxicity prior to each dose; dosing will occur only if the clinical assessment 
and local laboratory test values are acceptable.  If the timing of a protocol-mandated 
study visit coincides with a holiday and/or weekend that precludes the visit, the visit 
should be scheduled on the nearest following feasible date.
4.5.13.1
Screening and Pre-Treatment Assessments
Prior to signing the main consent form for the study, patients may specifically allow for 
the collection and testing of archival or fresh tumor tissue by signing the pre-screening 
consent form.  Written informed consent for participation in the study (on the main study 
Informed Consent Form) must be obtained before performing any study-specific 
screening tests or evaluations.  Informed Consent Forms for enrolled patients and for 
patients who are not subsequently enrolled will be maintained at the study site. 
Screening tests and evaluations will be performed within 28 days prior to randomization, 
unless otherwise specified.  Results of standard-of-care tests or examinations performed 
prior to obtaining informed consent and within 28 days (or as otherwise specified) prior 
to randomization may be used; such tests do not need to be repeated for screening.  All 
screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization.  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.
See Appendix 1 for the schedule of screening and pre-treatment assessments.
4.5.13.2
Assessments during Treatment/Observation
All visits must occur within 3 days from the scheduled date unless otherwise noted 
(see Appendix 1).  All assessments will be performed on the day of the specified visit 
unless a time window is specified.  Assessments scheduled on the day of study 
treatment administration (Day 1) of each cycle should be performed prior to study 


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treatment infusion unless otherwise noted.  Local laboratory assessments from each 
cycle must be reviewed prior to study treatment administration for each cycle.
See the table provided in Appendix 1 for the schedule of treatment/observation period 
assessments. 
The following assessments may be performed 96 hours before Day 1 of each cycle:  
ECOG performance status, limited physical examination, local/central laboratory tests, 
adverse event evaluation, and concomitant medication evaluation.
For patients in Arm A, if scheduled dosing is precluded because of a holiday, then 
dosing may be postponed to the soonest following date, with subsequent dosing 
continuing on a 21-day schedule.  If treatment was postponed for fewer than 2 days, the 
patient can resume the original schedule.  For patients in both arms, if scheduled study 
assessments cannot be obtained because of a holiday, these assessments should then 
be obtained at the soonest following date, provided that the soonest following date is not 
within 2 days of other regularly scheduled study assessments.
Assessments for disease recurrence should continue to occur as specified in 
Section 4.5.5, regardless of treatment delays.
After five cycles have been completed, one cycle may be delayed by 1 week 
(i.e., 28 days instead of 21 days for one cycle) for one time to allow for vacations.
Blood samples for pharmacodynamic biomarker analysis and pharmacokinetics will be 
obtained for patients in Arm A according to the schedule in Appendix 2.
4.5.13.3
Assessments at Treatment/Observation Discontinuation Visit 
Atezolizumab-treated patients (in Arm A) who discontinue early from treatment or who 
complete the study treatment in full (16 cycles or 1 year, whichever occurs first) will be 
asked to return to the clinic not more than 30 days after the last treatment for a treatment 
discontinuation visit.  The visit at which the decision is made to discontinue treatment 
(e.g., disease recurrence is determined or confirmed) may be used as the treatment 
discontinuation visit.  
Patients randomized to observation (in Arm B) and who discontinue early from the 
observation period or who complete observation in full (16 cycles or 1 year, whichever 
occurs first) will also be asked to return to the clinic not more than 30 days after the last 
cycle visit for an observation discontinuation visit.  The visit at which the decision is 
made to discontinue patient from the observation period (e.g., disease recurrence is 
determined or confirmed) may be used as the observation discontinuation visit.  
See Appendix 1 and Appendix 2 for the schedule of assessments performed at the 
treatment/observation discontinuation visit.


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4.6
FOLLOW-UP ASSESSMENTS
4.6.1
Ongoing Imaging Assessments for Disease Recurrence
Patients assigned to atezolizumab (Arm A) who complete the treatment phase 
(16 cycles or 1 year, whichever occurs first) will discontinue treatment with atezolizumab.  
Patients without recurrence will continue to undergo imaging assessments for 
recurrence (disease recurrence follow-up phase) every 12 weeks for 2 years (i.e., during 
Years 2 and 3); every 24 weeks for another 2 years (i.e., during Years 4 and 5); and at 
Year 6, until DFS event, loss to follow-up, withdrawal of consent, or study termination by 
the Sponsor, whichever occurs first. After the primary analysis, patients in Years 23 
of the study may be assessed for tumor recurrence every 24 weeks. Investigators may 
perform additional scans or more frequent assessments if clinically indicated.  Patients 
who discontinue study drug for reasons other than disease recurrence (e.g., toxicity) 
should continue to undergo scheduled imaging assessments for recurrence until DFS 
event, loss to follow-up, consent withdrawal, or study termination by the Sponsor 
whichever occurs first.
Patients assigned to observation (Arm B) who complete the initial observation period 
(16 cycles or 1 year, whichever occurs first) will also continue to undergo imaging 
assessments as specified above for Arm A patients.  Investigators may perform 
additional scans or more frequent assessments if clinically indicated.
4.6.2
Adverse Events
All adverse events, regardless of attribution, will be recorded until 30 days after the 
last dose of study drug (for patients in Arm A) or 30 days after the last day of the 
observation period (for patients in Arm B), or the initiation of another anticancer therapy, 
whichever occurs first.  Serious adverse events (see Section 5.2.2) and protocol defined 
adverse events of special interest (see Section 5.2.3) will be recorded until 90 days after 
the last dose of study drug or until the initiation of another anti-cancer therapy, 
whichever occurs first (for patients in Arm A).
After the treatment/observation discontinuation visit, adverse events should be followed 
as outlined in Section 5.6.
4.6.3
Anti-Therapeutic Antibody and Pharmacokinetic Assessments
For patients assigned to atezolizumab only, a post-treatment ATA and PK sample 
should be collected 120 days (30 days) after the last dose of study drug unless the 
patient withdraws consent or the study closes.
See the schedules of assessments provided in Appendix 1 and Appendix 2 for specified 
follow-up assessments.


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4.6.4
Survival and Subsequent Anti-Cancer Therapy
Survival follow-up information will be collected via telephone calls, patient medical 
records, and/or clinic visits approximately every 3 months from the completion or 
discontinuation of the treatment/observation period until death, loss to follow-up, or 
study termination by the Sponsor.  All patients will be followed for survival and all new
anti-cancer therapy information unless the patient requests to be withdrawn from 
follow-up (this request must be documented in the source documents and signed by the 
investigator) or the study is terminated by the Sponsor.  If the patient withdraws from 
study, the study staff may use a public information source (e.g., county records) to 
obtain information about survival status only.
Patients who have completed the treatment or observation phase and continue in 
disease recurrence follow-up should have survival follow-up 
approximately 
every 3 months. All patients must still be followed for new anti-cancer therapy. 
Before considering a patient lost to follow-up, at least three different documented 
attempts to contact them should be made.  If local regulations permit, the attempts 
should include but not be limited to:

A written contact (e.g., letter by certified mail or email with read receipt)

Contact with the patient’s primary care physician (where the patient has consented 
to this type of contact)
4.7
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.7.1
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
Every effort should be made to obtain information on patients who withdraw from the 
study.  Patients who withdraw their consent to be followed for the primary study endpoint 
(DFS) will be asked to continue follow-up for OS.  The primary reason for withdrawal 
from the study should be documented on the appropriate eCRF.  However, patients will 
not be followed for any reason after consent has been withdrawn.  Patients who 
withdraw from the study will not be replaced.
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4.7.2
Discontinuation from Study Drug
Patients must discontinue study treatment if they experience any of the following:

Pregnancy 

Disease recurrence (local recurrence, urinary tract recurrence, or distant metastasis 
of UC), as determined by the investigator, documented by radiographic evidence.  
For patients with UTUC, disease recurrence determined by visual appearance of UC 
in bladder is acceptable with histopathologic confirmation.  For UTUC patients with 
bladder recurrence of PUNLMP or low-grade pTa, continuation of study treatment is 
allowed after local resection.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not 
be replaced.
4.7.3
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 and all obligations have been 
fulfilled)
5.
ASSESSMENT OF SAFETY
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, and triple-negative breast cancer. Safety studies are
currently ongoing and the entire safety profile is not known at this time.  The following 
information is based on results from nonclinical and clinical studies and published data 
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5.1
SAFETY PLAN
Measures will be taken to ensure the safety of patients participating in this trial, including 
the use of stringent inclusion and exclusion criteria (see Sections 4.1.1 and 4.1.2) and 
close monitoring (as indicated below and in Section 4.5).  An iDMC has also been 
incorporated into the trial design to periodically review aggregate safety data (see the 
iDMC Charter for a detailed monitoring plan).
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.  
All adverse events and serious adverse events will be recorded during the trial.  Serious 
adverse events and adverse events of special interest will be recorded until 90 days 
after the last dose of study drug or until the initiation of another anti-cancer therapy 
(whichever occurs first) and all other adverse events will be recorded until 30 days after 
the last dose of study drug or until the initiation of another anti-cancer therapy, 
whichever occurs first.  After this period, investigators should report any serious adverse 
events that are believed to be related to prior treatment with study drug.  The potential 
safety issues anticipated in this trial, as well as measures intended to avoid or minimize 
such toxicities, are outlined in the following sections and management of atezolizumab-
specific adverse events are outlined in Appendix 9.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, and myositis.  Immune-mediated reactions may involve any organ 
system and may lead to hemophagocytic lymphohistiocytosis and macrophage 
activation syndrome (considered to be potential risks for atezolizumab).  Refer to 
Appendix 9 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure for 
a detailed description of anticipated safety risks for atezolizumab (see Appendix 6 for 
precautions for anaphylaxis).
5.1.2
General Plan to Manage Safety Concerns
5.1.2.1
Eligibility Criteria
Eligibility criteria were selected to guard the safety of patients in this trial.  Results from 
the nonclinical toxicology studies with atezolizumab, as well as the nonclinical/clinical 
data from other PD-L1/PD-1 inhibitors, were taken into account.  Specifically, patients at 
risk for study-emergent autoimmune conditions or with a prior diagnosis of autoimmune 
disease, patients with evidence of acute infections, and patients who have received a 
live, attenuated viral vaccine within 4 weeks of randomization are excluded from the 
study (see Section 4.1.2 for additional details).


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5.1.2.2
Monitoring
Safety will be evaluated in this study through the monitoring of all serious and 
non-serious adverse events defined and graded according to NCI CTCAE v4.0.  Patients 
will be assessed for safety (including laboratory values) according to the schedule in 
Appendix 1.  Laboratory values must be reviewed prior to each infusion.
General safety assessments will include serial interval histories, physical examinations, 
and specific laboratory studies, including serum chemistries and blood counts 
(see Appendix 1 and Appendix 2 for the list and timing of study assessments).
During the study, patients will be closely monitored for the development of any adverse 
events, including signs or symptoms of autoimmune conditions and infection.
All serious adverse events (see Section 5.2.2) and protocol-defined events of special 
interest (see Section 5.2.3) will be reported in an expedited fashion (see Section 5.4.2).  
In addition, the iDMC will review safety data as described in Section 3.1.1.
Patients who experience a serious adverse event or protocol defined events of special 
interest will be followed for safety for 90 days following their last dose of study drug or 
until they receive another anti-cancer therapy, whichever comes first.  Patients who 
experience all other adverse events will be followed for safety for 30 days following their 
last dose of study drug or until they receive another anti-cancer therapy, whichever 
comes first.
For patients in Arm A who have an ongoing study drugrelated adverse event upon 
treatment completion or at discontinuation from study treatment will be followed until the 
event has resolved to baseline grade, the event is assessed by the investigator as stable, 
new anti-cancer treatment is initiated, the patient is lost to follow-up, the patient 
withdraws consent, or it has been determined that study treatment or participation is not 
the cause of the adverse event.
5.1.3
Atezolizumab Dose Modification
There will be no dose reduction for atezolizumab in this study.  Patients may temporarily 
suspend study treatment for up to 42 days beyond the last dose if they experience 
adverse events that require a dose to be held.  If atezolizumab is held because of 
adverse events for 42 days beyond the last dose, then the patient will be discontinued 
from atezolizumab and will be followed for safety and efficacy.
If, in the judgment of the investigator, the patient is likely to derive clinical benefit from 
atezolizumab after a hold of 42 days, study drug may be restarted with the approval of 
the Medical Monitor. 
If a patient must be tapered off steroids used to treat adverse events, atezolizumab may 
be held for additional time beyond 42 days from the last dose until steroids are 


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discontinued or reduced to prednisone dose (or dose equivalent) 10 mg/day.  The 
acceptable length of interruption will depend on an agreement between the investigator 
and the Medical Monitor.
Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be 
allowed with Medical Monitor approval. The acceptable length of interruption will depend 
on agreement between the investigator and the Medical Monitor.
5.1.4
Management of Atezolizumab-Specific Adverse Events
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, may be used to determine 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 primary approach to Grade 12 immune-mediated adverse events is supportive and 
symptomatic care with continued treatment with atezolizumab; for higher grade 
immune-mediated adverse events, atezolizumab should be held and oral/parenteral 
steroids administered.  Recurrent Grade 2 immune-mediated adverse events may also 
mandate withholding atezolizumab or the use of steroids.  Consideration for benefitrisk 
balance should be made by the investigator, with consideration of the totality of 
information as it pertains to the nature of the toxicity and the degree of clinical benefit a 
given patient may be experiencing prior to further administration of atezolizumab.  
Atezolizumab should be permanently discontinued in patients with life-threatening 
immune-mediated adverse events.
See Appendix 9 for details on management of gastrointestinal, dermatologic, endocrine, 
pulmonary toxicity, hepatotoxicity, pancreatic, eye, neurologic, or renal toxicity, and other 
immune-mediated adverse events.  See Section 5.3.5.2 for guidelines for the recording
and reporting of infusion-related reactions (see Appendix 6 for precautions for 
anaphylaxis).
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.


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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 patient administered a 
pharmaceutical product, regardless of causal attribution.  For patients in the observation 
arm, an adverse event is any untoward medical occurrence.  An adverse event can 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 it is considered related to the medicinal product or not

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)

Late complications related to surgery (e.g., urinary infection, intestinal obstruction, 
wound dehiscence, anastomotic leak or stricture)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug


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
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) criteria; 
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 (Arm A Only; Immediately 
Reportable to the Sponsor)
For patients in the atezolizumab treatment arm (Arm A), adverse events of special 
interest are required to be reported by the investigator to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions).  Adverse events of special interest for this study include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.5.7)

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.

Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hypothyroidism and hypophysitis

Hepatitis, including AST or ALT 10 ULN

Systemic lupus erythematosus

Neurological disorders:  Guillain-Barre syndrome, myasthenic syndrome or 
myasthenia gravis, meningoencephalitis

Nephritis


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
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, influenza-like illness, and systemic inflammatory response syndrome

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)

Myositis

Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis

Autoimmune hemolytic anemia

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis)
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity
(see Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug for 
patients in Arm A or prior to the Cycle 1, Day 1 visit for patients in Arm B, 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).
For patients in Arm A, after initiation of study drug, all serious adverse events and 
adverse events of special interest, regardless of relationship to study drug, will be
reported until 90 days after the last dose of study drug or until the initiation of another 
anti-cancer therapy, whichever occurs first.  All other adverse events, regardless of 
relationship to study drug, will be reported until 30 days after the last dose of study drug 
or until the initiation of another anti-cancer therapy, whichever occurs first.
For patients in Arm B, all adverse events occurring from the date of the Cycle 1, Day 1 
visit until 30 days after the last day of the observation period or until the start of an 
anti-cancer therapy (whichever occurs first) will be reported. 


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Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE v4.0 will be used for 
assessing adverse event severity.  Table 8 will be used for assessing the severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 8
Adverse Event Severity Grading Scale
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:  On the basis of the NCI CTCAE (Version 4.0), which can be found at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5 11.pdf
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 one's self, 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 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 


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adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

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
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF.
5.3.5.1
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.
5.3.5.2
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured as a 
diagnosis (e.g., "infusion-related reaction") on the Adverse Event eCRF.  If possible, 
avoid ambiguous terms such as "systemic reaction."  Associated signs and symptoms 
should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient 
experiences both a local and systemic reaction to the same dose of study treatment, 
each reaction should be recorded separately on the Adverse Event eCRF, with 
signs and symptoms also recorded separately on the dedicated Infusion-Related 
Reaction eCRF.


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5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
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Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as 
adverse events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if 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.


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Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3 ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is a secondary efficacy endpoint.  All deaths must be 
recorded on the Study Completion/Discontinuation eCRF. 
Deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1) that are attributed by the investigator solely to recurrence of UC 
are not considered an adverse event and should not be recorded on the Adverse Event 
eCRF.  Rather, these deaths should be recorded on the Study 
Completion/Discontinuation eCRF.
All other 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 independent DSMB will monitor the frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").


