Clinical trial NCT02302807
Conditions: Bladder Cancer
Sponsor: Hoffmann-La Roche
Start date: 2015-01-13; Completion date: 2018-11-08
Enrollment: 931 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase III, global, multicenter, open-label, two-arm, randomized, controlled study designed to evaluate the efficacy and safety of atezolizumab compared with chemotherapy in participants with locally advanced or metastatic urothelial bladder cancer (UBC) who have progressed during or following a platinum-containing regimen. The anticipated time on study treatment is based on continued clinical benefit, i.e., until disease progression or unacceptable toxicity. The target sample size is 931 participants.

Detailed description:

Arms: arm 1: Atezolizumab will be administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants will receive atezolizumab as long as they continue to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator. arm 2: Participants randomized to the chemotherapy arm will receive vinflunine, paclitaxel, or docetaxel per the investigator's choice. Vinflunine 320 milligrams per square meter (mg/m\^2), paclitaxel 175 mg/m\^2, or docetaxel 75 mg/m\^2 will be administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.
Interventions: intervention 1: Atezolizumab (MPDL3280A) [TECENTRIQ], an engineered anti-PDL1 antibody intervention 2: Docetaxel intervention 3: Paclitaxel intervention 4: Vinflunine
Intervention descriptions: intervention 1: Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle. intervention 2: Docetaxel 75 mg/m\^2 will be administered intravenously on Day 1 of each 21-day cycle. intervention 3: Paclitaxel 175 mg/m\^2 will be administered intravenously on Day 1 of each 21-day cycle. intervention 4: Vinflunine 320 mg/m\^2 will be administered intravenously on Day 1 of each 21-day cycle.

Protocol documents:
Prot_SAP_001.pdf: 
 
Official Title: 
 
A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED 
STUDY TO INVESTIGATE THE EFFICACY AND SAFETY 
OF ATEZOLIZUMAB (ANTI−PD-L1 ANTIBODY) 
COMPARED WITH CHEMOTHERAPY IN PATIENTS WITH 
LOCALLY ADVANCED OR METASTATIC UROTHELIAL 
BLADDER CANCER AFTER FAILURE WITH PLATINUM 
CONTAINING CHEMOTHERAPY 
NCT Number: 
NCT02302807 
Document Dates: 
Protocol Amendment/Version 8: 01-Mar-2018 
SAP Version 1: 03-Aug-2016  
 
 
 


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 GO29294, Version 8
A PROTOCOL
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED 
STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB (ANTIPD-L1 ANTIBODY) COMPARED WITH 
CHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED 
OR METASTATIC UROTHELIAL BLADDER CANCER AFTER 
FAILURE WITH PLATINUM-CONTAINING CHEMOTHERAPY
PROTOCOL NUMBER:
GO29294
VERSION NUMBER:
8
EUDRACT NUMBER:
2014-003231-19
IND NUMBER:
120827
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D. 
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  5 September 2014
DATES AMENDED:
Version 2:  14 January 2015
Version 3:  26 March 2015 
Version 4:  21 September 2015
Version 5:  8 March 2016
Version 6:  21 June 2016
Version 7:  28 October 2016
Version 8:  See electronic date stamp below.
 
01-Mar-2018 22:03:46
Title
Approver's Name
Date and Time (UTC)


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol GO29294, Version 8
PROTOCOL AMENDMENT, VERSION 8:
RATIONALE
Protocol GO29294 has been amended to comply with the 
 
 requirement to include 
guidelines on the management of atezolizumab specific adverse events which are also 
included in the Atezolizumab Investigator's Brochure.  The resulting changes are 
summarized below:

Section 5.1.1 has been amended to align with current atezolizumab risk language.

Information regarding management of atezolizumab-specific adverse events has 
been added to Appendix 9.  Appendix 9 has been added.  (Sections 4.3.2.1, 4.4.1, 
4.5.7.5, 5.1, 5.1.4, and 5.1.5)
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Atezolizumab—F. Hoffmann-La Roche Ltd
3/Protocol GO29294, Version 8
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 28
1.1
Background on Urothelial Bladder Cancer............................. 28
1.1.1
First-Line Treatment for Urothelial Bladder 
Cancer................................................................................... 28
1.1.2
Second-Line Treatment for Urothelial Bladder 
Cancer................................................................................... 30
1.1.3
Targeted Therapy for Urothelial Bladder Cancer................... 32
1.2
Background on Atezolizumab................................................ 32
1.2.1
Summary of Nonclinical Studies............................................ 32
1.2.2
Clinical Experience with Atezolizumab .................................. 33
1.2.2.1
Ongoing Clinical Studies........................................................ 33
1.2.2.2
Clinical Safety........................................................................ 34
1.2.2.3
Clinical Activity....................................................................... 35
1.2.2.4
Clinical Pharmacokinetics and Immunogenicity..................... 37
1.3
Study Rationale and Benefit-Risk Assessment...................... 38
2.
OBJECTIVES.............................................................................................. 40
2.1
Efficacy Objectives ................................................................ 40
2.1.1
Primary Efficacy Objective..................................................... 40
2.1.2
Secondary Efficacy Objectives .............................................. 40
2.2
Safety Objectives................................................................... 40
2.3
Pharmacokinetic Objective .................................................... 40
2.4
Patient-Reported Outcome Objective .................................... 41
2.5
Exploratory Objectives........................................................... 41
3.
STUDY DESIGN......................................................................................... 41
3.1
Description of Study .............................................................. 41
3.1.1
Independent Data Monitoring Committee .............................. 45
3.2
End of Study.......................................................................... 45
3.3
Rationale for Study Design.................................................... 45
3.3.1
Rationale for Study Design.................................................... 45


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3.3.2
Rationale for Primary and Secondary Endpoints................... 45
3.3.3
Rationale for Inclusion of All Patients (All Levels 
of PD-L1 Expression by Immunohistochemistry) 
in the Study............................................................................ 46
3.3.4
Rationale for Testing Atezolizumab in Patients 
with UBC Who Have Failed Prior Platinum 
Therapy ................................................................................. 46
3.3.5
Rationale for Control Arm Therapy........................................ 47
3.3.5.1
Vinflunine............................................................................... 47
3.3.5.2
Paclitaxel or Docetaxel .......................................................... 47
3.3.6
Rationale for Stratification Factors......................................... 47
3.3.7
Rationale for Atezolizumab Dosage ...................................... 48
3.3.8
Rationale for Collection of Archival and/or 
Pre-Treatment Tumor Specimens ......................................... 49
3.3.9
Rationale for Blood Sampling for Biomarkers and 
for Collection of Optional Tumor Specimens ......................... 50
3.3.10
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 50
3.3.11
Rationale for Allowing Patients to Continue 
Atezolizumab Treatment beyond Initial 
Progression per RECIST v1.1 ............................................... 50
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 .................................................... 51
3.4.3
Pharmacokinetic Outcome Measures.................................... 51
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
4.1.2.1
Cancer-Specific Exclusions ................................................... 56
4.1.2.2
General Medical Exclusions .................................................. 58


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4.1.2.3
Exclusion Criteria Related to Paclitaxel ................................. 58
4.1.2.4
Exclusion Criteria Related to Docetaxel ................................ 58
4.1.2.5
Exclusion Criteria Related to Vinflunine................................. 59
4.1.2.6
Exclusion Criteria Related to Atezolizumab........................... 59
4.2
Method of Treatment Assignment and Blinding..................... 61
4.3
Study Treatment.................................................................... 61
4.3.1
Formulation, Packaging, and Handling.................................. 61
4.3.1.1
Atezolizumab......................................................................... 61
4.3.1.2
Vinflunine, Paclitaxel, and Docetaxel..................................... 62
4.3.2
Dosage, Administration, and Compliance.............................. 62
4.3.2.1
Atezolizumab......................................................................... 62
4.3.2.2
Paclitaxel ............................................................................... 63
4.3.2.3
Docetaxel............................................................................... 63
4.3.2.4
Vinflunine............................................................................... 63
4.3.3
Investigational Medicinal Product Accountability ................... 64
4.3.4
Post-Trial Access to Atezolizumab ........................................ 64
4.4
Concomitant Therapy ............................................................ 65
4.4.1
Permitted Therapy................................................................. 65
4.4.2
Excluded Therapy.................................................................. 66
4.4.2.1
Excluded and Cautionary Therapy for 
Atezolizumab-Treated Patients.............................................. 66
4.4.3
Concomitant Medications with Paclitaxel............................... 67
4.4.4
Concomitant Medications with Docetaxel .............................. 68
4.4.5
Concomitant Medications with Vinflunine .............................. 68
4.5
Study Assessments ............................................................... 68
4.5.1
Informed Consent Forms and Screening Log........................ 69
4.5.2
Description of Study Assessments ........................................ 69
4.5.2.1
Medical History and Demographic Data ................................ 69
4.5.2.2
Physical Examinations........................................................... 69
4.5.2.3
Vital Signs.............................................................................. 69
4.5.2.4
Tumor and Response Evaluations......................................... 70
4.5.2.5
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 71


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4.5.3
Anti-Therapeutic Antibody Testing 
(Atezolizumab-Treated Patients Only)................................... 74
4.5.4
Cardiac and Pulmonary Function Tests................................. 74
4.5.4.1
Electrocardiograms................................................................ 74
4.5.5
Patient-Reported Outcomes .................................................. 75
4.5.6
Optional Biopsies and Samples for RCR 
(Optional Future Research) ................................................... 76
4.5.6.1
Overview of the Roche Clinical Repository............................ 76
4.5.6.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 76
4.5.6.3
Optional Samples for Roche Clinical Repository ................... 76
4.5.6.4
Confidentiality........................................................................ 77
4.5.6.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 78
4.5.6.6
Withdrawal from the Roche Clinical Repository..................... 78
4.5.6.7
Monitoring and Oversight....................................................... 79
4.5.7
Timing of Study Assessments ............................................... 79
4.5.7.1
Screening and Pre-Treatment Assessments ......................... 79
4.5.7.2
Assessments during Treatment............................................. 79
4.5.7.3
Assessments at Treatment Discontinuation Visit................... 80
4.5.7.4
Follow-Up Assessments ........................................................ 80
4.5.7.5
Adverse Events ..................................................................... 81
4.5.7.6
Anti-Therapeutic Antibody and Pharmacokinetic 
Assessments ......................................................................... 81
4.5.7.7
Survival and Subsequent Anti-Cancer Therapy..................... 81
4.6
Patient, Study, and Site Discontinuation................................ 81
4.6.1
Patient Discontinuation.......................................................... 81
4.6.1.1
Discontinuation from Study Drug........................................... 82
4.6.2
Study and Site Discontinuation.............................................. 83
5.
ASSESSMENT OF SAFETY....................................................................... 84
5.1
Safety Plan ............................................................................ 84
5.1.1
Risks Associated with Atezolizumab ..................................... 84
5.1.2
Risks Associated with Vinflunine, Paclitaxel, and 
Docetaxel............................................................................... 84


Atezolizumab—F. Hoffmann-La Roche Ltd
7/Protocol GO29294, Version 8
5.1.3
General Plan to Manage Safety Concerns ............................ 85
5.1.3.1
Eligibility Criteria .................................................................... 85
5.1.3.2
Monitoring.............................................................................. 85
5.1.4
Atezolizumab Dose Modification............................................ 85
5.1.5
Management of Atezolizumab-Specific Adverse 
Events.................................................................................... 86
5.1.5.1
Systemic Immune Activation.................................................. 87
5.1.6
Paclitaxel Dose Modification and Management of 
Specific Adverse Events........................................................ 87
5.1.7
Docetaxel Dose Modification and Management of 
Specific Adverse Events........................................................ 88
5.1.7.1
Other Specific Toxicities Not Requiring Dose 
Adjustment............................................................................. 89
5.1.8
Vinflunine Dose Modification and Management of 
Specific Adverse Events........................................................ 90
5.2
Safety Parameters and Definitions ........................................ 93
5.2.1
Adverse Events ..................................................................... 93
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 93
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 94
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 95
5.3.1
Adverse Event Reporting Period ........................................... 95
5.3.2
Eliciting Adverse Event Information....................................... 96
5.3.3
Assessment of Severity of Adverse Events ........................... 96
5.3.4
Assessment of Causality of Adverse Events ......................... 96
5.3.5
Procedures for Recording Adverse Events............................ 97
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 97
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 97
5.3.5.3
Persistent or Recurrent Adverse Events................................ 98
5.3.5.4
Abnormal Laboratory Values ................................................. 98
5.3.5.5
Abnormal Vital Sign Values ................................................... 99
5.3.5.6
Deaths ................................................................................... 99
5.3.5.7
Preexisting Medical Conditions............................................ 100


Atezolizumab—F. Hoffmann-La Roche Ltd
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5.3.5.8
Worsening of Urothelial Bladder Cancer.............................. 100
5.3.5.9
Hospitalization or Prolonged Hospitalization........................ 100
5.3.5.10
Adverse Events Associated with an Overdoses or 
Error in Drug Administration ................................................ 101
5.3.5.11
Patient-Reported Outcome Data ......................................... 101
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 101
5.4.1
Emergency Medical Contacts.............................................. 102
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 102
5.4.2.1
Events that Occur prior to Study Drug Initiation................... 102
5.4.2.2
Events that Occur after Study Drug Initiation....................... 103
5.4.3
Reporting Requirements for Pregnancies............................ 103
5.4.3.1
Pregnancies in Female Patients.......................................... 103
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 104
5.4.3.3
Abortions ............................................................................. 104
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 104
5.5
Follow-Up of Patients after Adverse Events ........................ 104
5.5.1
Investigator Follow-Up......................................................... 104
5.5.2
Sponsor Follow-Up .............................................................. 105
5.6
Adverse Events that Occur After the Adverse 
Event Reporting Period........................................................ 105
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 105
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 106
6.1
Determination of Sample Size ............................................. 106
6.2
Analyses Timing .................................................................. 107
6.3
Summaries of Conduct of Study.......................................... 107
6.4
Summaries of Treatment Group Comparability ................... 107
6.5
Efficacy Analyses ................................................................ 107
6.5.1
Primary Efficacy Endpoint.................................................... 107
6.5.2
Secondary Efficacy Endpoints............................................. 108
6.5.2.1
Objective Response Rate.................................................... 109


Atezolizumab—F. Hoffmann-La Roche Ltd
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6.5.2.2
Progression-Free Survival ................................................... 109
6.5.2.3
Duration of Objective Response.......................................... 109
6.5.3
Handling of Missing Data..................................................... 110
6.6
Safety Analyses................................................................... 110
6.7
Pharmacokinetic Analyses................................................... 111
6.8
Outcome Analyses .............................................................. 111
6.9
Exploratory Analyses........................................................... 112
6.10
Sensitivity Analyses............................................................. 112
6.10.1
Loss to Follow-Up................................................................ 112
6.10.2
Subsequent Anti-Cancer Therapy ....................................... 113
6.11
Subgroup Analysis............................................................... 113
6.12
Interim Analyses .................................................................. 113
7.
DATA COLLECTION AND MANAGEMENT ............................................. 113
7.1
Data Quality Assurance....................................................... 113
7.2
Electronic Case Report Forms............................................. 114
7.3
Source Data Documentation................................................ 114
7.4
Use of Computerized Systems ............................................ 114
7.5
Retention of Records........................................................... 115
8.
ETHICAL CONSIDERATIONS.................................................................. 115
8.1
Compliance with Laws and Regulations .............................. 115
8.2
Informed Consent................................................................ 115
8.3
Institutional Review Board or Ethics Committee.................. 116
8.4
Confidentiality...................................................................... 117
8.5
Financial Disclosure ............................................................ 117
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 117
9.1
Study Documentation .......................................................... 117
9.2
Protocol Deviations.............................................................. 118
9.3
Site Inspections ................................................................... 118
9.4
Administrative Structure....................................................... 118
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 118
9.6
Protocol Amendment Sections ............................................ 119


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10. REFERENCES ......................................................................................... 120
LIST OF TABLES
Table 1
Randomized Phase III Trials in Previously Untreated 
Patients....................................................................................... 30
Table 2
Randomized Phase II Trials of Second-Line Therapy................. 31
Table 3
Efficacy-Evaluable Patients with UBC Dosed by 
20 November 2013 in Study PCD4989g:  ORR per 
RECIST v1.1 by PD-L1 Tumor Expression ................................. 37
Table 4
Dose Levels for Paclitaxel........................................................... 88
Table 5
Guidelines for Management of Specific Docetaxel-Related 
Adverse Events........................................................................... 88
Table 6
Guidelines for Management of Hepatotoxicity in 
Docetaxel-Treated Patients......................................................... 89
Table 7
Guidelines for the Management of Edema in Docetaxel-
Treated Patients.......................................................................... 90
Table 8
Dose Delay Guidelines for Vinflunine.......................................... 90
Table 9
Dose Modification Guidelines for Vinflunine................................ 91
Table 10
Dose Modification Guidelines for Vinflunine in Patients with 
Renal Impairment or Elderly Patients.......................................... 92
Table 11
Adverse Event Severity Grading Scale ....................................... 96
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 42
Figure 2
Conditions for Continuing Atezolizumab in the Presence of 
Increased Radiographic Tumor Size........................................... 83
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 125
Appendix 2
Anti-Therapeutic Antibody, Pharmacodynamic, 
and Pharmacokinetic Sampling Schedule................................. 132
Appendix 3
Modified Response Evaluation Criteria in Solid Tumors ........... 133
Appendix 4
Response Evaluation Criteria in Solid Tumors:  Modified 
Excerpt from Original Publication.............................................. 141
Appendix 5
Patient-Reported Outcomes Instruments.................................. 153
Appendix 6
Preexisting Autoimmune Diseases ........................................... 157


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Appendix 7
Anaphylaxis Precautions........................................................... 158
Appendix 8
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 159
Appendix 9
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 160


Atezolizumab—F. Hoffmann-La Roche Ltd
12/Protocol GO29294, Version 8
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB 
(ANTIPD-L1 ANTIBODY) COMPARED WITH 
CHEMOTHERAPY IN PATIENTS WITH LOCALLY 
ADVANCED OR METASTATIC UROTHELIAL 
BLADDER CANCER AFTER FAILURE WITH 
PLATINUM-CONTAINING CHEMOTHERAPY
PROTOCOL NUMBER:
GO29294
VERSION NUMBER:
8
EUDRACT NUMBER:
2014-003231-19
IND NUMBER:
120827
TEST PRODUCT:
Atezolizumab (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 retain the signed original of this form for your study files.  Please return a copy of 
this form to the Sponsors or their designee.  Contact details will be provided to the 
investigator prior to study start.  


Atezolizumab—F. Hoffmann-La Roche Ltd
13/Protocol GO29294, Version 8
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED 
STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB (ANTIPD-L1 ANTIBODY) COMPARED WITH 
CHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED OR 
METASTATIC UROTHELIAL BLADDER CANCER AFTER 
FAILURE WITH PLATINUM-CONTAINING CHEMOTHERAPY
PROTOCOL NUMBER:
GO29294
VERSION NUMBER:
8
EUDRACT NUMBER:
2014-003231-19
IND NUMBER:
120827
TEST PRODUCT:
Atezolizumab (RO5541267)
PHASE:
III
INDICATION:
Urothelial bladder cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives
For the primary and secondary efficacy objectives, a comparison of the treatment arms will be 
performed in different patient subpopulations according to tumor PD-L1 expression as 
evaluated by immunohistochemistry (IHC).  The IHC scores will have three categories (IC0, IC1, 
and IC2/3), which will also be used for stratification (IHC score of IC0/1 vs. IHC score of IC2/3).
Primary Efficacy Objective
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of atezolizumab treatment compared with chemotherapy treatment 
with respect to overall survival (OS) in patients with locally advanced or metastatic urothelial 
bladder cancer (UBC) who have progressed during or following a platinum-containing 
regimen
Secondary Efficacy Objectives
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of atezolizumab compared with chemotherapy with respect to 
anti-tumor effects as measured by objective response rate (ORR) per investigator with use 
of Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)

To evaluate the efficacy of atezolizumab compared with chemotherapy with respect to 
anti-tumor effects as measured by progression-free survival (PFS) per investigator with use 
of RECIST v1.1

To evaluate the efficacy of atezolizumab compared with chemotherapy with respect to 
anti-tumor effects as measured by duration of objective response (DOR) per RECIST v1.1
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of atezolizumab compared with chemotherapy


AtezolizumabF. Hoffmann-La Roche Ltd
14/Protocol GO29294, Version 8

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 in patients with locally advanced or 
metastatic UBC who have progressed during or following a platinum-containing regimen
Patient-Reported Outcome Objective
The patient-reported outcome (PRO) objective for this study is as follows:

To evaluate and compare PROs of patient health-related quality of life (HRQoL) between 
treatment arms as measured by the European Organisation for Research and Treatment of 
Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30)
Exploratory Objectives
The exploratory objectives for this study are as follows:

To evaluate the efficacy of atezolizumab with respect to anti-tumor effects as measured by 
PFS, ORR, and DOR per modified RECIST

To evaluate and compare disease control rate (DCR) between the two treatment arms

To evaluate the relationship between tumor tissue programmed deathligand 1 (PD-L1) 
expression and measures of efficacy

To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival 
and/or fresh tumor tissue and blood and their association with disease status and/or 
response to study treatment

To assess health status as measured using the EuroQol 5-Dimension, 3-level version 
(EQ-5D [3L]) questionnaire for health economic modeling
Study Design
Description of Study
This is a Phase III, global, multicenter, open-label, two-arm, randomized, controlled study 
designed to evaluate the efficacy and safety of atezolizumab compared with chemotherapy in 
patients with locally advanced or metastatic UBC who have progressed during or following a 
platinum-containing regimen.  Within the chemotherapy control arm, the percentage of patients 
who are treated with a taxane (paclitaxel or docetaxel) will be capped at 40%.  Until that cap is 
reached, the selection of the specific chemotherapy (vinflunine or taxane) for patients who are 
randomized to the chemotherapy arm will be per investigator’s choice.
Male and female patients aged 18 years with Eastern Cooperative Oncology Group (ECOG)
performance status of 0 or 1 who have histologically or cytologically proven, locally advanced or 
metastatic UBC and who have experienced disease progression during or following treatment 
for advanced disease consisting of platinum-based therapy are eligible.
Patients who experience disease progression during or within 12 months following completion 
of a platinum-based adjuvant or neoadjuvant regimen will also be eligible for enrollment into the 
study. 
Patients must have received at least one platinum containing regimen (e.g., gemcitabine and 
cisplatin [GC], methotrexate, vinblastine, doxorubicin, and cisplatin [MVAC], carboplatin and 
gemcitabine [CarboGem], etc.) for locally advanced or metastatic UBC.  The maximum number 
of prior therapies in the locally advanced or metastatic setting is restricted to two.
Tumor specimens from eligible patients will be prospectively tested for PD-L1 expression by a 
central laboratory.  Both patients and investigators will be blind to the PD-L1 expression status.  
The study will enroll all patients whose tissue is evaluable for expression testing, regardless of 
PD-L1 expression status.


AtezolizumabF. Hoffmann-La Roche Ltd
15/Protocol GO29294, Version 8
This study will enroll approximately 931 patients, including a minimum of 230 patients with a 
PD-L1 IHC score of IC2/3 and a minimum of 537 patients with a PD-L1 IHC score of IC1/2/3 
(enrollment of all patients will continue to reach the minimum requirement of patients with a 
PD-L1 IHC score of IC2/3).  Patients will be randomized in a 1:1 ratio to receive either 
atezolizumab or chemotherapy (vinflunine, paclitaxel, or docetaxel; see protocol for stratification 
factors):

Arm A (experimental arm):  Atezolizumab 1200 mg every 3 weeks (q3w)

Arm B (control arm):  Vinflunine 320 mg/m2 q3w, paclitaxel 175 mg/m2 q3w, or docetaxel 
75 mg/m2 q3w
Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on Day 1 of each 
21-day cycle.  Patients will receive atezolizumab as long as they continue to experience clinical 
benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration 
attributed to disease progression (i.e., pain secondary to disease or unmanageable ascites, etc.) 
as determined by the investigator after an integrated assessment of radiographic data, biopsy 
results (if available), and clinical status.
During treatment, patients will be permitted to continue atezolizumab treatment after 
RECIST v1.1 criteria for progressive disease are met if they meet all of the following criteria:

Evidence of clinical benefit as assessed by the investigator

Absence of symptoms and signs (including worsening of laboratory values [e.g., new or 
worsening hypercalcemia]) indicating unequivocal progression of disease

No decline in ECOG performance status that can be attributed to disease progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed and stabilized by protocol-allowed medical interventions 
Patients treated with atezolizumab in whom radiographic disease progression is confirmed at a 
subsequent tumor assessment may be considered for continued study treatment at the 
discretion of the investigator if they continue to meet the criteria above.
Patients randomized to the chemotherapy arm will receive vinflunine, paclitaxel, or docetaxel 
per the investigator’s choice.  Vinflunine 320 mg/m2, paclitaxel 175 mg/m2, or docetaxel 
75 mg/m2 will be administered intravenously on Day 1 of each 21-day cycle until disease 
progression per standard RECIST v1.1 or unacceptable toxicity.
Given the unique characteristics associated with the chemotherapy arm, including toxicities 
(i.e., mucositis, neutropenia, febrile neutropenia, and alopecia) and the premedications required 
(i.e., steroid, anti-emetics, and potentially growth factor support), this will be an open-label study.
No crossover will be allowed from the control arm to the experimental arm.
Patients will undergo scheduled tumor assessment at baseline and every 9 weeks thereafter for 
54 weeks following randomization.  After 54 weeks from randomization, patients will undergo 
tumor assessment every 12 weeks until disease progression per modified RECIST or until 
treatment discontinuation (for patients who continue to receive atezolizumab following disease 
progression).  For patients randomized to the chemotherapy arm, assessments will continue 
until disease progression per RECIST v1.1, regardless of whether treatment has been 
discontinued.  In the absence of disease progression, tumor assessments should continue, 
regardless of whether patients start new anti-cancer therapy, until death, loss of follow-up, 
withdrawal of consent, or study termination by Sponsor.  Follow-up data capture, including 
subsequent anti-cancer therapies (including targeted therapies and immunotherapies), will 
continue for each patient until death, loss of follow-up, withdrawal of consent, or study 
termination by Sponsor.
For patients randomized to the atezolizumab arm, response will be assessed by the investigator 
with use of RECIST v1.1 and modified RECIST.  For patients randomized to the chemotherapy 
arm, response will be assessed by the investigator with use of RECIST v1.1 only.
Primary imaging data used for tumor assessment may be collected by the Sponsor to enable 
centralized, independent review of response endpoints if needed.


AtezolizumabF. Hoffmann-La Roche Ltd
16/Protocol GO29294, Version 8
Safety assessments will include the incidence, nature, and severity of adverse events and 
laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 4.0 (NCI CTCAE v4.0).  Laboratory safety assessments will include 
the regular monitoring of hematology and blood chemistry.  Serum samples will be collected to 
monitor atezolizumab pharmacokinetics and to detect the presence of antibodies to 
atezolizumab.  Patient samples, including archival tumor tissues, as well as serum and plasma 
and whole blood, 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
This study will enroll approximately 931 patients, including a minimum of 230 patients with a 
PD-L1 IHC score of IC2/3 and a minimum of 537 patients with a PD-L1 IHC score of IC1/2/3.
Target Population
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Ability to comply with protocol

Age 18 years

Histologically or cytologically documented locally advanced (T4b, any N; or any T, N 23) or 
metastatic (M1, Stage IV) UBC (also termed transitional cell carcinoma [TCC] or urothelial 
cell carcinoma [UCC] of the urinary tract; including renal pelvis, ureters, urinary bladder, 
and urethra)
Patients with mixed histologies are required to have a dominant transitional cell pattern.
Locally advanced bladder cancer must be inoperable on the basis of involvement of 
pelvic sidewall or adjacent viscera (clinical stage T4b) or bulky nodal metastasis 
(N2N3).