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Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Recurrence of Urothelial Carcinoma (UC)
Events that are clearly consistent with the expected pattern of disease recurrence should 
not be recorded as adverse events.  These data will be captured as efficacy assessment 
data only.  However in situations in which there is no confirmation of disease recurrence, 
the underlying symptoms should be captured as adverse events and assessed 
accordingly for seriousness, severity, and causality until a diagnosis or cause for such 
events is established or until confirmation of UC recurrence.  If the symptoms are later 
confirmed to be due to recurrence of disease, then symptoms reported as adverse 
events should be retracted.   
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 measurement for the study)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to recurrence/progression of the underlying cancer


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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 for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available
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 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
5.3.5.13
Patient-Reported Outcome Data
The methods for collecting and analyzing PRO data are different from those for the 
ascertainment of observed or volunteered adverse events.  Because of these differences, 
PRO data will not be reported as adverse events and no attempt will be made to resolve 
any noticeable discrepancies between PRO data and observed or volunteered adverse 
events.  PRO data will be presented in separate tables, figures, and data listings from 
the adverse event data, and will be included in the appropriate section of the final 
study report.
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 (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




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learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting post-study adverse events are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Roche Safety Risk Management.  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 the event that the EDC system is unavailable, the Clinical Trial Pregnancy 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 pregnancy), 
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.
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 


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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 patient exposed to study drug 
should be classified as a serious adverse event, recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
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.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (see Section 5.3.1), all deaths, 
regardless of cause, should be reported through use of the 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 or study procedure, the event should be 
reported through use of the Adverse Event eCRF.  However, if the EDC system is not 
available, the investigator should report these events directly to the Sponsor or its 


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designee, either by faxing or by scanning and emailing the paper Clinical Trial Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form using the fax number 
or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Atezolizumab Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An iDMC will monitor the incidence of these expected 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
6.1
DETERMINATION OF SAMPLE SIZE
Approximately 800 patients will be randomized in this study.
6.1.1
Type I Error Control
The type I error (alpha) for this study is 0.05 (two-sided).  Type I error will be controlled 
for the primary endpoint of DFS and the key secondary endpoint of OS.  To control the 
Type I error at alpha0.05 (two-sided) for DFS and OS endpoints, the treatment arms 
will be compared in a hierarchical fashion as follows:  If the DFS analysis results (as 
defined for United States registrational purposes; see Section 6.4.1) are statistically 
significant at alpha0.05 (two-sided), then the analysis of OS will be performed at 
alpha0.05 (two-sided) and the interim analysis boundaries for OS (see Section 6.9.2) 
will be calculated according to alpha0.05 (two-sided).


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6.1.2
Primary Endpoint:  Disease-Free Survival
The analysis of the primary endpoint of DFS will take place when approximately 
377 DFS events have occurred and at least 12 months after the last patient is enrolled
have elapsed.  The estimated number of events required for the analysis is based on the 
following assumptions:

Two-sided log-rank test at the 0.05 significance level (two-sided)

80% power

1:1 randomization ratio

Median DFS for the control (observation) arm of 20 months and estimated median 
DFS in the atezolizumab arm of 26.7 months (corresponding to a HR of 0.75)

No interim analysis of DFS
Accrual of the planned 800 patients is projected to occur over 32 months, assuming a 
ramp-up period of 13 months to a projected accrual rate of 35 patients per month.  
On the basis of these assumptions, and the projected probability of loss to follow-up for 
DFS of approximately 32% over 24 months after enrollment, the required number of DFS 
events is projected to occur at Month 50 from the time the first patient is randomized.  
Also on the basis of these assumptions, it is projected that an observed HR of 0.82 or 
lower will result in a statistically significant difference between treatment arms (i.e., an 
HR of 0.82 will be the minimally detectable difference at the analysis; this corresponds to 
an improvement of 4.5 months in median DFS, from 20 months in the control 
[observation] arm to 24. 5 months in the atezolizumab arm).
6.1.3
Secondary Endpoint:  Overall Survival
The final analysis of the secondary endpoint of OS will take place when approximately 
428 deaths have occurred on the basis of the following assumptions:

Two-sided log-rank test at the 0.05 significance level (two-sided)

80% power

1:1 randomization ratio

Median OS for the control (observation) arm of 34 months and estimated median 
OS in the atezolizumab arm of 44.7 months (corresponding to HR of 0.76)

Two interim analyses of OS
On the basis of these assumptions, the projected probability of loss to follow-up for OS 
of approximately 24% over 24 months after enrollment, and projected accrual, the 
required number of OS events for the final analysis of OS is projected to occur 
95 months from the time the first patient is randomized.  It is projected that an observed 
HR of 0.82 or lower will result in a statistically significant difference between treatment 
arms (i.e., an HR of 0.82 will be the minimally detectable difference at the analysis; this 
corresponds to an improvement of 7.4 months in median OS, from 34 months in the 
control [observation] arm to 41.4 months in the atezolizumab arm). 


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Two interim analyses of OS are planned; see Section 6.9 for details.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, major protocol deviations including major deviations of inclusion/exclusion 
criteria, and reasons for discontinuation from the study will be summarized by treatment 
arm for the ITT population.  Study treatment administration and reasons for 
discontinuation from the study treatment will be summarized by treatment arm for all 
treated patients.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic variables such as age, sex, race/ethnicity, stratification factors 
(nodal status, number of lymph nodes resected, tumor stage, PD-L1 status, and prior 
neoadjuvant chemotherapy), baseline and disease characteristics (e.g., ACCI, time 
since initial diagnosis, time since surgery, surgery-related information, type of urinary 
diversion, and ECOG Performance Status) will be summarized by treatment arm for all 
randomized patients.  Continuous variables will be summarized using means, standard 
deviations, medians, and ranges.  Categorical variables will be summarized by 
proportions. 
The baseline value of any variable will be defined as the last available value prior to the 
first administration of study treatment. 
6.4
EFFICACY ANALYSES
The efficacy analyses will include all randomized patients based on the ITT principle, 
with patients grouped according to the treatment assigned at randomization.  
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is investigator-assessed DFS, defined as the time from 
randomization to the time of first occurrence of a DFS event, defined as any of the 
following: local (pelvic) recurrence of UC; urinary tract recurrence of UC; distant 
metastasis of UC; or death from any cause.  Data for patients without a DFS event will 
be censored at the last date the patient was assessed to be alive and recurrence free as 
determined with radiographic evidence.  Data for patients with no post-baseline disease 
assessment will be censored at the randomization date.
For United States registrational purposes, the primary efficacy endpoint of DFS will be 
defined as described above with an additional censoring rule for missed visits.  Data for 
patients with a DFS event who missed two or more scheduled assessments immediately 
prior to the DFS event will be censored at the last tumor assessment as determined with 
radiographic evidence prior to the missed visits.  Type I error control (see Section 6.1.1) 
will be applied to this analysis of DFS.  


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DFS will be analyzed in the ITT population.  The following analyses will be performed for 
both DFS endpoints described above.  DFS will be compared between treatment arms 
using the stratified log-rank test.  The hazard ratio (HR) for recurrence or death will be 
estimated using a stratified Cox proportional hazards model and the 95% CI for the HR 
will be provided.  The stratification factors will be the same as the randomization 
stratification factors (see Section 4.2); however, stratification factors may be combined 
for analysis purposes if necessary to minimize small stratum cell sizes. Combination of 
stratification factors, if any, would be specified in the Statistical Analysis Plan (SAP) prior 
to analysis. The stratification factors will be obtained from the IxRS at the time of 
randomization.  Results from an unstratified analysis will also be provided.  Kaplan-Meier 
methodology will be used to estimate median DFS for each treatment arm; Kaplan-Meier 
curves will be produced.  Brookmeyer-Crowley methodology will be used to construct the 
95% CI for the median DFS for each treatment arm.  The DFS rate at various timepoints 
(i.e., every 6 months after randomization) will be estimated by Kaplan-Meier 
methodology for each treatment arm, and the 95% CI will be calculated using 
Greenwood’s formula.
The following additional analyses will be performed for both DFS endpoints 
described above: 

Analyses at landmark timepoints, described in Section 6.8.1

Subgroup analyses, described in Section 6.8.2
6.4.2
Secondary Efficacy Endpoints
6.4.2.1
Overall Survival
OS is defined as the time from randomization to the date of death from any cause, 
regardless of whether the death occurs during study treatment or following treatment 
discontinuation.  Data for patients who have not died will be censored at the last date 
they were known to be alive.  Methods for comparison of OS between treatment arms 
will be the same as the methods for treatment comparison for the primary efficacy 
endpoint of DFS.
Three analyses of OS are planned (two interim analyses and one final analysis; see 
Section 6.9 for details).  The first interim analysis of OS will occur at the time that the 
primary endpoint of DFS is analyzed.  The type I error control for the secondary endpoint 
of OS is described in Section 6.1.1.
6.4.2.2
Disease-Specific Survival
DSS is defined as the time from randomization until the date of death from UC.  Data for 
patients who have not died will be censored at the last date they were known to be alive.  
Data for patients who died from causes other than UC will be censored at the date of 
death.  Methods for comparison of DSS between treatment arms will be the same as the 
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For the purposes of evaluating DSS, for each patient death, the cause of death will be 
assessed as related or not related to UC by the investigator.
6.4.2.3
Distant Metastasis-Free Survival
DMFS is defined as the time from randomization to the date of a DMFS event, defined 
as diagnosis of distant (i.e., non-locoregional) metastasis or death from any cause.  
Data for patients without a DMFS event will be censored at the last date the patient was 
assessed to be alive and free of distant metastasis.  Data for patients with no 
post-baseline disease assessment will be censored at the randomization date.  Methods 
for comparison of DMFS between treatment arms will be the same as the methods for 
treatment comparison for the primary efficacy endpoint of DFS.
6.4.2.4
Non-urinary Tract Recurrence-Free Survival
NURFS is defined as the time from randomization to the date of a NURFS event, defined 
as diagnosis of non-urinary tract recurrence (i.e., pelvic soft tissue or regional lymph 
node recurrence, or distant metastasis) or death from any cause.  Data for patients 
without a NURFS event will be censored at the last date the patient was assessed to be 
alive and free of non-urinary tract recurrence.  Data for patients with no post-baseline 
disease assessment will be censored at the randomization date.  Methods for 
comparison of NURFS between treatment arms will be the same as the methods for 
treatment comparison for the primary efficacy endpoint of DFS.
6.4.3
Handling of Missing Data
For DFS, data for patients without a DFS event will be censored at the last date the 
patient was assessed to be alive and recurrence free.  Data for patients with no 
post-baseline disease assessment will be censored at the randomization date.  In the 
analysis of DFS for United States registrational purposes, data for patients with a DFS 
event who missed two or more scheduled assessments immediately prior to the DFS 
event will be censored at the last tumor assessment with radiographic evidence prior to 
the missed visits (see Section 6.4.1).
For OS, data for patients not reported as having died will be censored on the date last 
known to be alive.
For DSS, data for patients without a DSS event will be censored at the last date the 
patients were assessed to be alive and free of UC.
For DMFS, data for patients without a DMFS event will be censored at the last date the 
patients were assessed to be alive and free of distant metastasis.
For NURFS, data for patients without a NURFS event will be censored at the last date 
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6.5
SAFETY ANALYSES 
Safety analyses will include all patients who received at least one dose of study 
treatment (atezolizumab) and all patients randomized to the observation arm with at 
least one safety assessment.  Exposure to atezolizumab treatment and length of safety 
follow-up will be summarized by arm.
Verbatim descriptions of adverse events will be mapped to MedDRA terms.  
Treatment-emergent events (defined as events occurring on or after the first dose 
of atezolizumab, or, for patients in the observation arm, after the date of randomization) 
will be summarized by MedDRA term, appropriate MedDRA levels, and NCI CTCAE v4.0 
grade.  For each patient, the maximum severity reported will be used in the summaries.  
Adverse events will be summarized regardless of relationship to study drug as assessed 
by the investigator.  All adverse events, adverse events leading to withdrawal of study 
drug, adverse events leading to dose reduction or interruption, Grade 3 adverse events, 
serious adverse events, and adverse events of special interest will be summarized.  
Deaths and cause of death will be summarized.  
Changes in NCI CTCAE grade for selected laboratory tests will be tabulated by arm.  
Changes in selected vital signs will be summarized.  ATA results will be summarized and 
listed by patient for patients in Arm A only.
6.6
PHARMACOKINETIC ANALYSES  
Atezolizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized for each cycle at which pharmacokinetics are to be measured (Cmax will be 
reported for Cycle 1 only; Cmin will be evaluated at Cycles 1, 2, 3, and 4; every 8 cycles 
starting on Cycle 8; and both at treatment discontinuation and at 120 days [30 days] 
after the last dose of atezolizumab).  Descriptive statistics will include means, medians, 
ranges, and SDs, as appropriate.
Additional PK and pharmacodynamic analyses will be conducted as appropriate.
6.7
PATIENT-REPORTED OUTCOME ANALYSES 
Results from the EQ-5D-5L (VAS) will be summarized descriptively for each timepoint as 
mean and median values, as well as mean and median change from baseline.  
The first five questions of the EQ-5D-5L will be used to build utilities for health economic 
modeling and will be summarized in a separate report.  
6.8
EXPLORATORY ANALYSES
6.8.1
Analyses at Landmark Timepoints
The rates of DFS, OS, DSS, and DMFS at various timepoints (i.e., every 6 months after 
randomization) will be estimated by the Kaplan-Meier methodology for each arm and the 
95% CI will be calculated using Greenwood’s formula.  The 95% CIs for the difference in 


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OS rates between the two arms will be estimated using the normal approximation 
method.  The difference in Kaplan-Meier rates between the two arms will be tested at 
annual landmark timepoints using z-statistics and the normal approximation. 
6.8.2
Subgroup Analyses
To assess the consistency of study results in subgroups defined by demographic and 
baseline characteristics, efficacy outcomes of DFS, OS, DSS and DMFS in these 
subgroups will be examined.  Summaries of these endpoints, including unstratified HRs 
estimated from Cox proportional hazards models and Kaplan-Meier estimates of the 
median will be produced separately for each level of the categorical variables.
The subgroups to be considered include, but are not limited to, the following:

Age at randomization (65 years, 65 years)

Race (non-White, White)

Sex (female, male)

Region (North America, Europe, Asia, Australia)

PD-L1 status (IC0/1, IC2/3)

Number of lymph nodes resected (10, 10)

Nodal status (positive, negative)

Tumor stage after resection (pT2, pT3/pT4)

Prior neoadjuvant chemotherapy (yes, no)

ACCI (01, 23, 4)

ECOG performance status at randomization (0, 12)

Primary disease (MIBC, UTUC)

Type of urinary diversion (ileal conduit, orthotopic, other)
6.8.3
Biomarker Analyses
Exploratory biomarker analyses will be performed in an effort to understand the 
association of these markers with study drug response, including efficacy and/or adverse 
events.  Biomarker analyses may be reported in a separate report.
6.9
INTERIM ANALYSES 
6.9.1
Disease-Free Survival
No interim efficacy analyses of DFS are planned for this study.
6.9.2
Overall Survival
A total of three analyses of OS will be performed by the Sponsor (two interim analyses 
and one final analysis).  The final analysis of OS will be performed when approximately 
428 deaths (54% of 800 patients) have occurred in the ITT population (see also 
Section 6.1.3).  On the basis of accrual projections and projected median OS for each 


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treatment arm (see Section 6.1.3), the final analysis of OS is projected to occur 
95 months from the time the first patient is randomized.  The interim analysis boundaries 
for statistical significance at each interim analysis will be determined on the basis of the 
Lan-DeMets implementation of the O’Brien-Fleming use function.
The first interim analysis of OS will be performed at the time of the DFS analysis.  On the 
basis of the projected median OS for each treatment arm and the projected time of the 
final analysis of DFS, it is projected that approximately 280 deaths (35% of 800 patients) 
will have occurred at the first interim analysis of OS, which corresponds to approximately 
65% of the 428 deaths required for the final analysis of OS.  It is projected that an 
observed HR of 0.74 or lower will result in a statistically significant difference between 
treatment arms at this analysis.  
The second interim analysis of OS will be performed when approximately 342 deaths 
(43% of 800 patients) have occurred, which corresponds to 80% of the 428 deaths 
required for the final analysis of OS.  The required number of OS events for the second 
interim analysis of OS is projected to occur 63 months from the time the first patient is 
randomized.  It is projected that an observed HR of 0.78 or lower will result in a 
statistically significant difference between treatment arms at this analysis.  
The interim analyses of OS will be performed by the Sponsor.  The boundary for 
statistical significance at each interim analysis and the final analysis will be determined 
based on the Lan-DeMets implementation of the O’Brien-Fleming use function 
Lan and DeMets 1983).  For example, with 0.05 (two-sided) and using the two-sided 
log-rank test, if 280 deaths have occurred at the time of the first OS interim analysis, 
statistical significance will be declared p 0. 011; if 342 deaths have occurred at the 
time of the second OS interim analysis, statistical significance will be declared if 
p 0.021; and if 428 deaths have occurred at the time of the final OS analysis, statistical 
significance will be declared if p 0.042.
An iDMC will be convened to evaluate safety results approximately every 6 months after 
enrollment of the first patient until the analysis of the primary endpoint (DFS) 
(see Section 3.1.1).  
6.9.3
Optional Interim Analysis
In addition to the planned interim analyses of OS, one additional interim analysis of OS 
may be performed at the discretion of the Sponsor.  The decision to conduct the optional 
interim analysis, along with the rationale, timing, and statistical details for the analysis 
will be documented in the SAP, and the SAP will be submitted to relevant health 
authorities prior to the conduct of the interim analyses.


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7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, with use of 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.  Data from paper PRO 
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 Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, 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, 


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


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


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


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Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
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
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 


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permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  
Approximately 200 sites globally will participate in the study and approximately 
800 patients will be randomized.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Trials Data at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
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.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
REFERENCES
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Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 1
Schedule of Assessments
Both Arms
Arm A (Atezolizumab)
Arm B (Observation)
Both Arms
Study Procedures
Screening for 
Randomization
All Cycles
Discon-
tinuation a
Cycles 1, 3, 5, 7, 
9, 11, 13, and 15
Cycles 2, 4, 6, 8, 
10, 12, 14, and 16
Discon-
tinuation a
Follow-Up
Days –28
to –1
Day 1
(3 Days for 
Cycles 2) b
30 Days after 
Last Dose
Day 1 
(3 Days for 
Cycles 2) b
Day 1 
(3 Days) b
30 Days 
after Last 
Visit
Signed Informed Consent Form(s) c
x
Review of eligibility criteria
x
Medical, surgical, and cancer histories, 
including demographic information d
x
Pregnancy test e
x
x
x
ECOG performance status
x
x f
x
x f
x
Age-adjusted Charlson comorbidity 
index (ACCI)
x
Complete physical examination g
x
x
x
Limited physical examination g
x f
x f
Weight
x
x
x
x
x
Height
x
Vital signs h
x
x
x
x
x
12-lead electrocardiogram i
x
x
x
HIV, HCV serology j
x
Hematology k
x
x f
x
x f
x
Serum chemistry l
x
x f
x
x f
x
Coagulation panel (aPTT, INR)
x
x
x


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
118/Protocol WO29636, Version 10
Both Arms
Arm A (Atezolizumab)
Arm B (Observation)
Both Arms
Study Procedures
Screening for 
Randomization
All Cycles
Discon-
tinuation a
Cycles 1, 3, 5, 7, 
9, 11, 13, and 15
Cycles 2, 4, 6, 8, 
10, 12, 14, and 16
Discon-
tinuation a
Follow-Up
Days –28
to –1
Day 1
(3 Days for 
Cycles 2) b
30 Days after 
Last Dose
Day 1 
(3 Days for 
Cycles 2) b
Day 1 
(3 Days) b
30 Days 
after Last 
Visit
Urinalysis m
x
x n,f
x
x n
x
TSH, free T3, free T4
x
x o,f
x
Auto-antibody testing p
x
x
Serum sample for ATA assessment 
See Appendix 2
Serum sample for PK sampling 
See Appendix 2
Blood samples for biomarkers 
See Appendix 2
Optional whole blood sample for RCR q
x q
x q
Study drug infusion r
x
Archival/screening FFPE tumor tissue 
specimen or 15 unstained slides s
x
Fresh biopsy (mandatory sample t and 
optional RCR sample u)
At the time of radiographic confirmation of disease recurrence t,u
Assessments for UC recurrence v
x
Every 12 weeks following randomization (7 days; at approximately every four cycles) in 
first 3 years; every 24 weeks (10 days) for Years 4 and 5; and at Year 6 (10 days), until 
death, disease recurrence, loss to follow-up, end of Year 6, or withdrawal of consent. After 
the primary analysis, patients in the first 3 years of the study may be assessed for tumor 
recurrence every 24 weeks.
Concomitant medications w
x
x
x
x
x
x


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
119/Protocol WO29636, Version 10
Both Arms
Arm A (Atezolizumab)
Arm B (Observation)
Both Arms
Study Procedures
Screening for 
Randomization
All Cycles
Discon-
tinuation a
Cycles 1, 3, 5, 7, 
9, 11, 13, and 15
Cycles 2, 4, 6, 8, 
10, 12, 14, and 16
Discon-
tinuation a
Follow-Up
Days –28
to –1
Day 1
(3 Days for 
Cycles 2) b
30 Days after 
Last Dose
Day 1 
(3 Days for 
Cycles 2) b
Day 1 
(3 Days) b
30 Days 
after Last 
Visit
Adverse events x
x
x
x
x
x
x
Telephone contact y
x
Survival and anticancer therapy 
follow-up z
x
Patient-reported outcomes aa
x bb
x
x
x
x
Note:  For Arm A, assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise noted.
a Patients will be asked to return to the clinic for a discontinuation visit not more than 30 days after the decision to discontinue treatment/observation 
early, or after the end of the one-year treatment/observation period.
b After five cycles have been completed, one cycle may be delayed by 1 week (i.e., 28 days instead of 21 days for one cycle) for one time to allow for 
vacations.
c Written informed consent is required for performing any study-specific tests or procedures.  Written informed consent (on the main study Informed 
Consent Form) can be obtained outside the 28 days screening period prior to randomization.  Prior to signing the main consent form for the study, 
patients may specifically allow for the collection and testing of archival or fresh tumor tissue by signing the pre-screening consent form.  Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to randomization (except where 
otherwise specified) may be used for screening assessments rather than repeating such tests.
d Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment.  Demographic information includes sex, age, and self-reported 
race/ethnicity.
e 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 Cycle 1 Day 1.  Starting from Cycle 3, either serum or urine pregnancy test (positive urine test results will be 
confirmed with a serum pregnancy test) must be performed every two cycles during the study treatment, and as clinically indicated thereafter.
f ECOG performance status, limited physical examination and local/central lab assessments may be obtained 96 hours before Day 1 of each cycle.


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
120/Protocol WO29636, Version 10
g Complete and limited physical examinations are defined in Section 4.5.3. 
h Vital signs include heart rate, respiratory rate, blood pressures, and temperature and will be performed as standard of care if clinically indicated for 
patients randomized to the observation arm.  For patients randomized to the atezolizumab treatment arm, for the first infusions of study drug, the 
patient’s vital signs should be determined up to 60 minutes before the start of infusion, and if clinically indicated, during and 30 (10) minutes after 
the infusion.  For subsequent infusions, vital signs will be recorded if clinically indicated or if symptoms occurred in the prior infusion.  
i ECG recordings will be obtained during screening and when clinically indicated during study.  ECGs for each patient should be obtained from the 
same machine wherever possible.  ECG recordings must be performed after the patient has been resting in a supine position for at least 
10 minutes.  
j See Section 4.5.6 for serology tests.  HIV testing to be performed in accordance with national and/or institutional guidelines.  HBV DNA must be 
collected on or before Cycle 1, Day 1 in patients who have negative serology for hepatitis B surface antigen and positive serology for anti HBc.  
k Blood samples collected to monitor safety will be collected in patients randomized to both arms.  Hematology consists of CBC, including RBC count, 
hemoglobin, hematocrit, WBC count with automated differential (neutrophils, lymphocytes, eosinophils, monocytes, basophils, and other cells), and 
platelet count.  A manual differential can be done if clinically indicated. Refer to Section 4.1.1 for a list of laboratory results to be obtained within 
14 days prior to the first dose of study treatment.
l Serum chemistry includes BUN, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, total bilirubin, 
ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.  Refer to Section 4.1.1 for a list of laboratory results to be obtained within 14 days 
prior to the first dose of study treatment. 
m Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood).  
n On Day 1 of Cycle 3 and every two cycles thereafter.
o On Day 1 of Cycle 5 and every four cycles thereafter.
p Baseline sample to be collected on Cycle 1, Day 1 prior to the first dose of study treatment.  For patients who show evidence of immune mediated 
toxicity, additional samples will be collected, and all samples will be analyzed centrally.  Includes anti-nuclear antibody, anti-double stranded DNA, 
circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti neutrophil cytoplasmic antibody.  
q Whole blood for DNA isolation will be collected from patients who have consented to optional RCR sampling at baseline (pre-dose C1D1).  If, 
however, the RCR genetic blood sample is not collected during the scheduled visit, it may be collected as soon as possible (after randomization) 
during the conduct of the clinical study.


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
121/Protocol WO29636, Version 10
r Patients in Arm A will receive their first dose of study drug the day of randomization if possible.  If this is not possible, the first dose should occur no 
later than 7 days after randomization.  The initial dose of atezolizumab treatment will be delivered over 60 (15) minutes.  If the first infusion is well 
tolerated, all subsequent infusions may be delivered over 30 (10) minutes.  Atezolizumab treatment may be continued for a maximum of 16 cycles 
(or 12 months, whichever occurs first) until disease recurrence, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor.
s Tumor tissue from radical surgical resection should be of good quality based on total and viable tumor content (sites will be informed if the quality of 
the submitted specimen is inadequate to determine tumor PD-L1 status). Prior to signing the main consent form for the study, patients may 
specifically allow for the collection and testing of archival or fresh tumor tissue by signing the prescreening Informed Consent Form.  After signing of 
the Informed Consent Form, retrieval and submission of archival tumor sample can occur outside the 28-day screening period.
t All patients will undergo a mandatory tumor biopsy sample collection at the time of radiographic confirmation of disease recurrence (see
Section 4.5.5).  Acceptable samples include resections; core needle biopsies for deep tumor tissue or lymph nodes; or excisional, incisional, punch, 
or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.  For core needle biopsy specimens, at least three cores should be submitted 
for evaluation. After the primary analysis, a confirmatory tumor biopsy is optional at the time of disease recurrence.
u For patients who have consented to collection of optional biopsies on the Optional Collection of Samples for RCR Informed Consent Form, optional 
tumor biopsy samples may be collected by core needle or excisional/punch biopsy per investigator discretion. Optional biopsy tissue will be stored 
in the RCR.  Not applicable for sites that have not been granted approval for RCR sampling.
v Surveillance for tumor recurrence must include physical examination and imaging studies of the chest, abdomen, upper urinary tracts, and pelvis.  
Other examinations such as laboratory or urine cytology should be performed as clinically indicated.  Recurrence assessment at Year 6 will be 
performed at approximately 48 weeks after the last one in Year 5. Patients in Years 13 of the study may be assessed for tumor recurrence every
24 weeks. See Section 4.5.5 for details of assessment requirements.
w Concomitant medications include any prescription medications or over-the-counter medications.  At screening, any medications the patient has 
used within the 7 days prior to written informed consent should be documented.  At subsequent visits, changes to current medications or 
medications used since the last documentation of medications will be recorded.


A p p e n di x 1
S c h e d ul e of A s s e s s m e nt s ( c o nt.)
At e z oli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 2 2 /Pr ot o c ol W O 2 9 6 3 6, V er si o n 1 0
x Aft er i nf or m e d c o n s e nt h a s b e e n o bt ai n e d b ut pri or t o r a n d o mi z ati o n, o nl y s eri o u s a d v er s e e v e nt s c a u s e d b y a pr ot o c ol -m a n d at e d i nt er v e nti o n 
s h o ul d b e r e p ort e d. U p o n r a n d o mi z ati o n i nt o st u d y, p ati e nt s w h o e x p eri e n c e a s eri o u s a d v er s e e v e nt or pr ot o c ol -d efi n e d a d v er s e e v e nt s of s p e ci al 
i nt er e st will b e f oll o w e d f or s af et y f or 9 0 d a y s f oll o wi n g t h eir l a st d o s e of st u d y dr u g or u ntil t h e y r e c ei v e a n ot h er a nti-c a n c er t h er a p y, w hi c h e v er 
c o m e s fir st. P ati e nt s w h o e x p eri e n c e all ot h er a d v er s e e v e nt s will b e r e p ort e d f or p ati e nt s u ntil 3 0 d a y s aft er t h e l a st d o s e of st u d y tr e at m e nt 
(f or Ar m  A) or t h e l a st d a y i n t h e o b s er v ati o n p eri o d ( a p pr o xi m at el y D a y 3 6 5 f or Ar m B), or u ntil i niti ati o n of a n ot h er a nti-c a n c er t h er a p y, w hi c h e v er 
o c c ur s fir st. Aft er t hi s p eri o d, i n v e sti g at or s s h o ul d e n s ur e a n y d e at h s, s eri o u s a d v er s e e v e nt s, or ot h er a d v er s e e v e nt s of c o n c er n ar e r e p ort e d if 
t h e y ar e l at er a s s e s s e d t o b e r el at e d t o at e z oli z u m a b tr e at m e nt. T h e i n v e sti g at or s h o ul d f oll o w e a c h a d v er s e e v e nt u ntil t h e e v e nt h a s r e s ol v e d t o 
b a s eli n e gr a d e or b ett er, t h e e v e nt i s a s s e s s e d a s st a bl e b y t h e i n v e sti g at or, t h e p ati e nt i s l o st t o f oll o w u p, or t h e p ati e nt wit h dr a w s c o n s e nt. E v er y 
eff ort s h o ul d b e m a d e t o f oll o w all s eri o u s a d v er s e e v e nt s c o n si d er e d t o b e r el at e d t o at e z oli z u m a b tr e at m e nt or tri al -r el at e d pr o c e d ur e s u ntil a fi n al 
o ut c o m e c a n b e r e p ort e d.
y T hi s c li ni c c o nt a ct c a n b e eit h er vi a t el e p h o ne c all or f or m al cli ni c vi sit.
z S ur vi v al f oll o w-u p i nf or m ati o n will b e r e c or d e d vi a t el e p h o n e c all s, p ati e nt m e di c al r e c or d s, a n d/ or cli ni c vi sit s a p pr o xi m at el y e v er y 3 m o nt h s 
(7 d a y s) fr o m t he c o m pleti o n or dis c onti n u ati o n of t he tre at me nt/ o bser v ati o n peri o d u ntil d e at h, l o s s t o f oll o w -u p, or st u d y t er mi n ati o n b y R o c h e.  
All p ati e nt s (irr e s p e cti v e of w hi c h ar m t h e y ar e r a n d o mi z e d t o) will b e f oll o w e d f or s ur vi v al a n d n e w a nti c a n c er t h er a p y i nf o r m ati o n u nl e s s t h e 
p ati e nt r e q u e st s t o b e wit h dr a w n fr o m f oll o w -u p; t hi s r e q u e st m u st b e d o c u m e nt e d i n t h e s o ur c e d o c u m e nt s a n d si g n e d b y t h e i n v e sti g at or.  If t h e 
p ati e nt wit h dr a w s fr o m st u d y, t h e st u d y st aff m a y u s e a p u bli c i nf or m ati o n s o ur c e ( e. g., c o u nt y r e c or d s) t o o bt ai n i nf or m ati o n a b o ut s ur vi v al st at u s 
o nl y.  P ati e nt s w h o h a v e c o m pl et e d t h e tr e at m e nt or o b s er v ati o n p h a s e a n d c o nti n u e i n di s e a s e r e c urr e n c e f oll o w -u p s h o ul d h a v e 
m o nt h s. All p ati e nt s m u st still b e f ol l o w e d f or n e w a nti-c a n c er t h er a p y .
a a T h e P R O q u e sti o n n air e E Q -5 D -5 L will b e c o m pl et e d b y t h e p ati e nt s at t h e i n v e sti g ati o n al sit e.  All P R O q u e sti o n n air e s ar e r e q uir e d t o b e 
a d m i ni st er e d pri or t o a d mi ni str ati o n of st u d y tr e at m e nt ( Ar m A) a n d/ or pri or t o an y  ot h er st u d y a s s e s s m e nt( s) t o e n s ur e t h at t h e v ali dit y of t h e 
i n str u m e nt i s n ot c o m pr o mi s e d a n d t o e n s ur e t h at d at a q u alit y m e et s r e g ul at ory r e q uir e m e nt s.  St u d y p er s o n n el s h o ul d r e vi e w a ll q u e sti o n n air e s f or 
c o m pl et e n e s s b ef or e t h e p ati e nt l e a v e s t h e i n v e sti g ati o n al sit e, a n d t h e h ar d c o p y ori gi n al s of t h e q u e sti o n n air e s m u st b e m ai nt ai n e d a s p art of t h e 
p ati e nt’ s m e di c al r e c or d w h e n r el e v a nt at t h e sit e f or s o ur c e d at a v erifi c ati o n.  Aft er di s c o nti n u ati o n of t h e tr e at m e nt/ o b s er v ati o n p eri o d, f or p ati e nt s 
w h o h a v e n ot e x p eri e n c e d di s e a s e r e c urr e n c e, t h e E Q -5 D -5 L will b e a d mi ni st er e d at t h e s a m e s c h e d ul e a s t h e a s s e s s m e nt s f or di s e a s e 
r e c urr e n c e ( s e e S e cti o n 4. 5. 5 ).  T h e E Q-5 D -5 L will al s o b e r e c or d e d at 6, 1 2, a n d 2 4 w e e k s aft er di s e a s e r e c urr e n c e p er t el e p h o n e i nt er vi e w b y 
tr ai n e d sit e st aff a n d i n c o m pli a n c e wit h b e st pr a cti c e s a n d r ec o m m e n d ati o n s b y E ur o Q ol.  St u d y p er s o n n el will r e c or d p ati e nt r e s p o n s e s o n a 
p a p er c o p y of t h e E Q -5 D -5 L d uri n g t h e t el e p h o n e i nt er vi e w a s r e c or d of s o ur c e d o c u m e nt ati o n.
After t he p r i m ar y an al ysis, t he E Q -5 D -5 L 
assess me nts are n o l o n ger re q uire d f or p atie nts w h o are i n dise ase re c urre n ce f oll o w -u p or w h o h a ve h a d a D F S e ve nt.  
b b O d d -n u m b er e d c y cl e s o nl y (i. e., C y cl e s 1, 3, 5, 7, 9, 1 1, 1 3, a n d 1 5).
i n parallel a p pr o xi m at el y e v er y 3
s ur vi v al f oll o w- u p


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Appendix 2
Schedule of Pharmacodynamic and Pharmacokinetic 
Assessments
Study Visit
Time
Sample
Arm A
Arm B
Cycle 1, Day 1
Predose
Serum atezolizumab ATAs
x
Serum atezolizumab PK 
x
PD biomarker a
x
x
30 min 
(10 min) 
after end of 
atezolizumab
infusion
Serum atezolizumab PK
x
Cycles 2, 3, and 4, 
Day 1 
Predose
Serum atezolizumab ATAs
x
Serum atezolizumab PK 
x
PD biomarker (Cycle 3,
Day 1 only) a
x
x
Cycles 8, Day 1, 
every 8 cycles starting 
Cycle 8
Predose
Serum atezolizumab ATAs 
x
Serum atezolizumab PK
x
At time of fresh biopsy (e.g., at the 
time of first radiographic confirmation 
of disease recurrence)
PD biomarker a
x
x
Treatment 
discontinuation visit
At visit
Serum atezolizumab ATAs
x
Serum atezolizumab PK
x
PD biomarkera
x
120 days (30 days) 
after last dose of 
atezolizumab b  
At visit
Serum atezolizumab ATAs
x
Serum atezolizumab PK
x
ATAs anti-therapeutic antibodies; PDpharmacodynamics; PKpharmacokinetics.
a Pharmacodynamic samples may include plasma, serum, and whole blood (see laboratory 
manual for details on sample collection).
b To be collected unless the patient withdraws consent or the study closes.