Patients with a history of treated asymptomatic CNS metastases are eligible, provided they 
meet all of the following criteria:
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, 
pons, medulla or spinal cord)
No ongoing requirement for corticosteroids as therapy for CNS disease
No stereotactic radiation within 7 days
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study 
Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases.  Following treatment, 
these patients may then be eligible without the need for an additional brain scan prior 
to enrollment [or randomization], if all other criteria are met.

Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens 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.
TURBT specimens must contain a muscle invasive component (i.e., T2 or greater) of 
the bladder tumor as verified by local pathology review.  If the TURBT specimens do 
not contain a muscle invasive component, then specimens obtained at the time of 
cystectomy/nephroureterectomy or metastatic spread (i.e., sample from a metastatic 
lesion) will be required prior to randomization.  An archival specimen, if available, 
should also be submitted.


AtezolizumabF. Hoffmann-La Roche Ltd
17/Protocol GO29294, Version 8
Patients who do not have tissue specimens meeting eligibility requirements may 
undergo a biopsy during the screening period.  Acceptable samples include core 
needle biopsies for deep tumor tissue (minimum three cores) or excisional, incisional, 
punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is 
therefore not acceptable.
Patients having additional tissue samples from procedures performed at different times 
during the course of their UBC 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.  In situations where 
multiple specimens were received from different sites or at different times, the highest 
score will be used for both primary and secondary analyses.

Disease progression during or following treatment with at least one platinum-containing 
regimen (e.g., GC, MVAC, CarboGem, etc.) for inoperable, locally advanced or metastatic 
UBC or disease recurrence
A regimen is defined as patients receiving at least two cycles of a platinum-containing 
regimen.
Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed within
12 months of treatment with a platinum-containing adjuvant/neoadjuvant regimen will 
be considered as second-line patients.
Patients may have received no more than two prior regimens of treatment (including
the required platinum-based regimen) for their advanced UBC. Patients must have 
demonstrated disease progression during or following all prior regimen(s).
Patients who have received one cycle of a platinum-containing regimen but 
discontinued because of a Grade 4 hematologic toxicity or a Grade 3/4 
non-hematologic toxicity may also be eligible.
Patients with disease progression following chemoradiotherapy must demonstrate 
progression outside the prior radiotherapy port.

ECOG performance status of 0 or 1 

Life expectancy 12 weeks

Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions should not be counted as target lesions.

Adequate hematologic and end-organ function, 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 500/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 times the upper limit of normal (ULN), with 
the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5ULN
Patients with documented liver or bone metastases:  alkaline phosphatase
5ULN
Serum bilirubin 1.0ULN
Patients with known Gilbert disease who have serum bilirubin level 3ULN may 
be enrolled.
INR and aPTT 1.5ULN


AtezolizumabF. Hoffmann-La Roche Ltd
18/Protocol GO29294, Version 8
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be on a stable dose.
Calculated creatinine clearance 30 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, 3 months after the last dose of vinflunine and 6 months from the last dose of 
paclitaxel or docetaxel.
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.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
1% per year during the treatment period and for at least 3 months after the last dose 
of vinflunine and 6 months from the last dose of paclitaxel or docetaxel.  Men must 
refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for at least 28 days after the last dose of vinflunine, paclitaxel, or 
docetaxel.
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 Exclusions

Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 
3 weeks prior to initiation of study treatment; the following exceptions are allowed:
Palliative radiotherapy for bone metastases or soft tissue lesions should be completed 
7 days prior to baseline imaging
Hormone-replacement therapy or oral contraceptives

Treatment with any other investigational agent or participation in another clinical trial with 
therapeutic intent within 28 days prior to enrollment

Active or untreated CNS metastases as determined by computed tomography (CT) or 
magnetic resonance imaging (MRI) evaluation during screening and prior radiographic 
assessments
Patients with treated asymptomatic CNS metastases are eligible, provided they meet all 
of the following criteria:
Evaluable or measurable disease outside the CNS
No metastases to midbrain, pons, medulla, cerebellum, or within 10 mm of the optic 
apparatus (optic nerves and chiasm)


AtezolizumabF. Hoffmann-La Roche Ltd
19/Protocol GO29294, Version 8
No history of intracranial or spinal cord hemorrhage
No ongoing requirement for dexamethasone as therapy for CNS disease; 
anti-convulsants at a stable dose are allowed
No evidence of significant vasogenic edema
No stereotactic radiation, whole-brain radiation or neurosurgical resection with 
4 weeks prior to Cycle 1, Day 1
Radiographic demonstration of interim stability (i.e., no progression) between the 
completion of CNS-directed therapy and the screening radiographic study
Screening CNS radiographic study 4 weeks since completion of radiotherapy or 
surgical resection and 2 weeks since discontinuation of corticosteroids

Leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently)

Patients with indwelling catheters (e.g., PleurX) are allowed.

Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to enrollment.
Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not presently associated 
with spinal cord compression) should be considered for loco-regional therapy if 
appropriate prior to enrollment.

Uncontrolled hypercalcemia (defined as any one or more of the following criteria:
1.5 mmol/L ionized calcium
Serum calcium 12 mg/dL 
Corrected serum calcium ULN (if serum albumin 4.0 g/dL)
Symptomatic hypercalcemia requiring continued use of bisphosphonate therapy 
or denosumab
Patients who are receiving bisphosphonate therapy or denosumab specifically to 
prevent skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible.
Patients who are receiving denosumab prior to enrollment must be willing and eligible 
to discontinue its use and replace it with a bisphosphonate instead while on study.

Malignancies other than UBC within 5 years prior to Cycle 1, Day 1
Patients with localized low risk prostate cancer (defined as Stage T2b, Gleason 
score 7, and prostate-specific antigen [PSA] at prostate cancer diagnosis 20 ng/mL) 
treated with curative intent and without PSA recurrence are eligible.
Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score 6, and 
PSA 10 ng/mL) who are treatment-naive and undergoing active surveillance are 
eligible.
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of 
metastasis or death 5% at 5 years) are eligible provided they meet all of the following 
criteria:
Malignancy treated with expected curative intent (such as adequately treated 
carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal 
carcinoma in situ treated surgically with curative intent)
No evidence of recurrence or metastasis by follow-up imaging and any 
disease-specific tumor markers


AtezolizumabF. Hoffmann-La Roche Ltd
20/Protocol GO29294, Version 8
General Medical Exclusions

Pregnant and lactating

Evidence of significant uncontrolled concomitant disease that could affect compliance with 
the protocol or interpretation of results, including significant liver disease (such as cirrhosis, 
uncontrolled major seizure disorder, or superior vena cava syndrome)

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction within 3 months prior to randomization, unstable 
arrhythmias, or unstable angina

Patients with a known left ventricular ejection fraction (LVEF) 40% will be excluded.
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or LVEF 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.

Severe infections within 4 weeks prior to randomization including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
randomization
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection 
or chronic obstructive pulmonary disease) are eligible.

Major surgical procedure within 4 weeks prior to randomization or anticipation of need for a 
major surgical procedure during the course of the study other than for diagnosis

Inability to understand the local language(s) for which the EORTC QLQ-C30 and 
EQ-5D (3L) questionnaires are available
Exclusion Criteria Related to Paclitaxel

Prior treatment with paclitaxel for assignment of paclitaxel in the chemotherapy control arm 
prior to randomization

History of severe hypersensitivity to paclitaxel or to other drugs formulated with 
polyoxyethylated castor oil
Exclusion Criteria Related to Docetaxel

Prior treatment with docetaxel for assignment of docetaxel in the chemotherapy control arm 
prior to randomization

History of severe hypersensitivity to docetaxel or to other drugs formulated with 
polysorbate 80

Grade 2 peripheral neuropathy as defined by NCI CTCAE v4.0 criteria

Inability to discontinue use of strong cytochrome P450 (CYP)3A4 inhibitors including but not 
limited to ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole
Exclusion Criteria Related to Vinflunine

Prior treatment with vinflunine for assignment of vinflunine in the chemotherapy control arm 
prior to randomization

History of severe hypersensitivity to vinflunine or other vinca alkaloids
Exclusion Criteria Related to Atezolizumab

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation


AtezolizumabF. Hoffmann-La Roche Ltd
21/Protocol GO29294, Version 8

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 1 diabetes mellitus on a stable insulin regimen may be 
eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis) are permitted provided that 
they meet the following conditions:
Rash must cover less than 10% of body surface area (BSA)
Disease is well controlled at baseline and only requiring low potency topical 
steroids
No acute exacerbations of underlying condition within the last 12 months (not 
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency or oral steroids)

Patients with prior allogeneic stem cell or solid organ transplantation

History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest 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 (defined as having a positive hepatitis B surface antigen 
[HBsAg] test at screening) or hepatitis C 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as having a negative HBsAg test and a positive antibody to hepatitis B core antigen 
[anti-HBc] antibody test) are eligible.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV RNA.

Active tuberculosis (TB)

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 March 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) 28 days prior to randomization, during 
treatment or within 5 months following the last dose of atezolizumab (for patients 
randomized to atezolizumab).

Prior treatment with CD137 agonists, antiprogrammed death1 (PD-1), or antiPD-L1 
therapeutic antibody or pathway-targeting agents
Patients who have had prior anticytotoxic T lymphocyteassociated antigen 4 
(CTLA-4) may be enrolled, provided the following requirements are met:
Minimum of 12 weeks from the first dose of antiCTLA-4 and 6 weeks from the last 
dose
No history of severe immune-related adverse effects from antiCTLA-4 (NCI CTCAE 
Grade 3 and 4)

Treatment with systemic immunostimulatory agents (including but not limited to interferons 
or interleukin [IL]2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior 
to randomization


AtezolizumabF. Hoffmann-La Roche Ltd
22/Protocol GO29294, Version 8

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 [TNF] agents) within 2 weeks 
prior to randomization 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) may be enrolled in 
the study after discussion with and approval by the Medical Monitor.
The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids 
(i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed.
End of Study
The end of the study is defined as the date when all patients have one of the following: 

Experienced an OS event

Been lost to follow-up

Withdrawn consent
In addition, the Sponsor may decide to terminate the study at any time.
Outcome Measures
Efficacy Outcome Measures
Primary Efficacy Outcome Measure

OS, defined as the time between the date of randomization and death due to any cause
Secondary Efficacy Outcome Measures

ORR, defined as the proportion of patients with an objective response (either a complete 
response [CR] or partial response [PR]) as determined by the investigator with use of 
RECIST v1.1

PFS, defined as the time between the date of randomization and the date of first 
documented disease progression as determined by the investigator with use of 
RECIST v1.1 or death due to any cause, whichever occurs first

DOR, defined as the time between the date of first documented response and the date of 
first documented disease progression as determined by the investigator with use of 
RECIST v1.1 or death due to any cause, whichever occurs first
Safety Outcome Measures

Incidence, nature, and severity of adverse events graded according to NCI CTCAE v4.0

Changes in vital signs, physical findings, and clinical laboratory results

Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters
Pharmacokinetic Outcome Measures

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, 4, 8, and 16, at treatment discontinuation, and at 120 days (30 days) after 
the last dose of atezolizumab
Patient-Reported Outcome Measure

UBC cancer symptoms, patient functioning, and HRQoL as measured by the EORTC 
QLQ-C30


AtezolizumabF. Hoffmann-La Roche Ltd
23/Protocol GO29294, Version 8
Exploratory Outcome Measures

PFS, ORR, and DOR with use of modified RECIST for patients randomized to atezolizumab

DCR, defined as the rate of patients with complete or partial response as best response or 
stable disease maintained for 18 weeks per RECIST v1.1

Status of tumor immune-related or disease typerelated exploratory biomarkers in archival 
and/or freshly obtained tumor tissues and association with disease status and/or response 
to atezolizumab

Status of exploratory biomarkers in plasma, whole blood, or serum (including but not limited 
to cytokines such as interleukin 6 [IL-6]) collected before or during treatment with 
atezolizumab or at progression and association with disease status and/or response to 
atezolizumab

Utility scores of the EQ-5D (3L) for use in economic models

Items from the EORTC QLQ-C30 that are not included in the main PRO outcome measure
Length of Study
The length of study will be approximately 25 months from first patient in (FPI).
Investigational Medicinal Products
Test Product
Atezolizumab is administered at a dose of 1200 mg by IV infusion on Day 1 of each 21-day 
cycle.
Comparators
Vinflunine is administered at a dose of 320 mg/m2 by IV infusion on Day 1 of each 21-day cycle.
Paclitaxel is administered at a dose of 175 mg/m2 over 3 hours by continuous IV infusion on
Day 1 of each 21-day cycle.
Docetaxel is administered at a dose of 75 mg/m2 on Day 1 of each 21-day cycle.
Statistical Methods
Primary Analysis
The primary efficacy endpoint is OS.  OS is defined as the time between the date of 
randomization and death due to any cause.  Data for patients who are not reported as having 
died by the time of the data cutoff date for primary analysis will be censored at the date when 
they were last known to be alive.  Patients who do not have post-baseline information will be 
censored at the date of randomization plus 1 day.
The primary analysis will occur when approximately 152, 403, and 652 deaths have been 
observed in the following populations:  patients with an IHC score of IC2/3, patients with an IHC 
score of IC1/2/3, and intent-to-treat (ITT) populations respectively, whichever occurs later.
Comparisons with respect to OS between the treatment and control arms will be tested using a 
hierarchical fixed-sequence procedure based on a stratified log-rank test at two-sided level of 
5% significance within the following populations:  patients with an IHC score of IC2/3, patients 
with an IHC score of IC1/2/3, and in the ITT population.
Determination of Sample Size
This study will enroll approximately 931 patients, including a minimum of 230 patients with a 
PD-L1 IHC score of IC2/3 and a minimum of 537 patients with a PD-L1 IHC score of IC1/2/3.
The number of events required to demonstrate efficacy of the atezolizumab experimental arm 
over the chemotherapy arm (i.e., vinflunine, paclitaxel, or docetaxel) with regard to OS are 
estimated based on the following assumptions:

Two-sided significance level of 5%

94% for the primary analysis of OS in the population of patients with an IHC score of IC2/3 
with an HR of 0.57, corresponding to an improvement in median OS from 7.5 months to 
13.2 months


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
98% power for the primary analysis of OS in the population of patients with an IHC score of 
IC1/2/3 with an HR of 0.68, corresponding to an improvement in median OS from 
7.5 months to 11 months

97% power for the primary analysis of OS in the ITT population with an HR of 0.74, 
corresponding to an improvement in median OS from 7.5 months to 10.1 months

1:1 randomization ratio

Dropout rate of 5% per year over 24 months
Interim Analyses
No interim efficacy analyses are planned for this study.
An iDMC will be set up to evaluate safety results approximately every 6 months after FPI.  All 
summaries/analyses by treatment arm for the iDMC’s review will be prepared by an external 
independent Data Coordinating Center (iDCC).  Members of the iDMC will be external to the 
Sponsor and will follow a charter that outlines their roles and responsibilities. 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
anti-HBc
antibody to hepatitis B core antigen
anti-HBs
antibody to hepatitis B surface antigen
ASCO
American Society of Clinical Oncology
ATA
anti-therapeutic antibody
BSC
best supportive care
CarboGem
carboplatin and gemcitabine
CL
clearance
Cmax
maximum observed serum concentration
Cmin
minimum observed serum concentration
CR
complete response
CRCL
creatinine clearance
CRF
Case Report Form
CRP
C-reactive protein
CT
computed tomography
CTLA-4
cytotoxic T lymphocyteassociated antigen 4
Ctrough
trough concentration
CYP
cytochrome P450
DCR
disease control rate
DLT
dose-limiting toxicity
DOR
duration of objective response
EBV
Epstein-Barr virus
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EORTC
European Organisation for Research and Treatment of Cancer
ePRO
electronic patient-reported outcome
EQ-5D (3L)
EuroQoL 5-Dimension, 3-level version
ESMO
European Society of Medical Oncology
FDA
U.S. Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FOLFOX
leucovorin, 5-fluorouracil, oxaliplatin
FPI
first patient in
GC
gemcitabine and cisplatin
HBsAg
hepatitis B surface antigen


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Abbreviation
Definition
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
U.S. Health Insurance Portability and Accountability Act
HR
hazard ratio
HRQoL
health-related quality of life
IC
PD-L1 tumor-infiltrating immune cell
ICH
International Conference on Harmonisation
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
IHC
immunohistochemistry
IGRA
interferon-gamma release assay
IMP
investigational medicinal product
IND
U.S. Investigational New Drug application
IRB
Institutional Review Board
ITT
intent to treat
IV
intravenous
IxRS
interactive Web/voice response system
LFT
liver function test
LVEF
left ventricular ejection fraction
M-CAVI
methotrexate, carboplatin, and vincristine
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MVAC
methotrexate, vinblastine, doxorubicin, and cisplatin
NaF
sodium fluoride
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NSCLC
nonsmall cell lung cancer
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD-1
programmed death1
PD-L1
programmed deathligand 1
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic


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Abbreviation
Definition
PPD
purified protein derivative
PRO
patient-reported outcome
PSA
prostate-specific antigen
q3w
every 3 weeks
QLQ-C30
Quality-of-Life Questionnaire Core 30
QTcF
Fridericia-corrected QT
RCC
renal cell carcinoma
RCR
Roche Clinical Repository
RECIST
Response Evaluation Criteria in Solid Tumors
SD
stable disease
TB
tuberculosis 
TC-99m
Technetium-99m
TCC
transitional cell carcinoma
TFPC
time from prior chemotherapy
TNF
tumor necrosis factor
TSH
thyroid-stimulating hormone
UBC
urothelial bladder cancer
UICC
Union Internationale Contre le Cancer
UCC
urothelial cell carcinoma
ULN
upper limit of normal
Vss
volume of distribution at steady state


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1.
BACKGROUND
1.1
BACKGROUND ON UROTHELIAL BLADDER CANCER
Urothelial bladder cancer (UBC, also termed transitional cell carcinoma [TCC] or 
urothelial cell carcinoma [UCC] of the urinary tract) is the most common cancer of the 
urinary system worldwide with UBC of the bladder being the predominant histologic type 
and location.  Although less common, UBC may originate in the renal pelvis, ureter, or 
urethra.  It was estimated that in 2013, there would be 72,570 new cases of bladder 
cancer and 15,210 deaths in the United States (American Cancer Society 2013).  Similar 
worldwide data estimate that there were 112,308 deaths in men and 37,974 in females 
in 2008 (GLOBOCAN 2008).
The overall 5-year survival rate for metastatic UBC is approximately 5.4% 
(National Cancer Institute 2013).  Poor prognostic factors for survival in patients with 
metastatic UBC include advanced stage of disease at the time of initial diagnosis, 
Karnofsky Performance Status (KPS) 80%, and visceral metastasis (i.e., lung, liver, or 
bone; Bajorin et al. 1999).  The presence of these unfavorable features was associated 
with a median survival of 4 months compared with 18 months in patients without these 
features (Loehrer et al. 1992).
The majority of urothelial tumors arise in the bladder with the remainder originating in the 
renal pelvis, urethra, or ureter.  UBC is the most common histologic subtype associated 
with bladder cancer and accounts for greater than 90% of all UBC cases in the 
industrialized world, whereas non-urothelial subtypes, including squamous cell, 
adenocarcinoma, and small-cell carcinoma, are more frequent in other areas of the 
world (Chalasani et al. 2009).
1.1.1
First-Line Treatment for Urothelial Bladder Cancer
Patients with previously untreated UBC typically receive platinum-based chemotherapy.  
The first evidence that chemotherapy produced a significant benefit in patients with 
advanced UBC came in the mid-1980s; two studies showed that the combination of 
methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) produced overall response 
rates greater than 70% with approximately 35% of patients achieving a complete 
response (CR; Sternberg et al. 1985; 1989).  Subsequently, two prospective randomized 
Phase III trials demonstrated the superiority of MVAC with regard to OS in patients with 
advanced disease (Logothetis et al. 1990; Loehrer et al. 1992).  In an effort to develop a 
less toxic regimen, the combination of gemcitabine and cisplatin (GC) was tested against 
MVAC in the Phase III setting following the demonstration of activity in earlier phase 
trials.  In the Phase III trial, patients allocated to GC had a similar overall survival (OS) to 
those randomized to MVAC (14.0 months for GC vs. 15.2 months for MVAC; hazard 
ratio [HR]1.09; 95% CI: 0.88, 1.34, p0.66) with less Grade 3 or 4 toxicity (including 
neutropenia, neutropenic sepsis, and mucositis) and, as a result, GC has largely 
displaced MVAC as the standard of care (von der Maase et al. 2005). 


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The benefit conferred by cisplatin-based chemotherapy regimens appears to have 
reached a plateau in median OS (1315 months) and leaves a significant population in 
need of salvage therapy options.
Poor performance status, impaired renal function, advanced age, and multiple 
comorbidities (e.g., neuropathy, congestive heart failure, and hearing loss) are fairly 
common in patients with advanced UBC and can prohibit the use of cisplatin-based 
regimens.  Carboplatin-based regimens are feasible in these patients, but trials suggest 
they are less effective than cisplatin-based regimens (Dogliotti et al. 2007).  The benefit 
of carboplatin-based therapy in medically “unfit” patients was demonstrated in the 
European Organisation for the Research and Treatment of Cancer (EORTC) Trial 30986.  
In this trial, 238 patients with previously untreated advanced UBC and either a poor 
performance status and/or impaired renal function (glomerular filtration rate [GFR] 
60 but 30 mL/min) were enrolled to gemcitabine and carboplatin (CarboGem) or 
methotrexate, carboplatin, and vincristine (M-CAVI; De Santis et al. 2012).  The 
objective response rate (ORR) of CarboGem was 41% versus 30% for the M-CAVI arm 
and demonstrated no difference in the median OS (9.3 vs. 8.1 months).  Notably, those 
with both impaired renal function and poor performance status had especially poor 
outcomes and increased acute toxicity with combination chemotherapy in this trial.
Despite the limited survival benefit conferred by cytotoxic chemotherapy, platinum-based 
regimens remain the standard first-line option for most patients with locally advanced 
and metastatic UBC.  Virtually all patients progress following first-line chemotherapy, 
with median progression-free survival (PFS) ranging from 7.7 months to 8.3 months.  As 
a result, most patients with UBC will continue to need more effective second-line 
treatment options.
A summary of randomized Phase III trials in previously untreated patients is provided in
Table 1.


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Table 1
Randomized Phase III Trials in Previously Untreated Patients
First-Line Therapy Regimen (Reference)
No. of 
Patients
ORR
(%)
Median OS
(months)
Cisplatin-based regimens
MVAC vs. Cis (Loehrer et al. 1992)
246
36 vs. 11
12.5 vs. 8.2
MVAC vs. CISCA (Logothetis et al. 1990)
110
65 vs. 46
12.6 vs. 10
MVAC vs. HD-MVAC (Sternberg et al. 1985)
263
58 vs. 72
14.1 vs. 15.5
MVAC vs. GC (von der Masse et al. 2005)
405
49 vs. 46
15.2 vs. 14
MVAC vs. CaP (Dreicer et al. 2004)
85
36 vs. 28
15.4 vs. 13.8
MVAC/GCSF vs. CD/GCSF (Bamias et al. 2004)
220
54 vs. 37
14.2 vs. 9.3
Cisplatin-based regimen vs. carboplatin-based regimen
GC vs. CarboGem (Dogliotti et al. 2007)
110
49 vs. 40
12.8 vs. 9.8
Carboplatin-based regimens
CarboGem vs. MTX/Carbo/Vinblast 
(De Santis et al. 2012)
238
41 vs. 30
9.3 vs. 8.1
CaPcarboplatin and paclitaxel; CarboGem gemcitabine and carboplatin; CDcisplatin and 
docetaxel; Cis cisplatin; CISCAcisplatin, cyclophosphamide, and doxorubicin; 
GCgemcitabine and cisplatin; GCSFgranulocyte colony-stimulating factor; HD high dose 
intensity; MVACmethotrexate, vinblastine, doxorubicin, and cisplatin; ORRobjective response 
rate; OSoverall survival.
Note:  Adapted from Garcia et al. 2006.
1.1.2
Second-Line Treatment for Urothelial Bladder Cancer
Despite the efficacy of first-line regimens for patients with advanced UBC, nearly all 
patients experience disease progression and will require second line therapy.  There are 
currently no approved second-line therapies for UBC in the United States and only one 
approved agent (vinflunine) in the European Union.  Whereas several chemotherapeutic 
agents have been studied in the second-line setting over the last two decades, the 
overall response rates are low and associated with considerable toxicity (see Table 2).  
No survival benefit has been demonstrated with second-line chemotherapy.  The 
National Comprehensive Cancer Network (NCCN) guidelines recommend participation 
in a clinical trial of new agents.  If no trials are available, treatment with a single-agent 
taxane or gemcitabine is preferred for palliation.  Additional recommended palliative 
options include single-agent cisplatin, carboplatin, doxorubicin, 5-fluorouacil (5-FU), 
ifosfamide, pemetrexed, methotrexate, and vinblastine.  European Society of Medical 
Oncology (ESMO) and European Association of Urology (EAU) clinical practice 
guidelines recommend vinflunine but also highlight that other agents used in this space 
may have similar benefit and recommend clinical trials of other treatments 
(Bellmunt et al. 2011; Stenzl et al. 2011).  The registrational Phase III study of vinflunine 
as a second-line agent compared vinflunine versus best supportive care (BSC) alone in 
370 patients progressing after a platinum-containing therapy.  The intent-to-treat (ITT)


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analysis showed an improvement in response rate (8.6% vs. 0%) but did not show a 
statistically significant OS benefit for vinflunine compared with placebo 
(6.9 vs. 4.6 months, HR0.88; 95% CI: 0.69, 1.12; p0.287).  Key toxicities included 
Grade 3 or 4 neutropenia (50%), febrile neutropenia (6%), anemia (19%), fatigue (19%), 
and constipation (16%).  A summary of Randomized Phase II trials of second-line 
therapy is provided in Table 2.
Table 2
Randomized Phase II Trials of Second-Line Therapy
Second-Line Therapy Regimen
RR
(%)
PFS
(months)
OS
(months)
Weekly paclitaxel (n31)
10
2.2
7.2
Nab-paclitaxel (n47)
28
6.0
10.8
Irinotecan (n40)
5
2.1
5.4
Ixabepilone (n42)
11.9
2.7
8.0
Bortezomib (n25)
0
1.4
5.7
Pemetrexed (n47)
27.7
2.9
9.6
Oxaliplatin (n18)
6
1.5
7.0
Ifosfamide (n56)
20
2.4
5.5
Lapatinib (n59)
3
2
4.5
Pemetrexed (n12)
8


Docetaxel (n30)
13

9.0
Gemcitabine (n35)
11
4.9
8.7
Gemcitabine (n44)
22.5

5.0
Topotecan (n44)
9.1
1.5
6.3
Ifosfamidegemcitabine (n 34)
21
4.0
9.0
Carboplatinpaclitaxel (n44)
16
4.0
6.0
Vinflunine (n51)
18
3.0
6.6
Vinflunine (n253)
8.6
3.0
6.9
Gefitinib (n31)
3

3.0
Sorafenib (n27)
0

6.8
Sunitinib (n45)
7
2.4
6.9
Pazopanib (n41)
17.1
2.6
4.7
OSoverall survival; PFSprogression-free survival; RRresponse rate.
Note:  Adapted from Sonpavde et al. 2010.  


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1.1.3
Targeted Therapy for Urothelial Bladder Cancer
Although there is an increasing understanding of the molecular biology and signaling 
pathways underlying bladder cancer development and progression (particularly the 
fibroblast growth factor receptor [FGFR], vascular endothelial growth factor [VEGF], and 
epidermal growth factor receptor [EGFR]/human epidermal growth factor 2 
[HER2]pathways), no targeted agents currently have a role in the treatment of UBC.
1.2
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 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.
Atezolizumab is being investigated as a potential therapy against solid tumors and 
hematologic malignancies in humans.
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.
See the Atezolizumab Investigator’s Brochure for details on the nonclinical studies.