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Appendix 3
Criteria for PD-L1 Diagnostic Assessment in Study WO29636
Description of IHC Scoring Algorithm
IHC IC score
Absence of any discernible PD-L1 staining
OR
Presence of discernible PD-L1 staining of any intensity in 
tumor-infiltrating immune cells (IC) covering1% of tumor area 
occupied by tumor cells, associated intratumoral, and 
contiguous peri-tumoral desmoplastic stroma
IHC IC0
(IC1%)
Presence of discernible PD-L1 staining of any intensity in 
tumor-infiltrating immune cells covering between 1 % to 5% 
of tumor area occupied by tumor cells, associated intratumoral, 
and contiguous peri-tumoral desmoplastic stroma
IHC IC1
(5%IC1%)
Presence of discernible PD-L1 staining of any intensity in tumor 
infiltrating immune cells covering between 5 % to 10% of
tumor area occupied by tumor cells, associated intratumoral, 
and contiguous peri-tumoral desmoplastic stroma
IHC IC2
(10%IC5%)
Presence of discernible PD-L1 staining of any intensity in tumor 
infiltrating immune cells covering 10% of tumor area occupied 
by tumor cells, associated intratumoral, and contiguous 
peri-tumoral desmoplastic stroma
IHC IC3
(IC10%)


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Appendix 4
Age-Adjusted Charlson Comorbidity Index (ACCI) Worksheet
Weight
Comorbidity
1
Myocardial infarction
Congestive heart failure
Peripheral vascular disease or bypass
Cerebrovascular disease or transient 
ischemic disease
Dementia or Alzheimer’s
Chronic obstructive pulmonary disease
Rheumatic or connective tissue disease
Gastric or peptic ulcer
Diabetes without end-organ damage
Warfarin
Depression
Hypertension
2
Hemiplegia
Mild liver disease
Renal disease
Diabetes with end-organ damage
Any solid tumor, leukemia or lymphoma
Skin ulcers/cellulitis
3
Severe liver disease
6
Metastatic solid tumor
HIV or AIDS
1
For each decade over age 40
ACCI scores will be calculated by the method previously reported by Charlson et al. (1987), in 
which comorbid conditions are weighted and scored, with additional points added for age.
REFERENCE
Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic 
comorbidity in longitudinal studies: development and validation. J Chronic Dis 
1987;40(5):373-383.


Appendix 4
Age-Adjusted Charlson Comorbidity Index (ACCI) Worksheet (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
126/Protocol WO29636, Version 10
ACCI scores will be calculated by the method previously reported by Charlson et al. (1987), in 
which comorbid conditions are weighted and scored, with additional points added for age.
REFERENCE
Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in 
longitudinal studies: development and validation. J Chronic Dis 1987;40(5):373-383.


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Appendix 5
Preexisting Autoimmune Diseases
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease are excluded from participating in the study.  
Possible exceptions to this exclusion could be patients with a medical history of such 
entities as atopic disease or childhood arthralgias where the clinical suspicion of 
autoimmune disease is low.  Patients with a history of autoimmune-related 
hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this 
study.  In addition, transient autoimmune manifestations of an acute infectious disease 
that resolved upon treatment of the infectious agent are not excluded (e.g., acute Lyme 
arthritis).  Contact the Medical Monitor regarding any uncertainty over autoimmune 
exclusions.
Acute disseminated 
encephalomyelitis
Addison’s disease
Ankylosing spondylitis
Antiphospholipid antibody
syndrome
Aplastic anemia
Autoimmune hemolytic anemia
Autoimmune hepatitis
Autoimmune 
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune 
thrombocytopenic purpura
Behcet’s disease
Bullous pemphigold
Chronic fatigue syndrome
Chronic inflammatory
demyelinating polyneuropathy
Churg-Strauss syndrome
Crohn’s disease 
Dermatomyositis
Dysautonomia
Epidermolysis bullosa acquista
Gestational pemphigoid
Giant cell arteritis
Goodpasture’s syndrome
Graves’ disease
Guillain-Barré syndrome
Hashimoto’s disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki’s disease
Lambert-Eaton myasthenia
syndrome
Lupus erythematosus
Lyme disease – chronic
Mooren’s ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus 
syndrome
Optic neuritis
Ord’s thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodusa
Polyarthritis
Polyglandular autoimmune
syndrome
Primary biliary cirrhosis
Psoriasis
Reiter’s syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Stiff-Person syndrome
Takayasu’s arteritis
Ulcerative colitis
Vitiligo
Vogt-Kovanagi-Harada 
disease
Wegener’s granulomatosis


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Appendix 6
Anaphylaxis Precautions
EQUIPMENT NEEDED

Tourniquet

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice 

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study drug infusion, 
the following procedures should be performed:
1. Stop the study drug infusion.
2. Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
drug.  Do not obstruct arterial flow in the limb.
3.
Maintain an adequate airway.
4.
Administer antihistamines, epinephrine, or other medications as required by patient
status and directed by the physician in charge.
5. 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
Patient-Reported Outcomes Instrument


Appendix 8
Patient-Reported Outcomes Instrument (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
131/Protocol WO29636, Version 10


Appendix 8
Patient-Reported Outcomes Instrument (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
132/Protocol WO29636, Version 10


Atezolizumab—F. Hoffmann-La Roche Ltd
133/Protocol WO29636, Version 10
Appendix 9
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents. 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the 
immune-mediated event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and 
the Medical Monitor. 
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 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
134/Protocol WO29636, Version 10
Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary 
event, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL.

Initiate treatment with 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, 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 oral prednisone 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 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
135/Protocol WO29636, Version 10
HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits. 
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with 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
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor.


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
136/Protocol WO29636, Version 10
Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 

Initiate treatment with 12 mg/kg/day oral prednisone 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.
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor.
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
137/Protocol WO29636, Version 10
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 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
138/Protocol WO29636, Version 10
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 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 4.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., TSH, 
growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
139/Protocol WO29636, Version 10
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and thyroid 
function is improving.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:

Continue atezolizumab.

Monitor TSH every 4 weeks.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and thyroid 
function is improving.

Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated hyperthyroidism. c
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
140/Protocol WO29636, Version 10
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.

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 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
141/Protocol WO29636, Version 10
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 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
142/Protocol WO29636, Version 10
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 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 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
143/Protocol WO29636, Version 10
IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited to, 
laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, 
dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of GI 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 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
144/Protocol WO29636, Version 10
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

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Consider treatment with 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 resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-mediated
myocarditis, Grade 3-4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. a,b

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over1 month.
ECMOextracorporeal membrane oxygenation; VAD ventricular assist device.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
145/Protocol WO29636, Version 10
INFUSION-RELATED REACTIONS and Cytokine-Release Syndrome
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines, 
anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  
Metamizole (dipyrone) is prohibited in treating atezolizumab associated IRRs because 
of its potential for causing agranulocytosis.
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells 
and/or other immune effector cells.  Symptoms can be progressive, always include fever 
at the onset, and may include hypotension, capillary leak (hypoxia), and end-organ 
dysfunction (Lee et al. 2019).  CRS has been well documented with chimeric antigen 
receptor T-cell therapies and bispecific T-cell engager antibody therapies but has also 
been reported with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; 
Adashek and Feldman 2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 7.  For 
subsequent cycles, IRRs should be managed according to institutional guidelines.


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
146/Protocol WO29636, Version 10
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome
Event
Management
Grade 1 a
Fever b with or 
without 
constitutional 
symptoms 

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset.

If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment, c including maintenance of IV 
fluids for hydration.

In case of rapid decline or prolonged CRS (2 days) or in patients 
with significant symptoms and/or comorbidities, consider managing 
as per Grade 2.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or analgesics, 
and monitor closely for IRRs and/or CRS.
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.

Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e

Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact Medical Monitor.

If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of atezolizumab may be administered.  For subsequent 
infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics and monitor closely 
for IRRs and/or CRS.

If symptoms do not resolve to Grade 1 or better for 3 consecutive 
days, contact Medical Monitor.


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
147/Protocol WO29636, Version 10
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. f

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus and vasopressor as 
needed.

Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended.  Administer IV fluids 
as clinically indicated, and manage constitutional symptoms 
and organ toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS.

Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e

Hospitalize patient until complete resolution of symptoms.  If 
no improvement within 24 hours, manage as per Grade 4, that 
is, admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed; for patients who are refractory to anti-cytokine therapy, 
experimental treatments may be considered at the discretion of 
the investigator and in consultation with the Medical Monitor.
Grade 4 a
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin)
and/or
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation)

Permanently discontinue atezolizumab and contact Medical 
Monitor. f

Administer symptomatic treatment. c

Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed.  Monitor other organ function closely.  Manage 
constitutional symptoms and organ toxicities as per 
institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS.

Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e  For patients who are 
refractory to anti-cytokine therapy, experimental treatments g
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.

Hospitalize patient until complete resolution of symptoms.


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
148/Protocol WO29636, Version 10
ASTCT American Society for Transplantation and Cellular Therapy; BiPAP bi-level 
positive airway pressure; CAR chimeric antigen receptor; CPAP continuous positive 
airway pressure; CRS cytokine-release syndrome; CTCAE Common Terminology 
Criteria for Adverse Events; eCRF electronic Case Report Form; 
HLH hemophagocytic lymphohistiocytosis; ICU intensive care unit; IRR infusion-
related reaction; MAS macrophage activation syndrome; NCCN National Cancer 
Comprehensive Network; NCI National Cancer Institute.
Note:  The management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for management guidelines is based on ASTCT consensus grading for 
CRS.  NCI CTCAE (version as specified in the protocol) should be used when 
reporting severity of IRRs, CRS, or organ toxicities associated with CRS on the 
Adverse Event eCRF.  Organ toxicities associated with CRS should not influence 
overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In 
patients who develop CRS and then receive anti-pyretic, anti-cytokine, or 
corticosteroid therapy, fever is no longer required when subsequently determining 
event severity (grade).  In this case, the grade is driven by the presence of 
hypotension and/or hypoxia.
c
Symptomatic treatment may include oral or IV antihistamines, anti-pyretics,
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, 
additional treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as 
oxygen delivered at 6 L/min.
e
There are case reports where anti-cytokine therapy has been used for treatment of 
CRS with immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 
2019), but data are limited, and the role of such treatment in the setting of antibody-
associated CRS has not been established.
f
Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.  For subsequent infusions, administer 
oral premedication with antihistamines, anti-pyretics, and/or analgesics, and monitor 
closely for IRRs and/or CRS.  Premedication with corticosteroids and extending the 
infusion time may also be considered after consulting the Medical Monitor and 
considering the benefitrisk ratio.
g Refer to Riegler et al. (2019) for information on experimental treatments for CRS.


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
149/Protocol WO29636, Version 10
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table 8.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
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 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
150/Protocol WO29636, Version 10
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-mediated
pancreatitis, 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 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
151/Protocol WO29636, Version 10
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority 
of cases of rash were mild in severity and self-limited, with or without pruritus.  
A dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy 
should be considered unless contraindicated.  Management guidelines for dermatologic 
events are provided in Table 9.
Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue atezolizumab.

Consider treatment with topical corticosteroids and/or other
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue atezolizumab.

Consider patient referral to dermatologist.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if
event does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist.

Initiate treatment with 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
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
152/Protocol WO29636, Version 10
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic workup is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-mediated
neuropathy, 
Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Immune-mediated
neuropathy, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c 

Initiate treatment as per institutional guidelines.
Myasthenia gravis 
and Guillain-Barré 
syndrome 
(any grade)

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
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 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
153/Protocol WO29636, Version 10
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.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor.
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
154/Protocol WO29636, Version 10
(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.
Table 12 Management Guidelines for Renal Events 
Event
Management
Renal event, 
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine, closely until values resolve to 
within normal limits or to baseline values. 
Renal event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to renal specialist.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact Medical 
Monitor. c
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor. 

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
155/Protocol WO29636, Version 10
IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13.
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 agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
156/Protocol WO29636, Version 10
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 
12 mg/kg/day oral prednisone or equivalent upon improvement.
!
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
!
If event resolves to Grade 1 or better, resume atezolizumab. b
!
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
!
For recurrent events, treat as a Grade 4 event.
Immune-mediated 
myositis, Grade 4
!
Permanently discontinue atezolizumab and contact Medical 
Monitor. c
!
Refer patient to rheumatologist or neurologist.
!
Initiate treatment as per institutional guidelines.
!
Respiratory support may be required in more severe cases.
!
Initiate treatment with corticosteroids equivalent to 1∀2 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, 
or weakness that severely limits mobility); convert to 
1∀2 mg/kg/day oral prednisone or equivalent upon improvement.
!
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
!
If event resolves to Grade 1 or better, taper corticosteroids over 
# 1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., (12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
%10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over #1 month to the 
equivalent of %10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
157/Protocol WO29636, Version 10
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), 
which are considered to be potential risks for atezolizumab.  
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
–
Platelet count 100109/L (100,000/L)
–
ANC 1.0109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard deviations 
above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14.


Appendix 9
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
158/Protocol WO29636, Version 10
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue atezolizumab and contact Medical Monitor.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.

Consider initiation of IV corticosteroids and/or an immunosuppressive 
agent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLHhemophagocytic lymphohistiocytosis; MASmacrophage activation syndrome.
REFERENCES
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819.

SAP_001.pdf: 
 
Official Title: 
 
A Phase III, Open-Label, Multicenter, Randomized Study of 
Atezolizumab (Anti−PD-L1 Antibody) Versus Observation as Adjuvant 
Therapy in Patients With High-Risk Muscle-Invasive Urothelial 
Carcinoma After Surgical Resection 
NCT Number: NCT02450331  
Document Date: SAP Version 1: 01-February-2019 
 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Atezolizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan WO29636
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER,
RANDOMIZED STUDY OF ATEZOLIZUMAB
(ANTI−PDL1 ANTIBODY) VERSUS OBSERVATION
AS ADJUVANT THERAPY IN PATIENTS WITH
HIGH-RISK MUSCLE-INVASIVE UROTHELIAL
CARCINOMA AFTER SURGICAL RESECTION
PROTOCOL NUMBER:
WO29636
STUDY DRUG:
Atezolizumab (MPDL3280A; RO5541267)
VERSION NUMBER:
1
IND NUMBER:
120827
EUDRACT NUMBER:
2014-005603-25
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
, Ph.D.
DATE FINAL:
See electronic date stamp below.
Name                                                             Reason for Signing                              Date and Time
(UTC)
01-Feb-2019 16:59:25
Company Signatory


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan WO29636
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 5
2.
STUDY DESIGN........................................................................................... 5
2.1
Protocol Synopsis.................................................................... 7
2.2
Determination of Sample Size ................................................. 7
2.2.1
Type I Error Control................................................................. 7
2.2.2
Primary Endpoint: Disease-Free Survival................................ 7
2.2.3
Secondary Endpoint:  Overall Survival .................................... 8
2.3
Analysis Timing ....................................................................... 8
2.3.1
Primary Analysis Timing for DFS............................................. 8
2.3.2
Interim and Final Analysis Timing for OS................................. 8
3.
STUDY CONDUCT..................................................................................... 10
3.1
Randomization Issues ........................................................... 10
3.2
Data Monitoring ..................................................................... 10
4.
STATISTICAL METHODS .......................................................................... 11
4.1
Analysis Populations ............................................................. 11
4.1.1
IntentToTreat Population ................................................... 11
4.1.2
Safety Population .................................................................. 11
4.1.3
PharmacokineticEvaluable Population................................. 11
4.1.4
ADA-Evaluable Population .................................................... 11
4.1.5
PatientReported OutcomeEvaluable 
Population.............................................................................. 11
4.2
Analysis of Study Conduct..................................................... 11
4.3
Analysis of Treatment Group Comparability .......................... 11
4.4
Efficacy Analyses .................................................................. 12
4.4.1
Primary Efficacy Endpoint...................................................... 12
4.4.2
Secondary Efficacy Endpoints............................................... 13
4.4.2.1
Overall Survival (OS)............................................................. 13
4.4.2.2
Disease-Specific Survival (DSS) ........................................... 14
4.4.2.3
Distant Metastasis-Free Survival (DMFS).............................. 14
4.4.2.4
Non-Urinary Tract Recurrence-Free Survival 
(NURFS)................................................................................ 14


Atezolizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan WO29636
4.4.3
Exploratory Efficacy Endpoints.............................................. 14
4.4.3.1
DFS and OS Analyses by PD-L1 status ................................ 14
4.4.3.2
Analyses at Landmark Timepoints......................................... 14
4.4.3.3
Additional DFS and OS Analyses.......................................... 15
4.4.3.4
Biomarker Analyses............................................................... 15
4.4.4
Sensitivity Analyses............................................................... 15
4.4.4.1
Sensitivity Analyses on DFS for Patients in Any 
Treatment Arm Receiving Protocol Prohibited 
AntiCancer Therapy............................................................. 15
4.4.4.2
Sensitivity Analyses on OS for Patients in 
Observation Arm Receiving Atezolizumab or 
Similar Immunotherapy.......................................................... 15
4.4.5
Subgroup Analyses ............................................................... 16
4.5
Safety Analyses..................................................................... 16
4.5.1
Exposure of Study Medication............................................... 17
4.5.2
Adverse Events ..................................................................... 17
4.5.3
Laboratory Data..................................................................... 17
4.5.4
Vital Signs.............................................................................. 17
4.6
Pharmacokinetic Analyses..................................................... 17
4.7
Immunogenicity analyses ...................................................... 18
4.8
Patient-reported outcome analyses....................................... 18
4.9
Missing Data.......................................................................... 18
4.10
Exploratory analyses ............................................................. 18
5.
REFERENCES ........................................................................................... 19
LIST OF TABLES
Table 1
Overall Survival Interim and Final Analysis Characteristics .......... 9
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 5


Atezolizumab—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan WO29636
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 20
Appendix 2
Schedule of Assessments........................................................... 31


Atezolizumab—F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan WO29636
1.
BACKGROUND
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Study WO29636 (IMvigor010). The analyses described in this 
SAP will supersede those specified in Protocol WO29636.
2.
STUDY DESIGN
Study WO29636 is a global Phase III, openlabel, randomized, controlled trial designed 
to evaluate the efficacy and safety of adjuvant treatment with atezolizumab compared 
with observation in patients with muscle invasive urothelial carcinoma (UC), who are at 
high risk for recurrence following resection. The study schema is provided in Figure 1.
Figure 1
Study Schema
ICtumorinfiltrating immune cell; IVintravenous; nnumber; PD-L1programmed 
death-ligand 1; q3wevery 3 weeks; UC Urothelial carcinoma.