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1.2.2
Clinical Experience with Atezolizumab
1.2.2.1
Ongoing Clinical Studies
Current studies of atezolizumab include an ongoing Phase Ia monotherapy study, three 
ongoing combination studies, and three Phase II studies in patients with solid tumors 
(see the Atezolizumab Investigator’s Brochure for study descriptions as well as 
additional studies).
Phase Ia Study PCD4989g
Study PCD4989g is a multicenter, first-in-human, open-label, dose-escalation study 
evaluating the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of biologic activity of atezolizumab 
administered as a single agent by IV infusion every 3 weeks (q3w) to patients with 
locally advanced or metastatic solid malignancies or hematologic malignancies.  
Ongoing expansion cohorts are studying the efficacy in patients with pancreatic cancer, 
bladder cancer, breast cancer, esophageal cancer, prostate cancer, small-cell lung 
cancer, malignant lymphoma, multiple myeloma, and other less common tumor types.
Phase Ib Study GP28328
Ongoing Phase Ib Study GP28328 is evaluating the safety and pharmacology of 
atezolizumab administered with bevacizumab alone (Arm A) or with bevacizumab plus 
leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX; Arm B) in patients with advanced 
solid tumors.  Additional cohorts have been included to investigate atezolizumab in 
combination with carboplatin plus paclitaxel, in combination with carboplatin plus 
pemetrexed, as well as in combination with carboplatin plus nab-paclitaxel, pemetrexed, 
and cisplatin in patients with advanced or metastatic nonsmall cell lung cancer 
(NSCLC).
Phase Ib Study GP28384
Ongoing Phase Ib Study GP28384 is evaluating the safety and pharmacology of 
atezolizumab administered in combination with vemurafenib in patients with previously 
untreated BRAFV600 mutationpositive metastatic melanoma.
Phase Ib Study GP28363
Ongoing Phase Ib Study GP28363 is evaluating the safety and pharmacology of 
atezolizumab administered in combination with cobimetinib (MEK inhibitor) in locally 
advanced or metastatic solid tumors.
Phase II Study GO28625 (FIR)
Ongoing, single-arm, Phase II Study GO28625 is evaluating the safety and efficacy of 
atezolizumab monotherapy in PD-L1positive patients with NSCLC.  In particular, this 
study is evaluating whether archival or fresh tumor tissue is more predictive of response 
to atezolizumab.  Safety and efficacy data are not yet available for this study.


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Phase II Study GO28753 (POPLAR)
Ongoing Study GO28753 is a randomized, open-label, Phase II study in patients with 
locally advanced or metastatic NSCLC who have failed a prior platinum-containing 
regimen.  Patients in the control arm of Study GO28753 will receive docetaxel alone.  
Eligible patients will be enrolled regardless of PD-L1 status and will be stratified by 
PD-L1 expression.  The primary endpoint is OS for both the PD-L1positive population 
and the overall study population.
Phase II Study GO28754 (BIRCH)
Ongoing, single-arm, Phase II Study GO28754 is evaluating the safety and efficacy of 
atezolizumab monotherapy in PD-L1positive patients with NSCLC.  Safety and efficacy 
data are not yet available for this study.
Phase III Study GO28915 (OAK)
Ongoing Study GO28915 is a randomized, open-label, Phase III study in patients with 
locally advanced or metastatic NSCLC who have failed a prior platinum-containing 
regimen.  Patients in the control arm of Study GO28915 will receive docetaxel alone.  
Eligible patients will be enrolled regardless of PD-L1 status and will be stratified by 
PD-L1 expression.  The primary endpoint is OS for both the PD-L1positive population 
and the overall study population.
Phase II Study WO29074
Ongoing Phase II Study WO29074 is evaluating the safety and efficacy of atezolizumab 
monotherapy or the combination of atezolizumab and bevacizumab versus sunitinib in 
treatment-naive patients with renal cell carcinoma (RCC).  Safety and efficacy data are 
not yet available for this study.
Phase II Study GO29293
Ongoing Study GO29293 is a single-arm, open label, Phase II study to assess the 
clinical benefit of atezolizumab as a single agent in patients with locally advanced or 
metastatic UBC.  The co-primary endpoints of this study are independent review facility 
(IRF)assessed ORR according to Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) and investigator-assessed ORR according to modified 
Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
1.2.2.2
Clinical Safety
The presented safety data for atezolizumab have been derived from the treatment of 
patients in Study PCD4989g.  As of 1 January 2014, the clinical database contained 
safety data from 386 safety-evaluable patients, defined as patients who 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.


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Adverse Events
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, and pruritus.  Treatment-related adverse events (per 
investigator’s assessment of causality) were reported in 277 patients (71.8%). 
Treatment-related adverse events (all grades) occurring in 10% of patients included 
fatigue (22%), decreased appetite (12.7%), pyrexia (11.7%), nausea (11.4%), and rash 
(10.4%) for Study PCD4989g.
Adverse Events in Patients with Urothelial Bladder Cancer
Safety data are available for 68 patients with UBC from Study PCD4989g.  In patients 
with UBC, 62 (91.2%) reported an adverse event regardless of attribution.  Adverse 
events reported in 10% of patients included decreased appetite (22.1%), pyrexia 
(17.6%), fatigue (17.6%), nausea (17.6%), anemia (16.2%), urinary tract infection 
(14.7%), abdominal pain (13.2%), vomiting (13.2%), constipation (13.2%), back pain 
(11.8%), and asthenia (10.3%).  In 57.4% of patients, the adverse events had a 
maximum severity of either Grade 1 or 2.  Adverse events were assessed by the 
investigator as related to atezolizumab therapy in 39 of 68 (57.4%) treated patients with 
UBC.  The most common events related to study drug that occurred in 5% of patients 
were decreased appetite (11.8%), fatigue (11.8%), nausea (11.8%), pyrexia (8.8%), and 
asthenia (7.4%).  Overall, the preliminary safety data from the UBC cohort show a safety 
profile similar to that of all atezolizumab-treated patients.
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, which are considered potential adverse drug reactions 
associated with atezolizumab.
See the Atezolizumab Investigator’s Brochure for further information regarding safety 
data from Study PCD4989g.
1.2.2.3
Clinical Activity
As of the data cutoff date of 1 January 2014, efficacy analyses were performed on 
362 efficacy-evaluable patients who were defined as those patients with measurable 
disease at baseline and who were treated by 20 November 2013 in Study PCD4989g.  
Patients with multiple tumor types were included in the study, with the largest cohorts 
consisting of patients with NSCLC, RCC, and bladder cancer.  In the overall 
efficacy-evaluable population, the ORR (confirmed and unconfirmed) per RECIST v1.1 
was 19.6% (95% CI: 15.6%23.9%).  Objective responses with atezolizumab 
monotherapy were observed in a broad range of malignancies, including NSCLC, RCC, 


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melanoma, bladder cancer, colorectal cancer, head and neck cancer, gastric cancer, 
breast cancer, and sarcoma.  Altogether, there were 71 patients with responses with a 
median duration of response of 75.7 weeks (range: 0.1to 85.9weeks, where “” 
denotes censored value).  The majority of these responses have been durable, with 73.2% 
(52 of 71) of responses ongoing as of the clinical cutoff date.
Clinical Activity in Patients with Urothelial Bladder Cancer
As of the clinical cutoff date of 1 January 2014, efficacy analyses have been performed 
on efficacy-evaluable patients with locally advanced or metastatic UBC who had an
immunohistochemistry (IHC) score of PDL1positive tumor-infiltrating immune cell 
(IC)2/3 (30 patients) and in patients with an IHC score of IC0/1 (35 patients) who were 
dosed by 20 November 2013 in Study PCD4989g (see Table 3).
In the population of efficacy-evaluable patients with UBC and an IHC score of IC2/3 
(n30), the median follow-up was 4.2 months (range: 1.1to 8.5 months).  The 
investigator-assessed ORR per RECIST v1.1 in patients with an IHC score of IC2/3 was 
43.3% (95% CI: 25.5%, 62.6%) with two complete responses.  Among the 
efficacy-evaluable patients with UBC and an IHC score of IC2/3, there were 
13 responding patients, of which 11 are confirmed responses (two responders did not 
have follow-up scans to confirm their response prior to the clinical cutoff date).  In 
responding patients (n13), the median time to first response was 43 days 
(range: 3885 days).  The median duration of response was not reached (range: 0.1to 
30.3weeks).  The majority of these responses have been durable, with 92.3% (12 of 13) 
of responses still ongoing as of the clinical cutoff date.
Among the population of efficacy-evaluable patients with UBC and an IHC score of IC0/1 
(n35), there are 4 patients with responses, none of which is a confirmed response.  
The investigator-assessed ORR per RECIST v1.1 in patients with an IHC score of IC0/1 
is 11.4% (95% CI: 4.0%, 26.3%).  Median duration of follow-up for these patients is 
2.7 months (range: 0.7to 3.6 months).  For these four responses, the median duration 
of response has not been reached (range: 0.1, 6.0weeks).  In patients with an IHC 
score of IC0/1, all responses were still ongoing as of the clinical cutoff date.


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Table 3 Efficacy-Evaluable Patients with UBC Dosed by 
20 November 2013 in Study PCD4989g:  ORR per RECIST v1.1 by 
PD-L1 Tumor Expression
IHC Score
ORR
(CR or PR)
ORR (CR or PR) of 
Combined IHC Groups
IHC score of IC3 
(IC 10%)
50% (5 of 10)
(95% CI: 22.2%, 77.8%)
43% (13 of 30)
(95% CI: 25.5%, 62.6%)
IHC score of IC2 
(10%IC 5%)
40.0% (8 of 20)
(95% CI: 20.9%, 63.9%)
IHC score of IC1 
(5% IC 1%)
13% (3 of 23)
(95% CI: 3.7%, 31.7%)
11% (4 of 35)
(95% CI: 4.0%, 26.3%)
IHC score of IC0 
(IC 1%)
8% (1 of 12)
(95% CI: 0.4%, 34.9%)
CRcomplete response; IC PD-L1positive tumor-infiltrating immune cell; 
IHCimmunohistochemistry; ORRobjective response rate; PD-L1programmed 
deathligand 1; PRpartial response; RECIST v1.1Response Evaluation Criteria in 
Solid Tumors, Version 1.1; UBCurothelial bladder cancer.
Notes:  This table shows efficacy-evaluable patients with UBC dosed by 
20 November 2013.  Two patients had unknown IHC scores.
ORR covers both confirmed and unconfirmed responses.
See the Atezolizumab Investigator’s Brochure for further information regarding efficacy 
data from Study PCD4989g.
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4.43 mL/day/kg and 48.1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 of ATAs 
has not had a significant impact on pharmacokinetics for doses from 10 to 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.


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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).  
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 UBC 
(Nakanishi et al. 2007; Mu et al. 2011).
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed or refused standard-of-care therapies.  As 
of the data cutoff date of 1 January 2014, efficacy data are available for 362 patients 
treated in the atezolizumab Phase Ia Study PCD4989g.  In the overall efficacy-evaluable 
population, the ORR per RECIST v1.1 was 15.5%.  RECIST v1.1 responses were 
observed across multiple tumor types, including NSCLC, RCC, melanoma, colorectal 
cancer, gastric cancer, head and neck cancer, sarcoma, breast cancer, and bladder 
cancer (see Section 1.2.2.3).
Importantly, preliminary evidence suggests that patients with UBC and high 
PD-L1expressing tumors (IHC score of IC2/3) are more likely to benefit from PD-L1 
pathwaytargeted therapies than are patients with low PD-L1expressing (IHC score of 
IC0/1) tumors.  Data from the Phase Ia Study PCD4989g showed that patients with UBC 
and a PD-L1 IHC score of IC2/3 have a numerically higher ORR to atezolizumab than 
patients with an IHC score of IC 0/1 (43.3% vs. 11.4%; see Table 3).


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In this study, a PD-L1 IHC assay will be used to stratify patients by tumor PD-L1 
expression (IHC score of IC0/1 vs. IHC score of IC2/3).  Comparisons of OS between 
the treatment and control arms will be evaluated first in the population of patients with an 
IHC score of IC2/3 and subsequently in the population of patients with IHC1/2/3, 
followed by the ITT population in a hierarchical fixed-sequence procedure (see 
Section 6.5.1).
Study GO29294 will enroll only second- and third-line patients; to date, no therapy has 
demonstrated a survival benefit in this population.  In contrast to the cytotoxic therapies 
approved for the treatment of UBC, atezolizumab has been generally well tolerated and 
has not been associated with bone marrow suppression or other systemic toxicities 
(i.e., neuropathy, peripheral edema, nephrotoxicity, or febrile neutropenia) that may limit 
the ability to administer subsequent treatments (see Section 1.2.2.2).  Therefore, 
second-line patients enrolled in this study may remain eligible for standard therapies 
after discontinuation of atezolizumab.
Data from Study PCD4989g have demonstrated a numerically higher RECIST v1.1 
response rate in patients with UBC (see Table 3) on atezolizumab when compared with 
historical response rates of 9%11% observed in randomized studies of second-line 
patients who progressed on prior platinum-based chemotherapy (Bellmunt et al. 2009; 
Choueiri et al. 2012).  These responses to atezolizumab have been rapid.  Although 
follow-up in the UBC cohort is limited, when all responders across different tumor types 
(i.e., NSCLC, RCC, melanoma, colorectal cancer, gastric cancer, head and neck cancer, 
sarcoma, breast cancer, and bladder cancer) in Study PCD4989g were added up the 
median duration of response was 75.7 weeks with approximately 73.2% of responses 
still ongoing as of the data cutoff date of 1 January 2014, suggesting response to 
atezolizumab could be durable (see Section 1.2.2.3).
Atezolizumab has been generally well tolerated (see Section 1.2.2.2); adverse events 
with potentially immune-related causes consistent with an immunotherapeutic agent, 
including rash, hypothyroidism, hepatitis/transaminitis, colitis, and myasthenia gravis, 
have been observed in ongoing studies of atezolizumab. To date, these events have 
been monitorable and treatable.
In summary, treatment with atezolizumab offers the potential for clinical benefit in 
patients with UBC.  Because most atezolizumab-related toxicities observed to date have 
been mild and transient in nature and do not overlap with the adverse effects of 
chemotherapy, patients who do not respond to study treatment are considered likely to 
be able to subsequently receive standard therapies for which they would otherwise have 
been eligible.  Patients will be fully informed of the risk of continuing study treatment in 
spite of apparent radiographic progression, and investigators should make a careful 
assessment of the potential benefit of doing so, considering radiographic data, biopsy 
results, and the clinical status of the patient.