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Patients were randomized to one of the following arms in a 1:1 ratio:

Arm A (experimental arm): atezolizumab 1200 mg q3w

Arm B (control arm): observation
The randomization was stratified by the following factors:  number of lymph nodes 
resected (10 vs.≥10), nodal status (positive vs. negative), tumor stage after surgical 
resection (pT2 vs. pT3/pT4), PD-L1 status (IC0/1 vs. IC2/3), and prior neoadjuvant 
chemotherapy (yes vs. no).
Note: The study design was revised in Protocol Version (v) 6 from a diagnostically 
selected population with PDL1 status (tumorinfiltrating immune cell [IC] score 
measured in tumor) of IC2/3 to include all patients regardless of PDL1 status. 
Ageadjusted Charlson comorbidity index, which was a stratification factor prior to 
Protocol v6, was removed as a stratification factor in Protocol v6 and replaced with 
PDL1 status (IC0/1 vs IC2/3).  Patients enrolled prior to Protocol v6 have been 
categorized as IC2/3 for stratification purposes.
For patients in Arm A, atezolizumab will be administered intravenously (IV) on Day 1 of 
each 21-day cycle for 16 cycles (up to 1 year). In Arm B, patients will continually 
undergo observation starting on Day 1 of each 21-day cycle for 16 cycles (up to 1 year).
Treatment/observation will be discontinued in the event of disease recurrence, 
unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor.
Patients in the control arm will not be allowed to cross over to receive atezolizumab 
treatment within this study.
All patients will undergo scheduled assessments for tumor recurrence at baseline and 
every 12 weeks (approximately every 4 cycles) in the first year following randomization. 
Upon completion of the treatment/observation period, surveillance for tumor recurrence 
will be performed every 12 weeks for years 2-3; every 24 weeks for years 4-5; and at 
year 6 (approximately 48 weeks after the last assessment in year 5). In the absence of 
a disease-free survival (DFS) event (defined as any of the following: local [pelvic] 
recurrence of UC; upper urinary tract or urethral recurrence of UC; distant metastasis of 
UC; or death from any cause), surveillance for tumor recurrence should continue 
regardless of whether patients start new anticancer therapy, until withdrawal of consent, 
loss to follow-up, or study termination by the Sponsor, whichever occurs first.
The primary efficacy endpoint is DFS as assessed by the investigator and the key 
secondary endpoint is overall survival (OS). See Section 2.2 for further details on 
primary efficacy endpoints, as well as secondary and other safety, pharmacokinetic (PK), 
and exploratory endpoints.


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There are no interim analyses planned for DFS and two interim analyses are planned for 
OS in this study. See Section 2.3 for detailed analysis timing.
An external independent Data Monitoring Committee (iDMC) was convened to evaluate 
safety data on an ongoing basis.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details on study assessments, 
see the Schedule of Assessments in Appendix 2.
2.2
DETERMINATION OF SAMPLE SIZE
Approximately 800 patients will be randomized in this study.
2.2.1
Type I Error Control
The Type I error (alpha) for this study is 0.05 (two-sided).  Type I error will be controlled 
for the primary endpoint of DFS and the key secondary endpoint of overall survival (OS).
To control the Type I error at alpha0.05 (twosided) for DFS and OS endpoints, the 
treatment arms will be compared in a hierarchical fashion as follows:

If the DFS analysis results are statistically significant at alpha0.05 (twosided), 
then the analysis of OS will be performed at alpha0.05 (twosided) and the interim 
analysis boundaries for OS (see Section 2.3.2) will be calculated according to 
alpha0.05 (twosided).
2.2.2
Primary Endpoint: Disease-Free Survival
The analysis of the primary endpoint of DFS will take place when approximately 377 
DFS events have occurred in the intenttotreat (ITT) population (defined in 
Section 4.1.1) and at least 12 months after the last patient is enrolled have elapsed.
The estimated number of events required for the analysis is based on the following 
assumptions:

Two-sided, log-rank test at the 0.05 significance level (two-sided)

80% power

1:1 randomization ratio

Median DFS for the control (observation) arm of 20 months and estimated median 
DFS in the atezolizumab arm of 26.7 months (corresponding to a HR of 0.75)

No interim analysis for DFS
Accrual of the planned 800 patients is projected to occur over 32 months, assuming a 
ramp-up period of 13 months to a projected accrual rate of 35 patients per month.  On 
the basis of these assumptions, and the projected probability of loss to follow-up for DFS 
of approximately 32% over 24 months after enrollment, the required number of DFS 
events is projected to occur at Month 50 from the time the first patient is randomized.  


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Also on the basis of these assumptions, it is projected that an observed HR of 0.82 or
lower will result in a statistically significant difference between treatment arms (i.e., an 
HR of 0.82 will be the minimally detectable difference at the analysis; this corresponds to 
an improvement of 4.5 months in median DFS, from 20 months in the control 
[observation] arm to 24.5 months in the atezolizumab arm).
2.2.3
Secondary Endpoint: Overall Survival
The final analysis of the secondary endpoint of OS will take place when approximately 
428 deaths have occurred in the ITT population on the basis of the following 
assumptions:

Two-sided, log-rank test at the 0.05 significance level (two-sided)

80% power

1:1 randomization ratio

Median OS for the control (observation) arm of 34 months and estimated median 
OS in the atezolizumab arm of 44.7 months (corresponding to HR of 0.76)

Two interim analyses for OS (see Section 2.3.2 for details)
On the basis of these assumptions, the projected probability of loss to followup for OS 
of approximately 24% over 24 months after enrollment, and projected accrual, the 
required number of OS events for the final analysis of OS is projected to occur 
95 months from the time the first patient is randomized.  It is projected that an observed 
HR of 0.82 or lower will result in a statistically significant difference between treatment 
arms (i.e., an HR of 0.82 will be the minimally detectable difference at the analysis; this 
corresponds to an improvement of 7.4 months in median OS, from 34 months in the 
control [observation] arm to 41.4 months in the atezolizumab arm).
2.3
ANALYSIS TIMING 
2.3.1
Primary Analysis Timing for DFS
No interim analyses are planned for the primary endpoint of DFS in this study. The 
analysis of the primary endpoint DFS will take place when approximately 377 DFS 
events have occurred in the ITT population and at least 12 months after the last patient 
is enrolled have elapsed.  Based on the assumptions described in Section 2.2.2, the 
required number of DFS events is projected to occur at Month 50 from the time the first 
patient is randomized.
2.3.2
Interim and Final Analysis Timing for OS
There are no interim analyses planned for DFS, and a total of three analyses of OS will 
be performed by the Sponsor (two interim analyses and one final analysis; see Table 1
below for details about each analysis).
The first interim analysis of OS will be performed at the time of the DFS analysis. On the 
basis of the projected median OS for each treatment arm and the projected time of the 
final analysis of DFS, it is projected that approximately 280 deaths (35% of 800 patients) 


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will have occurred at the first interim analysis of OS, which corresponds to approximately 
65% of the 428 deaths required for the final analysis of OS.  It is projected that an 
observed HR of 0.74 or lower will result in a statistically significant difference between 
treatment arms at this analysis.
The second interim analysis of OS will be performed when approximately 342 deaths 
(43% of 800 patients) have occurred, which corresponds to 80% of the 428 deaths 
required for the final analysis of OS.  The required number of OS events for the second 
interim analysis of OS is projected to occur at Study Month 63 from the time the first 
patient is randomized.  It is projected that an observed HR of 0.78 or lower will result in a 
statistically significant difference between treatment arms at this analysis.
The final analysis of OS will take place when approximately 428 OS events have 
occurred in the ITT population.  Based on the assumptions described in Section 2.2.3, 
the required number of OS events is projected to occur at Month 95 from the time the 
first patient is randomized. It is projected that an observed HR of 0.82 or lower will result 
in a statistically significant difference between treatment arms at this analysis.
The boundary for statistical significance at each interim analysis and the final analysis 
will be determined based on the Lan-DeMets implementation of the O’BrienFleming 
use function (Lan and DeMets 1983).  For example, with α 0.05 (twosided) and using 
the twosided logrank test, if 280 deaths have occurred at the time of the first OS 
interim analysis, statistical significance will be declared if p 0.011; if 342 deaths have 
occurred at the time of the second OS interim analysis, statistical significance will be 
declared if p 0.021; and if 428 deaths have occurred at the time of the final OS 
analysis, statistical significance will be declared if p 0.042.  The projected pvalue 
boundary for statistical significance above is based on the number of projected events; 
actual boundary pvalues will be calculated at the time of analysis based on the actual 
number of events observed in the ITT population.
Table 1
Overall Survival Interim and Final Analysis Characteristics
ITT population
n800
Target HR
0.76
median (observation arm)
34 months
median (atezolizumab arm)
44.7 months
Power 
80%
Alpha level (two-sided) 
0.05
Projected enrollment complete
Study Month 32
First interim OS (to be performed at time of final DFS analysis) 
—
Projected cutoff date a
Study Month 50
Projected number of events (% of final events)
280 (65%)


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ITT population
n800
Projected MDD b
0.74
Projected boundary (p-value) c
p0.011
Second interim OS 
—
Number of events (% of final events)
342 (80%)
Projected cutoff date a
Study Month 63
Projected MDD b
0.78
Projected boundary (p-value) c
p0.021
Final OS 
—
Number of events (% of final events)
428 (100%)
Projected cutoff date a
Study Month 95
   Projected MDD b
0.82
   Projected boundary (p-value) c
p0.042
DFS disease-free survival; HR hazard ratio; MDD minimally detectable difference; 
OS overall survival
Note:  The projected probability of loss to follow-up for OS of approximately 24% over 24 
months after enrollment
a Study month at which required number of events are projected to occur, where Study 
Month 1 is the month the first patient is enrolled.  Analysis results will be available after 
data cleaning
b The largest observed HR that is projected to be statistically significant
c The projected boundary for statistical significance for the number of events shown (actual 
boundary to be calculated at time of analysis based on actual number of events).
3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
Eligible patients will be randomized in a 1:1 ratio to either receiving atezolizumab
(arm A) or observation (arm B) with the use of a stratified permutedblock randomization.
The randomization will be stratified for the following factors:

PDL1 status (IC0/1 vs. IC2/3)

Nodal status (positive vs. negative)

Tumor stage after surgical resection (pT2 vs. pT3/pT4)

Prior neoadjuvant chemotherapy (yes vs. no)

Number of lymph nodes resected (10 vs.10)
3.2
DATA MONITORING 
An independent Data Monitoring Committee (iDMC) will be convened to evaluate safety 
data until the analysis of the primary endpoint (DFS), after which iDMC review of the 
study data will be discontinued.  The iDMC will evaluate study safety data on a periodic 


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basis, approximately every 6 months after enrollment of the first patient.  Members of the 
iDMC will be external to the Sponsor and will follow a charter that outlines their roles and 
responsibilities.  The Sponsor will remain blinded to the results until the analysis of the 
primary endpoint of DFS.  All summaries and analyses by treatment arm for the iDMC 
review will be prepared by an external independent data coordinating center.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
4.1.1
IntentToTreat Population
The ITT population is defined as all randomized patients, whether or not the patient 
received the assigned treatment (atezolizumab/observation).
4.1.2
Safety Population
The safety population is defined as patients who received at least one dose of 
atezolizumab, and all patients who did not receive any dose of atezolizumab who had at 
least one post-baseline safety assessment (e.g., adverse event, lab, vital signs, ECG, 
etc.), regardless of their assigned treatment (atezolizumab/observation).
4.1.3
PharmacokineticEvaluable Population 
The pharmacokineticevaluable population is defined as all patients who received any 
dose of atezolizumab and who have evaluable pharmacokinetic (PK) samples.
4.1.4
ADA-Evaluable Population
The anti-drug antibodies (ADA)evaluable population is defined as all patients treated 
with atezolizumab who have at least one postbaseline ADA result.
4.1.5
PatientReported OutcomeEvaluable Population
The patient-reported outcome (PRO) evaluable population is defined as all randomized 
patients with baseline and at least one postbaseline PRO assessment.
4.2
ANALYSIS OF STUDY CONDUCT
Enrollment, major protocol deviations (including major deviations of inclusion/exclusion 
criteria), and reasons for discontinuation from the study will be summarized overall and
by treatment arm for the ITT population.  Study treatment administration and reasons for 
discontinuation from study treatment will be summarized for patients in the safety 
population. Length of follow up will be summarized by treatment arm for the ITT 
population.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic variables (age, sex, race/ethnicity), stratification factors (nodal status, 
number of lymph nodes resected, tumor stage, PDL1 status, and prior neoadjuvant 
chemotherapy) and baseline and disease characteristics (e.g., ACCI, time since initial 


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diagnosis, time since surgery, surgeryrelated information, type of urinary diversion, and 
Eastern Cooperative Oncology Group [ECOG] Performance Status) will be summarized 
by treatment arm for the ITT population.
Unless otherwise noted, the baseline value of any variable will be defined as the last 
available value prior to the first administration of study treatment for the atezolizumab 
arm and prior to Cycle 1 Day 1 date of observation for the observation arm.  Descriptive 
statistics (mean, median, SD, range) will be presented for continuous variables, and 
frequencies and percentages will be presented for categorical variables.
4.4
EFFICACY ANALYSES
For efficacy analyses, patients will be grouped according to the treatment assigned at 
randomization by interactive voice/web response system (IxRS), whether or not the 
assigned treatment was received.
The stratification factors will be the same as the randomization stratification factors (see 
Section 3.1); however, in order to minimize small strata sizes, only PD-L1 status (IC0/1 
vs. IC2/3), nodal status (positive vs. negative) and tumor stage after surgical resection
(pT2 vs. pT3/pT4) will be used for stratified analysis purposes. Given the mechanism 
of action of atezolizumab, PDL1 status will be used for the stratified analysis. Based on 
the prognostic significance (Protocol Section 3.3.5), prior neoadjuvant chemotherapy 
(yes vs. no), and number of lymph nodes resected (10 vs.10) will not be used for the 
stratified analysis. The eight strata will be applied to all time-to-event endpoints where 
stratified analyses are planned, including stratified logrank test and stratified Cox 
regression model, unless otherwise specified.
Analyses based on stratification factors recorded on the electronic Case Report Form 
(eCRF) will also be provided if considerable discrepancy is observed between values 
from IxRS and eCRF records.
4.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is Investigator-assessed DFS, defined as the time from 
randomization to the first occurrence of a DFS event, defined as any of the following:

Local (pelvic) recurrence of UC

Urinary tract recurrence of UC

Distant metastasis of UC

Death from any cause
Data for patients without a DFS event will be censored at the last date the patient was 
assessed to be alive and recurrence free as determined with radiographic evidence. 
Data for patients with no postbaseline disease assessment will be censored at the 
randomization date.


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For U.S. registrational purposes, the primary efficacy endpoint of DFS will be defined as 
described above with an additional censoring rule for missed visits.  Data for patients 
with a DFS event who missed two or more consecutive scheduled assessments 
immediately prior to the DFS event will be censored at the last date the patient was 
assessed to be alive and recurrence free as determined with radiographic evidence prior 
to the missed visits or at the randomization date if there is no postbaseline tumor 
assessment prior to the DFS event.
DFS will be analyzed in the ITT population.  The following analyses will be performed for 
both DFS endpoints described above.  Treatment comparisons will be based on the 
stratified log-rank test at the twosided level of significance as described in Section 2.2.1.  
The stratification factors used for the analysis are described in Section 4.4 and the 
values will be those recorded in the IxRS.  The null and alternative hypotheses can be 
phrased in terms of the survival functions SA (t) and SB (t) in Arm A (atezolizumab) and 
Arm B (observation), respectively:
H0: SA(t)SB(t) versus H1: SA(t)≠SB(t)
The HR, λA/λB, where λA and λB represent the hazard of experiencing an DFS event in 
Arm A and Arm B, respectively, will be estimated using a stratified Cox regression model 
with the same stratification variables used for the stratified log-rank test, and the 95% CI 
for the HR will be provided. Results from an unstratified analysis will also be provided.
KaplanMeier methodology will be used to estimate median DFS for each treatment arm 
and to construct DFS curves for each treatment arm.  The BrookmeyerCrowley 
methodology will be used to construct the 95% CI for the median DFS for each treatment 
arm (Brookmeyer and Crowley 1982).
4.4.2
Secondary Efficacy Endpoints 
4.4.2.1
Overall Survival (OS) 
Overall survival is defined as the time from randomization to the date of death from any 
cause, regardless of whether the death occurs during study treatment or following 
treatment discontinuation.  Data for patients who have not died will be censored at the 
last date they were known to be alive.  Data for patients without postbaseline survival 
information will be censored at the randomization date.  Methods for comparison of OS 
between treatment arms will be the same as the methods for treatment comparison for 
the primary efficacy endpoint of DFS.
Three analyses of OS are planned (two interim analyses and one final analysis; see 
Section 2.3.2 for details).  The first interim analysis of OS will occur at the time that the 
primary endpoint of DFS is analyzed. The Type I error control for the secondary 
endpoint of OS is described in Section 2.2.1.


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4.4.2.2
Disease-Specific Survival (DSS) 
DSS is defined as the time from randomization to the date of death from UC.  Data for 
patients who have not died will be censored at the last date they were known to be alive.  
Data for patients who died from causes other than UC will be censored at the date of 
death.  Methods for comparison of DSS between treatment arms will be the same as the 
methods for treatment comparison for the secondary efficacy endpoint of OS.  For the 
purposes of evaluating DSS, for each patient death, the cause of death will be assessed 
as related or not related to UC by the investigator.
4.4.2.3
Distant Metastasis-Free Survival (DMFS)
DMFS is defined as the time from randomization to the date of a DMFS event, defined 
as diagnosis of distant (i.e., nonlocoregional) metastasis or death from any cause.  
Data for patients without a DMFS event will be censored at the last date the patient was 
assessed to be alive and free of distant metastasis.  Data for patients without post 
baseline disease assessment will be censored at the randomization date.  Methods for 
comparison of DMFS between treatment arms will be the same as the methods for 
treatment comparison for the primary efficacy endpoint of DFS.
4.4.2.4
Non-Urinary Tract Recurrence-Free Survival (NURFS)
NURFS is defined as the time from randomization to the date of a NURFS event, defined 
as diagnosis of non-urinary tract (nonUT) recurrence (i.e., pelvic soft tissue or regional 
lymph node recurrence, or distant metastasis) or death from any cause.  Data for 
patients without a NURFS event will be censored at the last date the patient was 
assessed to be alive and free of nonurinary tract recurrence.  Data for patients with no 
post baseline disease assessment will be censored at the randomization date day.  
Methods for comparison of NURFS between treatment arms will be the same as the 
methods for treatment comparison for the primary efficacy endpoint of DFS.
4.4.3
Exploratory Efficacy Endpoints
4.4.3.1
DFS and OS Analyses by PD-L1 status
To estimate the treatment benefit for patients with different PD-L1 status (IHC score of 
IC0/1 and IC2/3), the same stratified analysis used for the primary DFS analysis will also 
be performed for both DFS and OS in ITT patients within each PD-L1 subgroup (IC0/1 
and IC2/3), except that PDL1 status as a stratification factor for the primary DFS 
analysis will not be used for these stratified analysis.
4.4.3.2
Analyses at Landmark Timepoints
The rates of DFS, OS, DSS, DMFS, and NURFS at various timepoints (i.e., every 6 
months after randomization) will be estimated by the KaplanMeier methodology for 
each arm and the 95% CI will be calculated using Greenwood’s formula.  The 95% CIs 
for the difference in each of the event rates between the two arms will be estimated 
using the normal approximation method.


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4.4.3.3
Additional DFS and OS Analyses
In order to evaluate the robustness of the primary analyses in the event that 
proportionality of hazard rates may not be assumed, the following analyses may be 
performed for DFS and OS.
4.4.3.3.1
Restricted Mean Survival Time (RMST)
The RMST for each treatment arm may be computed for DFS and OS using the area 
under the corresponding survival curve from baseline to a several timepoints (e.g., 6 
months, 12 months, etc.). The difference with its 95% confidence interval will be 
displayed.
4.4.3.3.2
Weighted Log-rank (WLR) Test
WLR test (Fine 2007) may be performed for both DFS and OS using Fleming and 
Harrington weight function defined at time t as: W(t)(	)
 (1(	)).  The following two 
combinations of 
 and  will be considered: (
0, 1) and (
1, 1).  Both 
unstratified and stratified (using stratification factors mentioned in Section 4.4 analyses 
will be conducted.
4.4.3.4
Biomarker Analyses
The tumor biomarkers include but are not limited to tTMB using the cut-offs of10 
mutations/MB and16 mutations/MB separately (given data availability), PD-L1, CD8, 
and CD103, as defined by immunohistochemistry (IHC), quantitative reverse 
transcriptase−polymerase chain reaction (qRT−PCR), or other methods and would be 
dependent on sufficient tissue availability. Additional pharmacodynamic analyses of 
predictive, prognostic, and exploratory biomarkers in archival and/or fresh tumor tissue 
and blood and their association with disease status, mechanisms of resistance, and/or 
response to study treatment will be conducted as appropriate. These exploratory 
analyses may be provided in a separate report.
4.4.4
Sensitivity Analyses
4.4.4.1
Sensitivity Analyses on DFS for Patients in Any Treatment Arm 
Receiving Protocol Prohibited AntiCancer Therapy
The impact of protocol prohibited anti-cancer therapy on DFS may be assessed 
depending on the number of patients who receive such therapy before a DFS event.  
If5% of patients received protocol prohibited anti-cancer therapy before a DFS event in 
any treatment arm, data for these patients will be censored at the last disease 
assessment date before they received such therapy in DFS analyses that may be 
performed for the comparisons between treatment arms.
4.4.4.2
Sensitivity Analyses on OS for Patients in Observation Arm 
Receiving Atezolizumab or Similar Immunotherapy
The impact on OS by patients in observation arm subsequently receiving atezolizumab 
or another immunotherapy considered similar to atezolizumab in its mechanism of action 
may be assessed, depending on the number of such patients.  If more than 5% of 


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patients in observation arm have received atezolizumab or a similar immunotherapy, the 
following analyses may be performed to compare treatment arms at each of the interim 
analyses and final analysis, as applicable:

OS in the observation arm will be discounted according to a range of possible 
effects on OS after having received atezolizumab or another immunotherapy (e.g.,
10%, 20%, 30%, etc.)

Additional sensitivity analyses may be conducted if deemed necessary
4.4.5
Subgroup Analyses 
The consistency of DFS results in subgroups defined by demographic, baseline disease 
characteristics and stratification factors will be examined.  Summaries of DFS including 
the unstratified HR estimated from a Cox proportional hazards model and KaplanMeier 
estimates of median DFS will be produced separately for each level of the subgroup and 
displayed in a forest plot (Lewis and Clarke 2001).  KaplanMeier plots of DFS will also 
be produced for selected subgroups.
The subgroups to be considered include but are not limited to the following:

Age at randomization (65 years vs. 65 years)

Race (nonwhite vs. white)

Sex (female vs. male)

Region (North America, Europe, Asia, Australia)

PD-L1 status (IC0/1 vs. IC2/3)

Number of lymph nodes resected (10 vs.10)

Nodal status (positive vs. negative)

Tumor stage after resection (pT2 vs. pT3/pT4)

Prior neoadjuvant chemotherapy (yes vs. no)

Age-adjusted Charlson comorbidity index (ACCI) (0-1, 2-3, 4)

ECOG performance status at randomization (0 vs. 1-2)

Primary disease (MIBC vs. UTUC)

Type of urinary diversion (ileal conduct, orthotopic, other)
Similar analyses will be performed as appropriate for OS.
4.5
SAFETY ANALYSES
Unless specified otherwise, the safety analyses described below will be conducted for 
the safety population (see Section 4.1.2), with patients grouped according to whether 
any atezolizumab treatment was received (i.e., patients who received any dose of 
atezolilzumab will be included in the atezolizumab arm).


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4.5.1
Exposure of Study Medication
Study drug exposure, including treatment duration, number of cycles, and dose intensity, 
will be summarized with descriptive statistics for arm A only.
4.5.2
Adverse Events
Verbatim descriptions of adverse events will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRAterms). Treatment emergent events (defined as events 
occurring on or after the first dose of atezolizumab, or, for patients in the observation 
arm, after the date of randomization) will be summarized by MedDRA term, appropriate 
MedDRA levels, and NCI CTCAE (National Cancer Institute, Common Terminology 
Criteria for Adverse Events) v4.0 grade.  For each patient, multiple occurrences of the 
same event will be counted once at maximum severity reported will be used in the 
summaries.  Adverse events will be summarized regardless of relationship to study drug 
as assessed by the investigator.  All adverse events, adverse events leading to 
withdrawal of study drug, adverse events leading to dose interruption, Grade3 adverse 
events, serious adverse events, adverse events related to study drug, adverse events of 
special interest, and immunemediated adverse events will be summarized.  Deaths and 
cause of death will be summarized.
4.5.3
Laboratory Data
Laboratory data will be classified according to NCI CTCAE v4.0.  Highest NCI CTCAE 
v4.0 grade post-baseline will be reported and shift tables from baseline to worst value 
during the study postbaseline will be presented. Selected laboratory tests will be 
summarized descriptively over time including changes from baseline.
A Hy’s law analysis will be provided.  The potential Hy’s law quadrant is defined as 
alanine aminotransferase or aspartate aminotransferase increases above 3-fold the 
upper limit of normal (ULN) with concomitant total bilirubin increases above 2-fold the 
ULN.
4.5.4
Vital Signs
Changes in selected vital signs will be summarized by treatment arm and by change 
over time including change from baseline.
4.6
PHARMACOKINETIC ANALYSES
Atezolizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized according to the blood sampling schedule (Cmax will be reported for Cycle 1 
only; Cmin will be evaluated at Cycles 1, 2, 3, and 4; every 8 cycles starting on Cycle 8; 
and both at treatment discontinuation and at 120 days [30 days] after the last dose of 
atezolizumab).  Descriptive statistics will include means, medians, ranges, and SDs, as 
appropriate.  Additional PK analyses will be conducted as appropriate.


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4.7
IMMUNOGENICITY ANALYSES
Incidence of ADAs against atezolizumab will be summarized.  The analyses of 
pharmacokinetics, key efficacy, and safety by ADA status will be conducted to explore 
the potential impact of immunogenicity.  ADA results will be summarized and listed by 
patient for patients in Arm A only.
4.8
PATIENT-REPORTED OUTCOME ANALYSES
PROs will primarily be evaluated by treatment arm (as assigned at randomization) in the 
ITT population.  Sensitivity analyses may be conducted in the PRO-evaluable population.
Completion rates will be calculated as the number of completed assessments divided by 
the number of expected assessments at each time point.
Summary statistics (e.g., mean, median, SD, interquartile range, minimum, maximum) 
for the EuroQol 5-dimension, 5-level version (questionnaire; EQ-5D-5L) descriptive 
system (i.e., health utilities and individual items) and the visual analogue scale (VAS) 
scores and score changes from baseline will be presented for each time point.
Longitudinal mixed models (e.g., repeated measures, linear) will estimate least-squares 
mean change from baseline in EQ-5D-5L VAS scores by treatment arm and differences 
between arms at each assessment time point and/or at landmark time points. 
Withinand betweengroup differences will be evaluated descriptively.
4.9
MISSING DATA
Please refer to Section 4.4.1 and Section 4.4.2 for methods of handling missing data for 
the primary and secondary efficacy endpoints.
4.10
EXPLORATORY ANALYSES
Exploratory outcome measures defined in the protocol other than the analyses specified 
in Section 4.4.3 are outside of the scope of this SAP and will not be included in the 
Clinical Study Report.


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5.
REFERENCES
Brookmeyer, Ron, and John Crowley. "A confidence interval for the median survival 
time." Biometrics (1982): 29-41.
Fine, Gil D. "Consequences of delayed treatment effects on analysis of time-to-event 
endpoints." Drug Information Journal41.4 (2007): 535-539.
Gordon Lan, K. K., and David L. DeMets. "Discrete sequential boundaries for clinical 
trials." Biometrika 70.3 (1983): 659-663.
Lewis, Steff, and Mike Clarke. "Forest plots: trying to see the wood and the trees." BMJ: 
British Medical Journal 322.7300 (2001): 1479.


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.
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Appendix 1
Protocol Synopsis
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED 
STUDY OF ATEZOLIZUMAB (ANTIPD-L1 ANTIBODY) VERSUS 
OBSERVATION AS ADJUVANT THERAPY IN PATIENTS WITH 
HIGH-RISK MUSCLE-INVASIVE UROTHELIAL CARCINOMA 
AFTER SURGICAL RESECTION
PROTOCOL NUMBER:
WO29636
VERSION NUMBER:
8
EUDRACT NUMBER:
2014-005603-25
IND NUMBER:
120827
TEST PRODUCT:
Atezolizumab (MPDL3280A; RO5541267)
PHASE:
III
INDICATION:
Muscle-invasive urothelial carcinoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives: 
The primary efficacy objective for this study is as follows: 

To evaluate the efficacy of adjuvant atezolizumab treatment in patients with 
muscle-invasive urothelial carcinoma (UC) as measured by disease-free survival (DFS)
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by overall 
survival (OS)

To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by 
disease-specific survival (DSS)


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
To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by distant 
metastasis-free survival (DMFS)

To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by non-urinary 
tract recurrence-free survival (NURFS)
Safety Objectives 
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of atezolizumab in the adjuvant setting

To evaluate the incidence of anti-therapeutic antibodies (ATAs) against atezolizumab and to 
explore the potential relationship of the immunogenicity response with pharmacokinetics, 
safety, and efficacy
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is as follows:

To characterize the pharmacokinetics of atezolizumab
Patient-Reported Outcome Objective
The patient-reported outcome (PRO) objective for this study is as follows:

To assess health status as measured by the EuroQol 5-dimension, 5-level version 
(EQ-5D-5L) questionnaire
Exploratory Objective
The exploratory objective for this study is as follows:

To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival 
and/or fresh tumor tissue and blood and their association with disease recurrence
Study Design
Description of Study 
Study WO29636 is a global Phase III, open-label, randomized, controlled trial designed to 
evaluate the efficacy and safety of adjuvant treatment with atezolizumab compared with 
observation in patients with muscle-invasive UC, who are at high risk for recurrence following 
resection. 
Male and female patients aged 18 years with Eastern Cooperative Oncology Group (ECOG)
performance status 2 who have histologically confirmed muscle-invasive UC (also termed 
TCC) of the bladder or upper urinary tract (i.e., renal pelvis or ureters) are eligible.  Patients with 
upper urinary tract urothelial carcinoma (UTUC) will be limited to no more than approximately 10% 
of the study population.
Patients with bladder as the site of primary involvement must have undergone radical 
cystectomy with lymph node dissection.  Patients with UTUC as the site of primary involvement 
must have undergone radical nephroureterectomy (RNU) with excision of the bladder cuff 
regardless of the location of the tumor in the upper urinary tract.  RNU must include lymph node 
dissection.
Patients who have received prior neoadjuvant chemotherapy are eligible, but must have tumor 
staging of ypT24a or ypN+ (ypT2-4 or ypN+ for patients with UTUC) and M0 at pathological 
examination of the surgical resection specimen.  Patients who have not received prior 
neoadjuvant chemotherapy must be ineligible for or declined treatment with cisplatin-based 
adjuvant chemotherapy and have tumor staging of pT34a or pN+ (pT3-4 or pN+ for patients 
with muscle-invasive UTUC) and M0.
Tumor specimens from surgical resection (i.e., radical cystectomy, RNU, or lymph node 
dissection) from patients who have signed the Informed Consent Form will be evaluated for 
PD-L1 expression by IHC.  Only patients whose tumors have sufficient amounts of viable tumor 
and are evaluable for PD-L1 expression as confirmed by a central pathology laboratory prior to 
enrollment of the patient in the study will be eligible.