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2.
OBJECTIVES
2.1
EFFICACY OBJECTIVES
For the primary and secondary efficacy objectives, a comparison of the treatment arms 
will be performed in different patient subpopulations according to tumor PD-L1 
expression as evaluated by IHC.  The IHC scores will have three categories (IC0, IC1, 
and IC2/3), which will also be used for stratification (IHC score of IC0/1 vs. IHC score of 
IC2/3).
2.1.1
Primary Efficacy Objective
The primary efficacy objective of this study is as follows:

To evaluate the efficacy of atezolizumab treatment compared with chemotherapy 
treatment with respect to OS in patients with locally advanced or metastatic UBC 
who have progressed during or following a platinum-containing regimen
2.1.2
Secondary Efficacy Objectives
The secondary efficacy objectives of this study are as follows:

To evaluate the efficacy of atezolizumab compared with chemotherapy with respect 
to anti-tumor effects as measured by ORR per investigator with use of RECIST v1.1

To evaluate the efficacy of atezolizumab compared with chemotherapy with respect 
to anti-tumor effects as measured by PFS per investigator with use of RECIST v1.1

To evaluate the efficacy of atezolizumab compared with chemotherapy with respect 
to anti-tumor effects as measured by duration of objective response (DOR) per 
RECIST v1.1
2.2
SAFETY OBJECTIVES
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of atezolizumab compared with chemotherapy

To evaluate the incidence of ATAs against atezolizumab and to explore the potential 
relationship of the immunogenicity response with pharmacokinetics, safety, and 
efficacy
2.3
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is as follows:

To characterize the pharmacokinetics of atezolizumab in patients with locally 
advanced or metastatic UBC who have progressed during or following a 
platinum-containing regimen


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2.4
PATIENT-REPORTED OUTCOME OBJECTIVE
The patient-reported outcome (PRO) objective for this study is as follows:

To evaluate and compare PROs of patient health-related quality of life (HRQoL) 
between treatment arms as measured by the EORTC Quality-of-Life Questionnaire 
Core 30 (QLQ-C30)
2.5
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To evaluate the efficacy of atezolizumab with respect to anti-tumor effects as 
measured by PFS, ORR, and DOR per modified RECIST

To evaluate and compare disease control rate (DCR) between the two treatment 
arms

To evaluate the relationship between tumor tissue PD-L1 expression and measures 
of efficacy

To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in 
archival and/or fresh tumor tissue and blood and their association with disease 
status and/or response to study treatment

To assess health status as measured using the EuroQoL 5-Dimension, 3-level 
version (EQ-5D [3L]) questionnaire for health economic modeling
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This is a Phase III, global, multicenter, open-label, two-arm, randomized, controlled 
study designed to evaluate the efficacy and safety of atezolizumab compared with 
chemotherapy in patients with locally advanced or metastatic UBC who have progressed 
during or following a platinum-containing regimen.  Within the chemotherapy control arm, 
the percentage of patients who are treated with a taxane (paclitaxel or docetaxel) will be 
capped at 40%.  Until that cap is reached, the selection of the specific chemotherapy 
(vinflunine or taxane) for patients who are randomized to the chemotherapy arm will be 
per investigator’s choice. 
Figure 1 illustrates the study design.


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Figure 1
Study Schema
IHCimmunohistochemistry; PD-L1programmed deathligand 1; q3wevery 3 weeks; 
RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; UBCurothelial
bladder cancer.
a Patients may continue atezolizumab treatment after disease progression according to 
RECIST v1.1 if they meet criteria specified in Section 4.6.1.1.
Male and female patients aged 18 years with Eastern Cooperative Oncology Group 
(ECOG) performance status of 0 or 1 who have histologically or cytologically proven, 
locally advanced or metastatic UBC and who have experienced disease progression 
during or following treatment for advanced disease consisting of platinum-based therapy 
are eligible.


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Patients who experience disease progression during or within 12 months following 
completion of a platinum-based adjuvant or neoadjuvant regimen will also be eligible for 
enrollment into the study.
Patients must have received at least one platinum-containing regimen (e.g., GC, MVAC, 
CarboGem, etc.) for locally advanced or metastatic UBC.  The maximum number of prior 
therapies in the locally advanced or metastatic setting is restricted to two.
Tumor specimens from eligible patients will be prospectively tested for PD-L1 expression 
by a central laboratory.  Both patients and investigators will be blind to the PD-L1 
expression status.  The study will enroll all patients whose tissue is evaluable for 
expression testing, regardless of PD-L1 expression status.
This study will enroll approximately 931 patients, including a minimum of 230 patients 
with a PD-L1 IHC score of IC2/3 and a minimum of 537 patients with a PD-L1 IHC score 
of IC1/2/3 (enrollment of all patients will continue to reach the minimum requirement of 
patients with a PD-L1 IHC score of IC2/3).  Patients will be randomized in a 1:1 ratio to 
receive either atezolizumab or chemotherapy (vinflunine, paclitaxel, or docetaxel; see 
Section 4.2 for stratification factors):

Arm A (experimental arm):  Atezolizumab 1200 mg q3w

Arm B (control arm):  Vinflunine 320 mg/m2 q3w, paclitaxel 175 mg/m2 q3w, or 
docetaxel 75 mg/m2 q3w
Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle.  Patients will receive atezolizumab as long as they continue to 
experience clinical benefit in the opinion of the investigator until unacceptable toxicity or 
symptomatic deterioration attributed to disease progression (i.e., pain secondary to 
disease or unmanageable ascites, etc.) as determined by the investigator after an 
integrated assessment of radiographic data, biopsy results (if available), and clinical 
status.
During treatment, patients will be permitted to continue atezolizumab treatment after 
RECIST v1.1 criteria for progressive disease are met if they meet all of the following 
criteria:

Evidence of clinical benefit as assessed by the investigator

Absence of symptoms and signs (including worsening of laboratory values [e.g., 
new or worsening hypercalcemia]) indicating unequivocal progression of disease

No decline in ECOG performance status that can be attributed to disease 
progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed and stabilized by protocol-allowed medical 
interventions (see Section 4.4.1)


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Patients treated with atezolizumab in whom radiographic disease progression is 
confirmed at a subsequent tumor assessment may be considered for continued study 
treatment at the discretion of the investigator if they continue to meet the criteria above.
Patients randomized to the chemotherapy arm will receive vinflunine, paclitaxel, or 
docetaxel per the investigator’s choice.  Vinflunine 320 mg/m2, paclitaxel 175 mg/m2, or 
docetaxel 75 mg/m2 will be administered intravenously on Day 1 of each 21-day cycle 
until disease progression per standard RECIST v1.1 or unacceptable toxicity.
Given the unique characteristics associated with the chemotherapy arm, including 
toxicities (i.e., mucositis, neutropenia, febrile neutropenia, and alopecia) and the 
premedications required (i.e., steroid, anti-emetics, and potentially growth factor support), 
this will be an open-label study.
No crossover will be allowed from the control arm to the experimental arm.
Patients will undergo scheduled tumor assessment at baseline and every 9 weeks 
thereafter for 54 weeks following randomization.  After 54 weeks from randomization, 
patients will undergo tumor assessment every 12 weeks until disease progression per 
modified RECIST (see Appendix 3) or until treatment discontinuation (for patients who 
continue to receive atezolizumab following disease progression).  For patients 
randomized to the chemotherapy arm, assessments will continue until disease 
progression per RECIST v1.1 (see Appendix 4), regardless of whether treatment has 
been discontinued.  In the absence of disease progression, tumor assessments should 
continue, regardless of whether patients start new anti-cancer therapy, until death, loss 
of follow-up, withdrawal of consent, or study termination by Sponsor.  Follow-up data 
capture, including subsequent anti-cancer therapies (including targeted therapies and 
immunotherapies), will continue for each patient until death, loss of follow-up, withdrawal 
of consent, or study termination by Sponsor.
For patients randomized to the atezolizumab arm, response will be assessed by the 
investigator with use of RECIST v1.1 and modified RECIST.  For patients randomized to 
the chemotherapy arm, response will be assessed by the investigator with use of 
RECIST v1.1 only.
Primary imaging data used for tumor assessment may be collected by the Sponsor to 
enable centralized, independent review of response endpoints if needed.
Safety assessments will include the incidence, nature, and severity of adverse events 
and laboratory abnormalities graded per the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0).  Laboratory 
safety assessments will include the regular monitoring of hematology and blood 
chemistry.  Serum samples will be collected to monitor atezolizumab pharmacokinetics 
and to detect the presence of antibodies to atezolizumab.  Patient samples, including 


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archival tumor tissues, as well as serum and plasma and whole blood, 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).
3.1.1
Independent Data Monitoring Committee
An iDMC will be set up to evaluate safety data during the study.  The iDMC will evaluate 
study safety data on a periodic basis, approximately every 6 months from the point of 
first patient in (FPI).  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 blind to 
the results until the primary analysis.
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 is defined as the date when all patients have one of the following:

Experienced an OS event

Been lost to follow-up

Withdrawn consent
In addition, the Sponsor may decide to terminate the study at any time (see 
Section 4.6.2).
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Study Design
This Phase III study design is based on the assumption that, in patients with UBC who 
have failed prior platinum therapy, treatment with atezolizumab may prolong OS 
compared with treatment with single-agent chemotherapy.  Prospective evaluation of 
PD-L1 expression in tumor tissue will allow for the estimation of treatment benefit 
according to different levels of PD-L1 expression.
3.3.2
Rationale for Primary and Secondary Endpoints
Improvement in OS is generally accepted as the best measure of clinical benefit for 
patients with advanced/unresectable or metastatic UBC.  The assumption that treatment 
with atezolizumab will prolong OS compared with treatment with single-agent 
chemotherapy is based on the durable response rates observed in multiple tumor types 
in Phase I Study PCD4989g with atezolizumab.  Comparisons of OS between the 


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treatment and control arms will be evaluated in a hierarchical fixed-sequence testing 
procedure in the population of patients with an IHC score of IC2/3, the population of 
patients with an IHC score of IC1/2/3, and in the ITT population.
The secondary efficacy endpoints of PFS and ORR will allow the evaluation of 
differences in response and progression patterns between the two treatment arms.  
Patients will be evaluated for disease progression at predefined, standard intervals to 
minimize evaluation-time biases and will be followed off-treatment for continued safety 
monitoring and date of death.  Safety and tolerability of study treatments will be 
assessed.  Atezolizumab pharmacokinetics will be characterized and exploratory 
biomarker analyses performed.  The atezolizumab concentration results may be 
compared with available data from other atezolizumab clinical studies and correlated 
with efficacy endpoints and safety events as appropriate.  PRO data will allow further 
evaluation of the relative tolerability of treatment and the impact of therapy on disease 
symptoms between the two treatment groups.
3.3.3
Rationale for Inclusion of All Patients (All Levels of PD-L1 
Expression by Immunohistochemistry) in the Study
Responses to atezolizumab have been observed in both PD-L1positive (defined by 
IHC score of IC2 or IC3) and PD-L1negative patients (defined by IHC score of IC0 or 
IC1), although the response rate in patients with PD-L1positive UBC has been higher 
than that observed for the PD-L1negative patients in Phase I Study PCD4989g.  As 
indicated in Section 1.2.2.3, PD-L1negative patients had a response rate of 11.4%, 
which is comparable to the historical response rates of 9% to 11% observed in 
randomized studies of second-line patients who progressed on prior platinum-based 
chemotherapy (Bellmunt et al. 2009; Choueiri et al. 2012).  The inclusion of patients with 
all levels of PD-L1 expression by IHC will also enable a robust assessment of the 
hypothesis that PD-L1positive status is predictive of increased efficacy with 
atezolizumab treatment relative to PD-L1negative status and will also allow for the 
evaluation of OS benefit in the overall population with atezolizumab treatment relative to 
chemotherapy treatment irrespective of PD-L1 status.
3.3.4
Rationale for Testing Atezolizumab in Patients with UBC Who 
Have Failed Prior Platinum Therapy
Despite recent improvements in treatment, the prognosis for patients with advanced 
UBC remains dismal, with median OS of approximately 15 months (Garcia et al. 2006).  
Patients who receive second-line treatment for their disease have an even worse 
prognosis, with median survival duration of approximately 79 months 
(Sonpavde et al. 2010).  Approved therapies are associated with significant toxicities 
(e.g., neuropathy, febrile neutropenia, myelosuppression, and alopecia) that negatively 
impact quality of life.  Therefore, there is a continuing need for more efficacious, 
better-tolerated treatments for patients with advanced UBC who have failed prior 
platinum therapy.


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3.3.5
Rationale for Control Arm Therapy
Since a single, global standard of care is lacking for the second-line treatment of patients 
with UBC, three single-agent chemotherapy regimens were chosen to reflect the most 
commonly used therapies worldwide in this patient population.
3.3.5.1
Vinflunine
Vinflunine is the only second-line agent approved in the European Union only for the 
treatment of patients with UBC.  This regimen is recommended by the ESMO and EUA 
clinical practice guidelines.
3.3.5.2
Paclitaxel or Docetaxel
Single-agent taxane therapy is recommended by the NCCN guidelines as one of the 
preferred palliation options for the second-line treatment of patients with UBC.  In one 
study, patients were administered paclitaxel 175 to 250 mg/m2 by 24-hour infusion and 
one PR was reported among 3 patients who failed first-line therapy (Dreicer et al. 1996).  
Dose modifications were required because of myelosuppression or neurotoxicity for 
most patients dosed at 200 or 250 mg/m2.  Weekly paclitaxel given at a dose of 
80 mg/m2 has been tested in patients with previously treated UBC and has 
demonstrated a modest 10% ORR (Vaughn et al. 2002).  Since there are no data in this 
disease setting suggesting weekly paclitaxel to have advantages in terms of tolerability 
and/or efficacy compared with q3w paclitaxel, the paclitaxel 175 mg/m2 q3w regimen has 
been chosen for this study so patients randomized to either arm will be dosed with a q3w 
schedule.
Docetaxel has demonstrated similar survival benefit relative to vinflunine in patients with 
UBC.  In the randomized Phase II CONSORT study (n142), docetaxel plus vandetanib 
was compared with docetaxel plus placebo in patients with platinum-pretreated 
metastatic UBC (Choueiri et al. 2012).  OS was similar in both arms (HR1.21; 
95% CI: 0.81, 1.79).  Median OS in the docetaxel plus placebo arm was 7.39 months.
3.3.6
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 permuted-block randomization scheme will be used to 
ensure an approximately equal sample size and a similar distribution of stratification 
factors for the two treatment arms.
Chemotherapy (i.e., vinflunine vs. taxane) is included as a stratification factor because 
the second-line standards of care treatment for UBC, which may impact the final OS 
endpoint, differ among geographic regions.


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The PD-L1 IHC status (i.e., IHC score of IC0/1 vs. IHC score of IC2/3) is included as a 
stratification factor because the primary efficacy analysis for OS will be conducted in a 
hierarchical procedure for which the comparison between the treatment and control arms 
will be tested in the group of patients with IHC score of IC2/3 first followed by patients 
with an IHC score of IC1/2/3 and then in the overall population (ITT population).
In the second-line setting of UBC, OS differs on the basis of the presence of certain risk 
factors:  time from prior chemotherapy (TFPC) 3 months, ECOG performance status 
0, hemoglobin 10 g/dL, and liver metastasis.  The median OS of four groups based 
on 0, 1, 2, and 3/4 risk factors demonstrated significant divergence:  12.2, 6.7, 5.1, 
and 3.0 months, respectively (Bellmunt et al. 2010; Pond et al. 2013).  In the only 
randomized Phase III study in second-line UBC comparing vinflunine with BSC, which 
examined 16 potential prognostic factors for their association with survival, patients with 
liver metastasis had the worst OS outcome (Bellmunt et al. 2009).  Considering this 
observation, patients in this study will first be stratified on the basis of the number of risk 
factors (0 vs. 1/2/3):  TFPC 3 months, ECOG performance status 0, hemoglobin 
10 g/dL, and liver metastasis (yes vs. no) will be selected as a stand-alone stratification 
factor.
3.3.7
Rationale for Atezolizumab Dosage
The fixed dose of 1200 mg (equivalent to an average body weightbased dose of 
15 mg/kg) was selected on the basis of both nonclinical studies and available clinical 
data from Study PCD4989g as described below. 
The target exposure for atezolizumab was projected on the basis of nonclinical tissue 
distribution data in tumor-bearing mice, target-receptor occupancy in the tumor, the 
observed atezolizumab interim pharmacokinetics in humans, and other factors.  The 
target trough concentration (Ctrough) was projected to be 6 g/mL on the basis of several 
assumptions, including:  1) 95% tumor-receptor saturation is needed for efficacy and 
2) the tumor-interstitial concentration to plasma ratio is 0.30 based on tissue distribution 
data in tumor-bearing mice.
The atezolizumab dose is also informed by available clinical activity, safety, PK, and 
immunogenicity data.  Anti-tumor activity has been observed across doses from 1 mg/kg 
to 20 mg/kg.  The MTD of atezolizumab was not reached, and no DLTs have been 
observed at any dose in Study PCD4989g.  Available preliminary PK data 
(0.0320 mg/kg) from Study PCD4989g suggest that for doses 1 mg/kg, overall 
atezolizumab exhibits pharmacokinetics that are both linear and consistent with typical 
IgG1 antibodies.  Detectable ATAs were observed in patients at all dose levels but were 
associated with changes in pharmacokinetics for some patients in only the lower dose 
cohorts (0.3, 1, and 3 mg/kg).  It is unclear from currently available data in these lower 
dose cohorts if administration of higher doses to patients with both detectable 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 


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been observed.  Available data suggest that the development of detectable ATAs does 
not appear to have a significant impact on the pharmacokinetics for doses from 10 to 
20 mg/kg in most patients.  Correspondingly, patients dosed at the 10-, 15-, and 
20-mg/kg dose levels have maintained target trough levels of drug despite the detection 
of 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 safeguard against both
interpatient variability and the potential effect of ATAs that could lead to subtherapeutic 
levels of atezolizumab relative to the 10-mg/kg atezolizumab q3w regimen (or fixed-dose 
equivalent).  From inspection of available observed Ctrough data, moving further to the 
20-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 do not suggest any clinically meaningful differences in exposure following a 
fixed dose or a dose adjusted for weight.  On the basis of this analysis, a fixed dose of 
1200 mg has been selected (equivalent to an average body weightbased dose of 
15 mg/kg).
Selection of an every-21-day dosing interval is supported by this preliminary PK 
evaluation and allows for a convenient integration with common chemotherapeutic 
regimens.
3.3.8
Rationale for Collection of Archival and/or Pre-Treatment 
Tumor Specimens
Published results suggest that the expression of PD-L1 in tumors correlates with 
response to antiPD-1 therapy (Topalian et al. 2012).  This correlation is also observed 
with atezolizumab in preliminary data from Study PCD4989g (see Section 1.2.2.1).  In 
this study, tumor specimens from patients will be prospectively tested for PD-L1 
expression by a central laboratory during the screening period, and enrolling patients will 
be stratified according to tumor tissue PD-L1 expression.  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.
Patients having 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 UBC 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.


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3.3.9
Rationale for Blood Sampling for Biomarkers and for 
Collection of Optional 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.  Anti-tumor immune 
responses such as those associated with atezolizumab may result in objective 
responses that are delayed and that can be preceded by initial apparent radiological 
progression.  This initial apparent progression may occur as a result of either delayed 
anti-tumor activity and/or robust tumor immune cell infiltration with a concomitant 
increase in tumor size.  In addition, lesions that might otherwise be undetectable with 
conventional imaging may increase in size as a result of these processes and be 
recorded as new lesions (Hales et al. 2010).  Furthermore, patients agreeing to optional 
tumor biopsies will undergo tissue collection, if clinically feasible, at pre-treatment and at 
the first evidence of early radiographic disease progression.  These optional biopsy 
samples will be placed in the Roche Clinical Repository (RCR) (see Section 4.5.6).
3.3.10
Rationale for Patient-Reported Outcome Assessments
PROs provide an understanding of the impact a treatment has on a patient.  Currently, 
there are no fully validated PRO instruments to measure symptoms and HRQoL
specifically among patients with advanced/metastatic UBC. The EORTC QLQ-C30 is a 
validated instrument that has been widely used in assessing quality of life in patients 
with cancer.  The core instrument assesses global health status/quality of life, functions 
(physical, role, emotional, cognitive, and social), and general cancer symptoms.
3.3.11
Rationale for Allowing Patients to Continue Atezolizumab 
Treatment beyond Initial Progression per RECIST v1.1
Conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents because progressive disease (by initial radiographic 
evaluation) does not necessarily reflect therapeutic failure (see Section 3.3.9).  Because 
of the potential for pseudoprogression/tumor immune infiltration, this study will allow 
patients randomized to receive atezolizumab to remain on study treatment after
apparent radiographic progression, provided the benefit-risk ratio is judged to be 
favorable.  In Study PCD4989g, several patients with NSCLC who progressed by 
RECIST v1.1 criteria continued on atezolizumab treatment and demonstrated durable 
anti-tumor activity.  In addition, in some responding patients, the growth of known lesions 
or the appearance of new radiographic lesions were shown to contain immune cells and 
no viable cancer cells on biopsy.  Patients should be discontinued for unacceptable 
toxicity or symptomatic deterioration attributed to disease progression as determined by 


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the investigator after an integrated assessment of radiographic data and clinical status 
(see Section 4.6.2).
Although secondary endpoint measures of efficacy (ORR, PFS) comparing the 
atezolizumab and chemotherapy arms will use RECIST v1.1 criteria, noncomparative 
analyses of these measures with use of modified RECIST criteria (see Appendix 3) will 
be performed for patients randomized to receive atezolizumab.  Modified RECIST 
criteria allow the incorporation of new lesions into the calculation of total tumor burden 
after baseline.  Similar to the immune-related response criteria (Wolchok et al. 2009), it 
is recommended that radiological progression be confirmed at a subsequent tumor 
assessment to take into account the potential for pseudoprogression/tumor immune 
infiltration.  In addition, it is highly recommended that evidence of progressive disease in 
responding patients be confirmed by a biopsy of the growing or new lesion when feasible.
3.4
OUTCOME MEASURES
3.4.1
Efficacy Outcome Measures
3.4.1.1
Primary Efficacy Outcome Measure

OS, defined as the time between the date of randomization and death due to any 
cause
3.4.1.2
Secondary Efficacy Outcome Measures

ORR, defined as the proportion of patients with an objective response (either a CR 
or PR) as determined by the investigator with use of RECIST v1.1

PFS, defined as the time between the date of randomization and the date of first 
documented disease progression as determined by the investigator with use of 
RECIST v1.1 or death due to any cause, whichever occurs first

DOR, defined as the time between the date of first documented response and the 
date of first documented disease progression as determined by the investigator with 
use of RECIST v1.1 or death due to any cause, whichever occurs first
3.4.2
Safety Outcome Measures

Incidence, nature, and severity of adverse events graded according to 
NCI CTCAE v4.0

Changes in vital signs, physical findings, 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

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, 4, 8, and 16, at treatment discontinuation, and at 120 days 
(30 days) after the last dose of atezolizumab


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3.4.4
Patient-Reported Outcome Measure

UBC cancer symptoms, patient functioning, and HRQoL as measured by the 
EORTC QLQ-C30
3.4.5
Exploratory Outcome Measures

PFS, ORR, and DOR with use of modified RECIST (see Appendix 3) for patients 
randomized to atezolizumab

DCR, defined as the rate of patients with complete or partial response as best 
response or stable disease maintained for 18 weeks per RECIST v1.1

Status of tumor immune-related or disease typerelated exploratory biomarkers in 
archival and/or freshly obtained tumor tissues and association with disease status 
and/or response to atezolizumab

Status of exploratory biomarkers in plasma, whole blood, or serum (including but not 
limited to cytokines such as interleukin 6 [IL-6]) collected before or during treatment 
with atezolizumab or at progression and association with disease status and/or 
response to atezolizumab

Utility scores of the EQ-5D (3L) for use in economic models

Items from the EORTC QLQ-C30 that are not included in the main PRO outcome 
measure
4.
MATERIALS AND METHODS
4.1
PATIENTS
4.1.1
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Ability to comply with protocol

Age 18 years

Histologically or cytologically documented locally advanced (T4b, any N; or any T, 
N23) or metastatic (M1, Stage IV) UBC (also termed TCC or UCC of the urinary 
tract; including renal pelvis, ureters, urinary bladder, and urethra)
Patients with mixed histologies are required to have a dominant transitional cell 
pattern.
Locally advanced bladder cancer must be inoperable on the basis of 
involvement of pelvic sidewall or adjacent viscera (clinical stage T4b) or bulky 
nodal metastasis (N2N3).

Patients with a history of treated asymptomatic CNS metastases are eligible, 
provided they meet all of the following criteria:
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla or spinal cord)
No ongoing requirement for corticosteroids as therapy for CNS disease


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No stereotactic radiation within 7 days
No evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study 
Patients with new asymptomatic CNS metastases detected at the screening 
scan must receive radiation therapy and/or surgery for CNS metastases.  
Following treatment, these patients may then be eligible without the need for an 
additional brain scan prior to enrollment [or randomization], if all other criteria 
are met.

Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens 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.
TURBT specimens must contain a muscle invasive component (i.e., T2 or 
greater) of the bladder tumor as verified by local pathology review.  If the 
TURBT specimens do not contain a muscle invasive component, then 
specimens obtained at the time of cystectomy/nephroureterectomy or 
metastatic spread (i.e., sample from a metastatic lesion) will be required prior to 
randomization.  An archival specimen, if available, should also be submitted.
Patients who do not have tissue specimens meeting eligibility requirements may 
undergo a biopsy during the screening period.  Acceptable samples include 
core needle biopsies for deep tumor tissue (minimum three cores) or excisional, 
incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal 
lesions.
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and 
is therefore not acceptable.
Patients having additional tissue samples from procedures performed at 
different times during the course of their UBC 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.  In situations where multiple specimens 
were received from different sites or at different times, the highest score will be 
used for both primary and secondary analyses.


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
Disease progression during or following treatment with at least one 
platinum-containing regimen (e.g., GC, MVAC, CarboGem, etc.) for inoperable, 
locally advanced or metastatic UBC or disease recurrence
A regimen is defined as patients receiving at least two cycles of a 
platinum-containing regimen.
Patients who received prior adjuvant/neoadjuvant chemotherapy and 
progressed within 12 months of treatment with a platinum-containing 
adjuvant/neoadjuvant regimen will be considered as second-line patients.
Patients may have received no more than two prior regimens of treatment 
(including the required platinum-based regimen) for their advanced UBC. 
Patients must have demonstrated disease progression during or following all 
prior regimen(s). 
Patients who have received one cycle of a platinum-containing regimen but 
discontinued because of a Grade 4 hematologic toxicity or a Grade 3/4 
non-hematologic toxicity may also be eligible.
Patients with disease progression following chemoradiotherapy must 
demonstrate progression outside the prior radiotherapy port.

ECOG performance status of 0 or 1 (see Appendix 8).

Life expectancy 12 weeks

Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions should not be counted as target lesions.