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Patients will be randomized to one of the following arms in a 1:1 ratio:

Arm A (experimental arm):  atezolizumab 1200 mg q3w 

Arm B (control arm):  observation
Randomization will be stratified by the following factors:

Number of lymph nodes resected (10 vs. 10)

Nodal status (positive vs. negative)  

Tumor stage after surgical resection (pT2 vs. pT3/pT4)

PD-L1 IHC status (IHC score of IC0/1 vs. IHC score of IC2/3)

Prior neoadjuvant chemotherapy (yes vs. no) 
Randomization must occur within 14 weeks after surgical resection of the primary tumor and 
study drug administration should begin within 7 calendar days after randomization. 
For patients in Arm A, atezolizumab will be administered intravenously (IV) on Day 1 of each 
21-day cycle for 16 cycles (up to 1 year).  In Arm B, patients will continually undergo 
observation starting on Day 1 of each 21-day cycle for 16 cycles (up to 1 year).  
Treatment/observation will be discontinued in the event of disease recurrence, unacceptable 
toxicity, withdrawal of consent, or study termination by the Sponsor.
To ensure the same frequency of study assessments between the treatment arms, including 
assessments for disease recurrence and safety, patients in Arm B will be required to undergo 
q3w medical contacts for assessments during the first year, which will consist of formal clinic 
visits alternating with clinical contacts (either via telephone call or formal outpatient clinic visit) 
for symptom and adverse event assessment.  
Patients in the control arm will not be allowed to cross over to receive atezolizumab treatment 
within this study.
All patients will undergo scheduled assessments for tumor recurrence at baseline and every 
12 weeks (approximately every 4 cycles) in the first year following randomization.  Upon 
completion of the treatment/observation period, surveillance for tumor recurrence will be 
performed every 12 weeks for Years 23; every 24 weeks for Years 45; and at Year 6 
(approximately 48 weeks after the last assessment in Year 5).  In the absence of a DFS event 
(defined as any of the following:  local [pelvic] recurrence of UC; upper urinary tract or urethral 
recurrence of UC; distant metastasis of UC; or death from any cause), surveillance for tumor 
recurrence should continue regardless of whether patients start new anticancer therapy, until 
withdrawal of consent, loss to follow-up, or study termination by the Sponsor, whichever occurs 
first.  For patients with muscle-invasive bladder cancer (MIBC), surveillance for tumor 
recurrence will include physical examination, laboratory evaluation, and imaging studies of the 
chest, abdomen, upper urinary tracts, and pelvis.  Disease recurrence will be as determined by 
the investigator based on radiographic evidence (visual appearance of UC with histological 
confirmation is acceptable for recurrence in bladder).  For patients with UTUC, surveillance for 
tumor recurrence must include physical examination, cystoscopy, urine cytology and imaging 
studies of the chest, abdomen, and pelvis.   A confirmatory tumor biopsy is mandatory at the 
time of disease recurrence.  Cases for which biopsy results definitively rule out recurrence of 
UC will not be considered as disease recurrence for this study.  
Safety assessments will include the incidence, nature, and severity of adverse events, changes 
in vital signs, and laboratory abnormalities graded per National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0.  Serum samples will be 
collected to monitor atezolizumab pharmacokinetics and to detect the presence of ATAs to 
atezolizumab.  A sample of archived tumor tissues, as well as serum and plasma samples, will 
be collected for future exploratory biomarker assessments.
An external independent Data Monitoring Committee (iDMC) will evaluate safety data according 
to policies and procedures detailed in an iDMC Charter.
Number of Patients 
Approximately 800 patients will be enrolled in the study.  


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Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Ability to comply with protocol

Age 18 years

Histologically confirmed muscle-invasive UC (also termed TCC) of the bladder or upper 
urinary tract (i.e., renal pelvis or ureters)
Patients with mixed histologies are required to have a dominant transitional cell pattern.

TNM classification (UICC/AJCC 7th edition) at pathological examination of surgical 
resection specimen as follows: 
For patients treated with prior neoadjuvant chemotherapy:  tumor stage of ypT2 -4a or ypN+ 
(ypT2-4 or ypN+ for patients with UTUC) and M0
For patients who have not received prior neoadjuvant chemotherapy:  tumor stage of pT34a or 
pN+ (pT3-4 or pN+ for patients with UTUC) and M0

Surgical resection of muscle-invasive UC of the bladder, or UTUC upper tract
For patients with MIBC, radical cystectomy may be performed by the open, laparoscopic, or 
robotic approach.  Cystectomy must include bilateral lymph node dissection, the extent of which 
will be at the discretion of the treating surgeon but optimally should extend at a minimum from 
the mid common iliac artery proximally to Cooper's ligament distally, laterally to the 
genitofemoral nerve, and inferiorly to the obturator nerve.  The method of urinary diversion for 
patients undergoing cystectomy will be at the discretion of the surgeon and choice of the patient.
Patients with a negative surgical margin (i.e., R0 resection) or with carcinoma in situ (CIS) at the 
distal ureteral or urethral margin will be eligible.
Patients with a positive R2 margin (which is defined as a tumor identified at the inked 
perivesical fat margin surrounding the cystectomy specimen) or R1 margin (which is defined as 
evidence of microscopic disease identified at the tumor margin), except for CIS at the distal 
ureteral or urethral margin, will be excluded.
For patients with UTUC, RNU with excision of the bladder cuff is required and may be 
performed by the open or laparoscopic approach.  RNU must include lymph node dissection 
(LND), the extent of which will be at the discretion of the treating surgeon but optimally should 
include the para-aortic, paracaval or interaortocaval nodes from the renal hilum to the inferior 
mesenteric artery in renal pelvis and proximally ureteral tumors, or nodes from the renal hilum 
to the bifurcation of the common iliac artery and ipsilateral pelvic nodes in mid and lower 
ureteral tumors, respectively. 
Patients must have a negative surgical margin (i.e., R0 resection).  Patients with a positive R1 
or R2 surgical margin will be excluded.

Patients who have not received prior platinum-based neoadjuvant chemotherapy, have 
refused, or are ineligible (“unfit”) for cisplatin-based adjuvant chemotherapy
Patients who have received at least two cycles of a platinum-containing regimen will be 
considered as those who have received prior neoadjuvant chemotherapy.
Cisplatin ineligibility is defined by any one of the following criteria:
Impaired renal function (glomerular filtration rate [GFR] 60 mL/min); GFR should be assessed 
by direct measurement (i.e., creatinine clearance or ethyldediaminetetra-acetate) or, if not 
available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula)
A hearing loss (measured by audiometry) of 25 dB at two contiguous frequencies
Grade 2 or greater peripheral neuropathy (i.e., sensory alteration or parasthesis including 
tingling)
ECOG performance status of 2 


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
Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens from surgical 
resection (i.e., radical cystectomy, nephroureterectomy, or lymph node dissection) in 
paraffin blocks (blocks preferred) or at least 15 unstained slides, with an associated 
pathology report, for central testing and determined to be evaluable for tumor PD-L1 
expression prior to study enrollment 
Patients with fewer than 15 unstained slides available at baseline (but no fewer than 10) may be 
eligible following discussion with Medical Monitor.
Tumor tissue should be of good quality based on total and viable tumor content.  Fine-needle 
aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are 
not acceptable.  For core-needle biopsy specimens, at least three cores should be submitted for 
evaluation.
Tumor tissue of bladder or upper tract should be of good quality based on total and viable tumor 
content and must contain a muscle invasive component (i.e. T2 or greater) of the tumor as 
verified by local pathology review.  Fine-needle aspiration, brushing, cell pellet from pleural 
effusion, bone metastases, and lavage samples are not acceptable.  For core-needle biopsy 
specimens, at least three cores should be submitted for evaluation.In situations where multiple 
specimens were received from different sites or at different times, the score from the surgical 
resection of the primary tumor or lymph node dissection specimen will be used for both primary 
and secondary analyses.

Muscle-invasive UC with PD-L1 expression per IHC prospectively determined on the 
surgical resection or lymph node dissection tumor specimens by a central laboratory

Absence of residual disease and absence of metastasis, as confirmed by a negative 
baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan of the 
pelvis, abdomen, and chest no more than 4 weeks prior to randomization.
For patients with MIBC, imaging of the upper urinary tracts must include one or more of the 
following:  intravenous pyelogram (IVP), CT urography, renal ultrasound with retrograde 
pyelogram, ureteroscopy or MRI urogram, and must be completed no more than 4 weeks prior 
to randomization.
For patients with UTUC, cystoscopy and urine cytology must be completed no more than 4 
weeks prior to randomization, however upper tract imaging is not needed.
Other examinations should be performed as clinically indicated.
For patients with both primary MIBC and primary UTUC, imaging of the upper urinary tracts, 
cystoscopy, and urine cytology is not required.

Full recovery from cystectomy or nephroureterectomy within 14 weeks following surgery

ECOG performance status of 2

Life expectancy 12 weeks

Adequate hematologic and end-organ function, as defined by the following laboratory 
results obtained within 14 days prior to the first study treatment:
ANC 1500 cells/L (without granulocyte colonystimulating factor support within 2 weeks prior 
to Cycle 1, Day 1)
WBC counts 2500/L 
Lymphocyte count 300/L
Platelet count 100,000/L (without transfusion within 2 weeks prior to Cycle 1, Day 1)
Hemoglobin 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet this criterion.
AST, ALT, and alkaline phosphatase 2.5 the upper limit of normal (ULN)
Serum bilirubin 1.0 ULN
Patients with known Gilbert disease who have serum bilirubin level 3 ULN may be enrolled.
PTT/PT 1.5 ULN or INR 1.7 ULN
This applies only to patients who are not receiving therapeutic anticoagulation; patients 
receiving therapeutic anticoagulation should be on a stable dose.


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Calculated creatinine clearance 20 mL/min (Cockcroft-Gault formula)

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, and agreement to refrain from donating eggs during this same period
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached 
a postmenopausal state (12 continuous months of amenorrhea with no identified cause other 
than menopause), and has not undergone surgical sterilization (removal of ovaries and/or 
uterus).
Examples of 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:
Cancer-Specific Exclusion Criteria:

Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 
3 weeks prior to initiation of study treatment
Hormone-replacement therapy or oral contraceptives are allowed.

Adjuvant chemotherapy or radiation therapy for UC following surgical resection
Patients who have received primary chemoradiation for bladder preservation before cystectomy 
are eligible and will be treated as the same as patients who have received prior neoadjuvant 
chemotherapy.
Postsurgical intrapelvic/intravesical chemotherapy or BCG is not allowed for patients with UTUC.

Treatment with any other investigational agent or participation in another clinical trial with 
therapeutic intent within 28 days or five half-lives of the drug, whichever is longer, prior to 
enrollment

Malignancies other than UC within 5 years prior to Cycle 1, Day 1
Patients with high risk UTUC (defined as tumor stage ypT24a or ypN+) within 5 years prior to 
Cycle 1 Day 1 will be ineligible after the UTUC limit of approximately 10% has been met. 
Patients with localized low risk prostate cancer (defined as Stage T2b, Gleason score7, and 
PSA at prostate cancer diagnosis 20 ng/mL [if measured]) treated with curative intent and 
without prostate-specific antigen (PSA) recurrence are eligible. 
Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score 7and 
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
General Medical Exclusion Criteria:

Pregnancy or breastfeeding

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins


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
Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or 
any component of the atezolizumab formulation

History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis
Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible for this study.
Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen may be 
eligible for this study.

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Serum albumin 2.5 g/dL

Positive test for HIV

Patients with active hepatitis B virus (HBV; chronic or acute; defined as having a positive 
hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C
Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis 
B core antibody [HBc Ab] and absence of HBsAg) are eligible.  HBV DNA must be obtained in 
these patients prior to Cycle 1, Day 1.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV RNA.

Active tuberculosis

Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia
Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1

Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to 
prevent chronic obstructive pulmonary disease exacerbation) are eligible.

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction within the previous 3 months, unstable 
arrhythmias, or unstable angina
Patients with known coronary artery disease, congestive heart failure not meeting the above 
criteria, 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.

Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1 or 
anticipation of need for a major surgical procedure during the course of the study

Prior allogeneic stem cell or solid organ transplant

Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or 
anticipation that such a live, attenuated vaccine will be required during the study
Influenza vaccination should be given during influenza season only (approximately October 
through May in the Northern Hemisphere and approximately April through September in the 
Southern Hemisphere).  Patients must agree not to receive live, attenuated influenza vaccine 
(e.g., FluMist®) within 28 days prior to randomization, during treatment or within 5 months 
following the last dose of atezolizumab (for patients randomized to atezolizumab).

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications


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Medication-Related Exclusion Criteria:

Prior treatment with CD137 agonists or immune checkpointblockade therapies, including 
anti-CD40, antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies

Treatment with systemic immunostimulatory agents (including but not limited to interferons, 
IL-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, 
Day 1

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 [anti-TNF] agents) within 2 weeks 
prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive 
medications during the trial
Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a 
one-time dose of dexamethasone for nausea, multiple doses for contrast allergy) may be 
enrolled in the study. 
The use of inhaled or low-dose (e.g., ≤ 10 mg/day prednisone) corticosteroids for chronic 
obstructive pulmonary disease (COPD) or asthma, and mineralocorticoids (e.g., fludrocortisone 
for adrenal insufficiency) and low-dose corticosteroids for patients with orthostatic hypotension 
or adrenocortical insufficiency is allowed.
End of Study 
The end of the study as planned will occur when the required number of events for the final 
analysis of OS has occurred (projected to be approximately Month 95 from FPI).  However, the 
Sponsor may decide to terminate the study at any time.
Length of Study
The study is expected to last approximately 8 years after the first patient is randomized.
Outcome Measures
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is as follows: 

Investigator-assessed DFS, defined as the time from randomization to the time of first 
occurrence of a DFS event, defined as any of the following:
Local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes)
Urinary tract recurrence of UC (including all pathological stages and grades)
Distant metastasis of UC 
Death from any cause
The secondary efficacy outcome measures for this study are as follows: 

OS, defined as the time from randomization to the date of death from any cause

DSS, defined as the time from randomization to the date of death from UC per investigator 
assessment of cause of death

DMFS, defined as the time from randomization to the date of diagnosis of distant 
(i.e., non-locoregional) metastases or death from any cause

NURFS, defined as the time from randomization to the time of first occurrence of a NURFS 
event, defined as any of the following:
Local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes)
Distant metastasis of UC
Death from any cause
Safety Outcome Measures 
The safety outcome measures for this study are as follows:

Incidence, nature, and severity of adverse events graded according to NCI CTCAE v4.0


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
Changes in vital signs and clinical laboratory results

Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows:

Maximum observed serum atezolizumab concentration (Cmax) after infusion on Day 1 of 
Cycle 1

Minimum observed serum atezolizumab concentration (Cmin) prior to infusion on Day 1 of 
Cycles 1, 2, 3, and 4; every 8 cycles starting on Cycle 8; at treatment discontinuation; and 
at 120 days (30 days) after the last dose of atezolizumab
Patient-Reported Outcome Measure 
The PRO outcome measure for this study is as follows:

EQ-5D-5L as a measure of patient-reported health status
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows:

Status of tumor immune-related or disease type−related exploratory biomarkers in archival 
and/or freshly obtained tumor tissues and association with disease recurrence

Status of exploratory biomarkers in plasma, whole blood, or serum (including but not limited 
to cytokines such as IL-6) collected before or during treatment with atezolizumab or at 
recurrence and association with disease recurrence
Investigational Medicinal Products
Test Product (Investigational Drug) 
The dose level of atezolizumab to be tested in this study is 1200 mg (equivalent to an average 
body weightbased dose of 15 mg/kg) administered by IV infusion every 3 weeks (21 [3] days) 
for 16 cycles or 1 year (whichever occurs first). 
Statistical Methods
Primary Analysis 
The primary efficacy endpoint is investigator-assessed DFS, defined as the time from 
randomization to the time of first occurrence of a DFS event, defined as any of the following: 
local (pelvic) recurrence of UC; urinary tract recurrence of UC; distant metastasis of UC; or 
death from any cause.  Data for patients without a DFS event will be censored at the last date 
the patient was assessed to be alive and recurrence free as determined with radiographic 
evidence.  Data for patients with no post-baseline disease assessment will be censored at the 
randomization date.
For United States registrational purposes, the primary efficacy endpoint of DFS will be defined 
as described above with an additional censoring rule for missed visits.  Data for patients with a 
DFS event who missed two or more scheduled assessments immediately prior to the DFS event 
will be censored at the last tumor assessment as determined with radiographic evidence prior to 
the missed visits.  Type I error control will be applied to this analysis of DFS.  
DFS will be analyzed in the ITT population.  The following analyses will be performed for both 
DFS endpoints described above.  DFS will be compared between treatment arms using the 
stratified log-rank test.  The hazard ratio (HR) for recurrence or death will be estimated using a 
stratified Cox proportional hazards model and the 95% CI for the HR will be provided.  The 
stratification factors will be the same as the randomization stratification factors; however, 
stratification factors may be combined for analysis purposes if necessary to minimize small 
stratum cell sizes.  Combination of stratification factors, if any, would be specified in the 
Statistical Analysis Plan (SAP) prior to analysis.  The stratification factors will be obtained 
from the IxRS at the time of randomization.  Results from an unstratified analysis will also be 


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29/Statistical Analysis Plan WO29636
provided.  Kaplan-Meier methodology will be used to estimate median DFS for each treatment 
arm; Kaplan-Meier curves will be produced.  Brookmeyer-Crowley methodology will be used to 
construct the 95% CI for the median DFS for each treatment arm.  The DFS rate at various 
timepoints (i.e., every 6 months after randomization) will be estimated by Kaplan-Meier 
methodology for each treatment arm, and the 95% CI will be calculated using Greenwood’s 
formula.
The following additional analyses will be performed for both DFS endpoints described above:

Analyses at landmark timepoints

Subgroup analyses 
Determination of Sample Size 
Approximately 800 patients will be randomized in this study.
The type I error (alpha) for this study is 0.05 (two-sided).  Type I error will be controlled for the 
primary endpoint of DFS and the key secondary endpoint of OS.  To control the Type I error at 
alpha 0.05 (two-sided) for DFS and OS endpoints, the treatment arms will be compared in a 
hierarchical fashion as follows:  If the DFS analysis results (as defined for United States 
registrational purposes) are statistically significant at alpha 0.05 (two-sided), then the analysis 
of OS will be performed at alpha 0.05 (two-sided) and the interim analysis boundaries for OS 
will be calculated according to alpha 0.05 (two-sided).
The analysis of the primary endpoint of DFS will take place when approximately 377 DFS 
events have occurred and at least 12 months after the last patient is enrolled have elapsed.  
The estimated number of events required for the analysis is based on the following assumptions:

Two-sided log-rank test at the 0.05 significance level (two-sided)

80% power

1:1 randomization ratio

Median DFS for the control (observation) arm of 20 months and estimated median DFS in 
the atezolizumab arm of 26.7 months (corresponding to a HR of 0.75)

No interim analysis of DFS
Accrual of the planned 800 patients is projected to occur over 32 months, assuming a ramp-up 
period of 13 months to a projected accrual rate of 35 patients per month.  On the basis of these 
assumptions, and the projected probability of loss to follow-up for DFS of approximately 32% 
over 24 months after enrollment, the required number of DFS events is projected to occur at 
Month 50 from the time the first patient is randomized.  Also on the basis of these assumptions, 
it is projected that an observed HR of 0.82 or lower will result in a statistically significant 
difference between treatment arms (i.e., an HR of 0.82 will be the minimally detectable 
difference at the analysis; this corresponds to an improvement of 4.5 months in median DFS, 
from 20 months in the control [observation] arm to 24.5 months in the atezolizumab arm).
The final analysis of the secondary endpoint of OS will take place when approximately 
428 deaths have occurred on the basis of the following assumptions:

Two-sided log-rank test at the 0.05 significance level (two-sided)

80% power

1:1 randomization ratio

Median OS for the control (observation) arm of 34 months and estimated median OS in the 
atezolizumab arm of 44.7 months (corresponding to HR of 0.76)

Two interim analyses of OS
On the basis of these assumptions, the projected probability of loss to follow-up for OS of 
approximately 24% over 24 months after enrollment, and projected accrual, the required 
number of OS events for the final analysis of OS is projected to occur 95 months from the time 
the first patient is randomized.  It is projected that an observed HR of 0.82 or lower will result in 
a statistically significant difference between treatment arms (i.e., an HR of 0.82 will be the 
minimally detectable difference at the analysis; this corresponds to an improvement of 7.4 


Atezolizumab—F. Hoffmann-La Roche Ltd
30/Statistical Analysis Plan WO29636
months in median OS, from 34 months in the control [observation] arm to 41.4 months in the 
atezolizumab arm).
Two interim analyses of OS are planned.
Interim Analyses
No interim efficacy analyses of DFS are planned for this study.
A total of three analyses of OS will be performed by the Sponsor (two interim analyses and one 
final analysis).  The final analysis of OS will be performed when approximately 428 deaths (54% 
of 800 patients) have occurred in the ITT population.  On the basis of accrual projections and 
projected median OS for each treatment arm, the final analysis of OS is projected to occur 
95 months from the time the first patient is randomized.  The interim analysis boundaries for 
statistical significance at each interim analysis will be determined on the basis of the 
Lan-DeMets implementation of the O’Brien-Fleming use function.  
The first interim analysis of OS will be performed at the time of the DFS analysis.  On the basis 
of the projected median OS for each treatment arm and the projected time of the final analysis 
of DFS, it is projected that approximately 280 deaths (35% of 800 patients) will have occurred at 
the first interim analysis of OS, which corresponds to approximately 65% of the 428 deaths 
required for the final analysis of OS.  It is projected that an observed HR of 0.74 or lower will 
result in a statistically significant difference between treatment arms at this analysis. 
The second interim analysis of OS will be performed when approximately 342 deaths (43% of 
800 patients) have occurred, which corresponds to 80% of the 428 deaths required for the final 
analysis of OS.  The required number of OS events for the second interim analysis of OS is 
projected to occur 63 months from the time the first patient is randomized.  It is projected that an 
observed HR of 0.78 or lower will result in a statistically significant difference between treatment 
arms at this analysis.
The interim analyses of OS will be performed by the Sponsor.  The boundary for statistical 
significance at each interim analysis and the final analysis will be determined based on the 
Lan-DeMets implementation of the O’Brien-Fleming use function.  For example, with 0.05 
(two-sided) and using the two-sided log-rank test, if 280 deaths have occurred at the time of the 
first OS interim analysis, statistical significance will be declared p 0.011; if 342 deaths have 
occurred at the time of the second OS interim analysis, statistical significance will be declared if 
p 0.021; and if 428 deaths have occurred at the time of the final OS analysis, statistical 
significance will be declared if p 0.042.
An iDMC will be convened to evaluate safety results approximately every 6 months after 
enrollment of the first patient until the analysis of the primary endpoint (DFS).


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31/Statistical Analysis Plan WO29636
Appendix 2
Schedule of Assessments
Both Arms
Arm A (Atezolizumab)
Arm B (Observation)
Both Arms
Study Procedures
Screening for 
Randomization
All Cycles
Discon-
tinuation a
Cycles 1, 3, 5, 7, 
9, 11, 13, and 15
Cycles 2, 4, 6, 8, 
10, 12, 14, and 16
Discon-
tinuation a
Follow-Up
Days –28
to –1
Day 1
(3 Days for 
Cycles 2) b
30 Days after 
Last Dose
Day 1 
(3 Days for 
Cycles 2) b
Day 1 
(3 Days) b
30 Days 
after Last 
Visit
Signed Informed Consent Form(s) c
x
Review of eligibility criteria
x
Medical, surgical, and cancer histories, 
including demographic information d
x
Pregnancy test e
x
x
x
ECOG performance status
x
x f
x
x f
x
Age-adjusted Charlson comorbidity 
index (ACCI)
x
Complete physical examination g
x
x
x
Limited physical examination g
x f
x f
Weight
x
x
x
x
x
Height
x
Vital signs h
x
x
x
x
x
12-lead electrocardiogram i
x
x
x
HIV, HCV serology j
x
Hematology k
x
x f
x
x f
x
Serum chemistry l
x
x f
x
x f
x
Coagulation panel (aPTT, INR)
x
x
x


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32/Statistical Analysis Plan WO29636
Appendix 2
Schedule of Assessments (cont.)
Both Arms
Arm A (Atezolizumab)
Arm B (Observation)
Both Arms
Study Procedures
Screening for 
Randomization
All Cycles
Discon-
tinuation a
Cycles 1, 3, 5, 7, 
9, 11, 13, and 15
Cycles 2, 4, 6, 8, 
10, 12, 14, and 16
Discon-
tinuation a
Follow-Up
Days –28
to –1
Day 1
(3 Days for 
Cycles 2) b
30 Days after 
Last Dose
Day 1 
(3 Days for 
Cycles 2) b
Day 1 
(3 Days) b
30 Days 
after Last 
Visit
Urinalysis m
x
x n,f
x
x n
x
TSH, free T3, free T4
x
x o,f
x
Auto-antibody testing p
x
x
Serum sample for ATA assessment
See Protocol Appendix 2
Serum sample for PK sampling
See Protocol Appendix 2
Blood samples for biomarkers
See Protocol Appendix 2
Optional whole blood sample for RCR q
x q
x q
Study drug infusion r
x
Archival/screening FFPE tumor tissue 
specimen or 15 unstained slides s
x
Fresh biopsy (mandatory sample t and 
optional RCR sample u)
At the time of radiographic confirmation of disease recurrence t,u
Assessments for UC recurrence v
x
Every 12 weeks following randomization (7 days; at approximately every four cycles) in 
first 3 years; every 24 weeks (10 days) for Years 4 and 5; and at Year 6 (10 days), until 
death, disease recurrence, loss to follow-up, end of Year 6, or withdrawal of consent.
Concomitant medications w
x
x
x
x
x
x
Adverse events x
x
x
x
x
x
x
Telephone contact y
x


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33/Statistical Analysis Plan WO29636
Appendix 2
Schedule of Assessments (cont.)
Both Arms
Arm A (Atezolizumab)
Arm B (Observation)
Both Arms
Study Procedures
Screening for 
Randomization
All Cycles
Discon-
tinuation a
Cycles 1, 3, 5, 7, 
9, 11, 13, and 15
Cycles 2, 4, 6, 8, 
10, 12, 14, and 16
Discon-
tinuation a
Follow-Up
Days –28
to –1
Day 1
(3 Days for 
Cycles 2) b
30 Days after 
Last Dose
Day 1 
(3 Days for 
Cycles 2) b
Day 1 
(3 Days) b
30 Days 
after Last 
Visit
Survival and anticancer therapy 
follow-up z
x
Patient-reported outcomes aa
x bb
x
x
x
x
Note:  For Arm A, assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise noted.
a Patients will be asked to return to the clinic for a discontinuation visit not more than 30 days after the decision to discontinue treatment/observation 
early, or after the end of the one-year treatment/observation period.   
b After five cycles have been completed, one cycle may be delayed by 1 week (i.e., 28 days instead of 21 days for one cycle) for one time to allow for 
vacations.
c Written informed consent is required for performing any study-specific tests or procedures.  Written informed consent (on the main study Informed 
Consent Form) can be obtained outside the 28 days screening period prior to randomization.  Prior to signing the main consent form for the study, 
patients may specifically allow for the collection and testing of archival or fresh tumor tissue by signing the pre-screening consent form.  Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to randomization (except where 
otherwise specified) may be used for screening assessments rather than repeating such tests.
d Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment.  Demographic information includes sex, age, and self-reported 
race/ethnicity.
e 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 Cycle 1 Day 1.  Starting from Cycle 3, either serum or urine pregnancy test (positive urine test results will be 
confirmed with a serum pregnancy test) must be performed every two cycles during the study treatment, and as clinically indicated thereafter.
f ECOG performance status, limited physical examination and local/central lab assessments may be obtained 96 hours before Day 1 of each cycle.
g Complete and limited physical examinations are defined in Section 4.5.3.


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34/Statistical Analysis Plan WO29636
Appendix 2
Schedule of Assessments (cont.)
h Vital signs include heart rate, respiratory rate, blood pressures, and temperature and will be performed as standard of care if clinically indicated for 
patients randomized to the observation arm.  For patients randomized to the atezolizumab treatment arm, for the first infusions of study drug, the 
patient’s vital signs should be determined up to 60 minutes before the start of infusion, and if clinically indicated, during and 30 (10) minutes after 
the infusion.  For subsequent infusions, vital signs will be recorded if clinically indicated or if symptoms occurred in the prior infusion.  
i ECG recordings will be obtained during screening and when clinically indicated during study.  ECGs for each patient should be obtained from the 
same machine wherever possible.  ECG recordings must be performed after the patient has been resting in a supine position for at least 
10 minutes.  
j See Section 4.5.6 for serology tests.  HIV testing to be performed in accordance with national and/or institutional guidelines.  HBV DNA must be 
collected on or before Cycle 1, Day 1 in patients who have negative serology for hepatitis B surface antigen and positive serology for anti HBc.  
k Blood samples collected to monitor safety will be collected in patients randomized to both arms.  Hematology consists of CBC, including RBC count, 
hemoglobin, hematocrit, WBC count with automated differential (neutrophils, lymphocytes, eosinophils, monocytes, basophils, and other cells), and 
platelet count.  A manual differential can be done if clinically indicated. Refer to Section 4.1.1 for a list of laboratory results to be obtained within 14 
days prior to the first dose of study treatment.
l Serum chemistry includes BUN, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, total bilirubin, 
ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.  Refer to Section 4.1.1 for a list of laboratory results to be obtained within 14 days 
prior to the first dose of study treatment. 
m Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood).  
n On Day 1 of Cycle 3 and every two cycles thereafter.
o On Day 1 of Cycle 5 and every four cycles thereafter.
p Baseline sample to be collected on Cycle 1, Day 1 prior to the first dose of study treatment.  For patients who show evidence of immune mediated 
toxicity, additional samples will be collected, and all samples will be analyzed centrally.  Includes anti-nuclear antibody, anti-double stranded DNA, 
circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti neutrophil cytoplasmic antibody.  
q Whole blood for DNA isolation will be collected from patients who have consented to optional RCR sampling at baseline (pre-dose C1D1).  If, 
however, the RCR genetic blood sample is not collected during the scheduled visit, it may be collected as soon as possible (after randomization) 
during the conduct of the clinical study.
r Patients in Arm A will receive their first dose of study drug the day of randomization if possible.  If this is not possible, the first dose should occur no 
later than 7 days after randomization.  The initial dose of atezolizumab treatment will be delivered over 60 (15) minutes.  If the first infusion is well 
tolerated, all subsequent infusions may be delivered over 30 (10) minutes.  Atezolizumab treatment may be continued for a maximum of 16 cycles 
(or 12 months, whichever occurs first) until disease recurrence, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor.


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35/Statistical Analysis Plan WO29636
Appendix 2
Schedule of Assessments (cont.)
s Tumor tissue from radical surgical resection should be of good quality based on total and viable tumor content (sites will be informed if the quality of 
the submitted specimen is inadequate to determine tumor PD-L1 status). Prior to signing the main consent form for the study, patients may 
specifically allow for the collection and testing of archival or fresh tumor tissue by signing the prescreening Informed Consent Form.  After signing of 
the Informed Consent Form, retrieval and submission of archival tumor sample can occur outside the 28-day screening period.
t All patients will undergo a mandatory tumor biopsy sample collection at the time of radiographic confirmation of disease recurrence (see 
Section 4.5.5).  Acceptable samples include resections; core needle biopsies for deep tumor tissue or lymph nodes; or excisional, incisional, punch, 
or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.  For core needle biopsy specimens, at least three cores should be submitted 
for evaluation.  
u For patients who have consented to collection of optional biopsies on the Optional Collection of Samples for RCR Informed Consent Form, optional 
tumor biopsy samples may be collected by core needle or excisional/punch biopsy per investigator discretion. Optional biopsy tissue will be stored 
in the RCR.  Not applicable for sites that have not been granted approval for RCR sampling.
v Surveillance for tumor recurrence must include physical examination and imaging studies of the chest, abdomen, upper urinary tracts, and pelvis.  
Other examinations such as laboratory or urine cytology should be performed as clinically indicated.  Recurrence assessment at Year 6 will be 
performed at approximately 48 weeks after the last one in Year 5.  See Section 4.5.5 for details of assessment requirements.
w Concomitant medications include any prescription medications or over-the-counter medications.  At screening, any medications the patient has 
used within the 7 days prior to written informed consent should be documented.  At subsequent visits, changes to current medications or 
medications used since the last documentation of medications will be recorded.
x After informed consent has been obtained but prior to randomization, only serious adverse events caused by a protocol-mandated intervention 
should be reported. Upon randomization into study, patients who experience a serious adverse event or protocol-defined adverse events of special 
interest will be followed for safety for 90 days following their last dose of study drug or until they receive another anti-cancer therapy, whichever 
comes first. Patients who experience all other adverse events will be reported for patients until 30 days after the last dose of study treatment (for 
Arm A) or the last day in the observation period (approximately Day 365 for Arm B), or until initiation of another anti-cancer therapy, whichever 
occurs first. After this period, investigators should ensure any deaths, serious adverse events, or other adverse events of concern are reported if 
they are later assessed to be related to atezolizumab treatment. The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow up, or the patient withdraws consent. Every 
effort should be made to follow all serious adverse events considered to be related to atezolizumab treatment or trial-related procedures until a final 
outcome can be reported.
y This clinic contact can be either via telephone call or formal clinic visit.


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36/Statistical Analysis Plan WO29636
Appendix 2
Schedule of Assessments (cont.)
z Survival follow-up information will be recorded via telephone calls, patient medical records, and/or clinic visits approximately every 3 months 
(7 days) until death, loss to follow-up, or study termination by Roche.  All patients (irrespective of which arm they are randomized to) will be 
followed for survival and new anticancer therapy information unless the patient requests to be withdrawn from follow-up; this request must be 
documented in the source documents and signed by the investigator.  If the patient withdraws from study, the study staff may use a public 
information source (e.g., county records) to obtain information about survival status only. Patients who have completed the treatment or 
observation phase and continue in disease recurrence follow-up do not need to begin survival follow-up until a DFS event has occurred but must 
still be followed for new anti-cancer therapy.
aa The PRO questionnaire EQ-5D-5L will be completed by the patients at the investigational site.  All PRO questionnaires are required to be 
administered prior to administration of study treatment (Arm A) and/or prior to any other study assessment(s) to ensure that the validity of the 
instrument is not compromised and to ensure that data quality meets regulatory requirements.  Study personnel should review all questionnaires for 
completeness before the patient leaves the investigational site, and the hard copy originals of the questionnaires must be maintained as part of the 
patient’s medical record when relevant at the site for source data verification.  After discontinuation of the treatment/observation period, for patients 
who have not experienced disease recurrence, the EQ-5D-5L will be administered at the same schedule as the assessments for disease 
recurrence (see Section 4.5.5).  The EQ-5D-5L will also be recorded at 6, 12, and 24 weeks after disease recurrence per telephone interview by 
trained site staff and in compliance with best practices and recommendations by EuroQol.  Study personnel will record patient responses on a 
paper copy of the EQ-5D-5L during the telephone interview as record of source documentation.
bb Odd-numbered cycles only (i.e., Cycles 1, 3, 5, 7, 9, 11, 13, and 15).