Adequate hematologic and end-organ function, 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 500/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 times the upper limit of normal (ULN), 
with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5ULN
Patients with documented liver or bone metastases:  alkaline phosphatase
5ULN


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Serum bilirubin 1.0ULN
Patients with known Gilbert disease who have serum bilirubin level 
3ULN may be enrolled.
INR and aPTT 1.5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 (CRCL) 30 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, 3 months after the last dose of vinflunine and 6 months from 
the last dose of paclitaxel or docetaxel.
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.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures and agreement to refrain from donating sperm, as 
defined below:
With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of 1% per year during the treatment period and for at least 
3 months after the last dose of vinflunine and 6 months from the last dose of 
paclitaxel or docetaxel.  Men must refrain from donating sperm during this same 
period.
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 28 days after the last dose of 
vinflunine, paclitaxel, or docetaxel.
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.


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4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry.
4.1.2.1
Cancer-Specific Exclusions

Any approved anti-cancer therapy, including chemotherapy or hormonal therapy,
within 3 weeks prior to initiation of study treatment; the following exceptions are 
allowed:
Palliative radiotherapy for bone metastases or soft tissue lesions should be 
completed 7 days prior to baseline imaging
Hormone-replacement therapy or oral contraceptives

Treatment with any other investigational agent or participation in another clinical trial 
with therapeutic intent within 28 days prior to enrollment

Active or untreated CNS metastases as determined by computed tomography (CT) 
or magnetic resonance imaging (MRI) evaluation during screening and prior 
radiographic assessments
Patients with treated asymptomatic CNS metastases are eligible, provided they 
meet all of the following criteria:
Evaluable or measurable disease outside the CNS
No metastases to midbrain, pons, medulla, cerebellum, or within 10 mm of 
the optic apparatus (optic nerves and chiasm)
No history of intracranial or spinal cord hemorrhage
No ongoing requirement for dexamethasone as therapy for CNS disease; 
anti-convulsants at a stable dose are allowed
No evidence of significant vasogenic edema
No stereotactic radiation, whole-brain radiation or neurosurgical resection 
with 4 weeks prior to Cycle 1, Day 1
Radiographic demonstration of interim stability (i.e., no progression) 
between the completion of CNS-directed therapy and the screening 
radiographic study
Screening CNS radiographic study 4 weeks since completion of 
radiotherapy or surgical resection and 2 weeks since discontinuation of 
corticosteroids

Leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)

Patients with indwelling catheters (e.g., PleurX) are allowed.


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
Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone 
metastases or metastases causing nerve impingement) should be treated prior 
to enrollment.
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not 
presently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to enrollment.

Uncontrolled hypercalcemia (defined as any one or more of the following criteria:
1.5 mmol/L ionized calcium
Serum calcium 12 mg/dL 
Corrected serum calcium ULN (if serum albumin 4.0 g/dL)
Symptomatic hypercalcemia requiring continued use of bisphosphonate 
therapy or denosumab
Patients who are receiving bisphosphonate therapy or denosumab specifically 
to prevent skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible.
Patients who are receiving denosumab prior to enrollment must be willing and 
eligible to discontinue its use and replace it with a bisphosphonate instead while 
on study.

Malignancies other than UBC within 5 years prior to Cycle 1, Day 1
Patients with localized low risk prostate cancer (defined as Stage T2b, 
Gleason score 7, and prostate-specific antigen [PSA] at prostate cancer 
diagnosis 20 ng/mL) treated with curative intent and without PSA recurrence 
are eligible.
Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score 
6, and PSA 10 ng/mL) who are treatment-naive and undergoing active 
surveillance are eligible.
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk 
of metastasis or death 5% at 5 years) are eligible provided they meet all of the 
following criteria:
Malignancy treated with expected curative intent (such as adequately 
treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, 
or ductal carcinoma in situ treated surgically with curative intent)
No evidence of recurrence or metastasis by follow-up imaging and any 
disease-specific tumor markers


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4.1.2.2
General Medical Exclusions

Pregnant and lactating

Evidence of significant uncontrolled concomitant disease that could affect 
compliance with the protocol or interpretation of results, including significant liver 
disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena 
cava syndrome)

Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction within 3 months prior to 
randomization, unstable arrhythmias, or unstable angina

Patients with a known left ventricular ejection fraction (LVEF) 40% will be 
excluded.
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or LVEF 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.

Severe infections within 4 weeks prior to randomization including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Received therapeutic oral or IV antibiotics within 2 weeks prior to randomization
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease) are eligible.

Major surgical procedure within 4 weeks prior to randomization or anticipation of 
need for a major surgical procedure during the course of the study other than for 
diagnosis

Inability to understand the local language(s) for which the EORTC QLQ-C30 and 
EQ-5D (3L) questionnaires are available (see Appendix 5 for English versions)
4.1.2.3
Exclusion Criteria Related to Paclitaxel

Prior treatment with paclitaxel for assignment of paclitaxel in the chemotherapy 
control arm prior to randomization

History of severe hypersensitivity to paclitaxel or to other drugs formulated with 
polyoxyethylated castor oil
4.1.2.4
Exclusion Criteria Related to Docetaxel

Prior treatment with docetaxel for assignment of docetaxel in the chemotherapy 
control arm prior to randomization 

History of severe hypersensitivity to docetaxel or to other drugs formulated with 
polysorbate 80

Grade 2 peripheral neuropathy as defined by NCI CTCAE v4.0 criteria

Inability to discontinue use of strong cytochrome P450 (CYP)3A4 inhibitors including 
but not limited to ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole


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4.1.2.5
Exclusion Criteria Related to Vinflunine

Prior treatment with vinflunine for assignment of vinflunine in the chemotherapy 
control arm prior to randomization

History of severe hypersensitivity to vinflunine or other vinca alkaloids
4.1.2.6
Exclusion Criteria Related to Atezolizumab

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins

Known hypersensitivity or allergy 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 6 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 1 diabetes mellitus on a stable insulin regimen 
may be eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis) are 
permitted provided that they meet the following conditions:
Rash must cover less than 10% of body surface area (BSA)
Disease is well controlled at baseline and only requiring low potency topical 
steroids
No acute exacerbations of underlying condition within the last 12 months 
(not requiring PUVA [psoralen plus ultraviolet A radiation], 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high 
potency or oral steroids)

Patients with prior allogeneic stem cell or solid organ transplantation

History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced 
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic 
organizing pneumonia), or evidence of active pneumonitis on screening chest 
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 (defined as having a positive hepatitis B surface 
antigen [HBsAg] test at screening) or hepatitis C 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as having a negative HBsAg test and a positive antibody to hepatitis B 
core antigen [anti-HBc] antibody test) are eligible.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction (PCR) is negative for HCV RNA.

Active tuberculosis (TB)

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 March 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) 
28 days prior to randomization, during treatment or within 5 months following 
the last dose of atezolizumab (for patients randomized to atezolizumab).

Prior treatment with CD137 agonists, antiPD-1, or antiPD-L1 therapeutic antibody 
or pathway-targeting agents
Patients who have had prior anticytotoxic T lymphocyteassociated antigen 4 
(CTLA-4) may be enrolled, provided the following requirements are met:
Minimum of 12 weeks from the first dose of antiCTLA-4 and 6 weeks 
from the last dose
No history of severe immune-related adverse effects from antiCTLA-4 
(NCI CTCAE Grade 3 and 4)

Treatment with systemic immunostimulatory agents (including but not limited to 
interferons or IL-2) within 4 weeks or five half-lives of the drug, whichever is shorter, 
prior to randomization

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 [TNF] agents) within 2 weeks prior to randomization 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) may be 
enrolled in the study after discussion with and approval by the Medical Monitor.
The use of inhaled corticosteroids, physiologic replacement doses of 
glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., 
fludrocortisone) is allowed.


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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
This is an open-label study.
After written informed consent has been obtained and eligibility has been established 
(including determination of tumor PD-L1 status by central testing), the study site will 
enter demographic and baseline characteristics in the interactive voice/Web response 
system (IxRS).  For those patients who are eligible for enrollment, the study site will 
obtain the patient’s randomization number and treatment assignment from the IxRS.  
Randomization to the treatment and control arms will occur in a 1:1 ratio with use of a 
permuted-block randomization method.  Prior to the randomization, the investigator will 
have the option of choosing one of three chemotherapy regimens (vinflunine, paclitaxel, 
or docetaxel) for each patient.  Randomization will be stratified by the following factors:

Chemotherapy (vinflunine vs. taxane)

PD-L1 IHC status (IHC score of IC0/1 vs. IHC score of IC2/3)

Number of risk factors (0 vs. 1/2/3)
TFPC 3 months
ECOG performance status 0
Hemoglobin 10 g/dL

Liver metastasis (yes vs. no)
Patients should receive their first dose of study treatment on the day of randomization if 
possible.  If this is not possible, the first dose should occur no later than 3 days after 
randomization.
4.3
STUDY TREATMENT
Atezolizumab is considered the investigational medicinal product (IMP) in this study.
Vinflunine, paclitaxel, and docetaxel are considered non-IMPs in this study.  Depending 
on local legislation, vinflunine, paclitaxel, and docetaxel may be considered IMPs.  If 
considered an IMP, then appropriate information on formulation, packaging, handling, 
and administration will be provided.
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 Atezolizumab 
Investigator's Brochure and Pharmacy Manual.


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4.3.1.2
Vinflunine, Paclitaxel, and Docetaxel
See the local prescribing information for details on drug formulation, packaging, and 
handling.  Vinflunine, paclitaxel, or docetaxel will be provided by the Sponsor 
(F. Hoffmann-La Roche Ltd) where it is considered an IMP by local regulations.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Atezolizumab
The dose level of atezolizumab proposed 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).
Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies.  
For more detailed information on drug preparation, storage, and administration, refer to 
the Atezolizumab Investigator’s Brochure and Pharmacy Manual.
The initial dose of atezolizumab will be delivered over 60 (15) minutes.  If the first 
infusion is tolerated without infusion-associated adverse events, the second infusion 
may be delivered over 30 (10) minutes.  If the 30-minute infusion is well tolerated, all 
subsequent infusions may be delivered over 30 (10) minutes.  For the first infusion, the 
patient’s vital signs (heart rate, respiratory rate, blood pressure, and temperature) should 
be determined within 60 minutes before, during (every 15 [5] minutes), and 
30 (10) minutes after the infusion.  For subsequent infusions, vital signs will be 
collected within 60 minutes before the infusion and within 30 minutes after the infusion.
No premedication will be allowed for the first dose of atezolizumab.  Premedication may 
be administered for Cycles 2 at the discretion of the treating physician.  The 
management of infusion-related reactions will be according to severity as follows:

In the event that a patient experiences a mild (NCI CTCAE Grade 1) infusion-related 
event, the infusion rate should be reduced to half the rate being given at the time of 
event onset.  Once the event has resolved, the investigator should continue to 
deliver the infusion at the reduced rate for 30 minutes.  If tolerated, the infusion rate 
may then be increased to the original rate.

In the event that a patient experiences a moderate infusion-related event 
(NCI CTCAE Grade 2) or flushing, fever, or throat pain, the patient should have his 
or her infusion immediately interrupted and should receive aggressive symptomatic 
treatment.  The infusion should be restarted only after the symptoms have 
adequately resolved to the baseline grade.  The infusion rate at restart should be 
half of the rate that was in progress at the time of the onset of the infusion-related 
event.


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
For severe or life-threatening infusion-related events (NCI CTCAE Grade 3 or 4), 
the infusion should be stopped immediately, and aggressive resuscitation and 
supportive measures should be initiated.  Patients experiencing severe or 
life-threatening infusion-related events will not receive further infusion and will be 
further managed as clinically indicated until the event resolves.
For anaphylaxis precautions, see Appendix 7.
Guidelines for dosage modification, treatment interruption, or discontinuation and the 
management of specific adverse events are provided in 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 5.3.5.10).
4.3.2.2
Paclitaxel
Paclitaxel will be administered according to the local prescribing information.  The 
starting dose level of paclitaxel in this study will be 175 mg/m2 q3w administered via 
IV infusion over 3 hours.  Pretreatment with corticosteroids, diphenhydramine, and 
H2 antagonists will be required to prevent severe hypersensitivity reactions.  Dose 
modifications should be performed according to Section 5.1.6.
Vital signs will be collected for paclitaxel infusions according to Section 4.5.2.3.
4.3.2.3
Docetaxel
Docetaxel will be administered according to the local prescribing information.  The 
starting dose of docetaxel will be 75 mg/m2 q3w.  Dose modifications should be 
performed Section 5.1.7.
All patients randomized to receive docetaxel should be premedicated with oral 
corticosteroids, such as dexamethasone at 16 mg/day (e.g., 8 mg twice daily), for 3 days 
starting a day prior to docetaxel administration in order to reduce the incidence and 
severity of fluid retention as well as the severity of hypersensitivity reactions.
Anti-emetic prophylaxis may be administered at the treating physician’s discretion 
according to local practice.
Vital signs will be collected for docetaxel infusions according to Section 4.5.2.3.
4.3.2.4
Vinflunine
Vinflunine will be administered according to the locally approved label.  The starting 
dose of vinflunine will be 320 mg/m2 q3w in patients aged 75 years with an ECOG 
performance status of 0; 280 mg/m2 q3w in patients aged between 75 and 80 years, 
with an ECOG performance status of 1, moderate renal impairment (CRCL 40 to 


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60 mL/min), or previous pelvic radiation; or 250 mg/m2 q3w in patients aged 80 years 
or with severe renal impairment (CRCL 30 to 40 mL/min).  In order to prevent 
constipation, laxatives and dietary measures including oral hydration are recommended 
from Day 1 to Days 5 or 7 after each vinflunine administration.
For patients with ECOG performance status of 1 or prior pelvic radiation, the starting 
dose of vinflunine will be 280 mg/m2.  In the absence of any hematological toxicity during 
the first cycle causing treatment delay or dose reduction, the dose will be increased to 
320 mg/m2 for the subsequent cycles.
See local prescribing information/institutional guidelines for detailed guidelines on 
administration or dose adjustments for special populations.  Dose modifications for 
toxicities should be performed according to Section 5.1.8.
Vital signs will be collected for vinflunine infusions according to Section 4.5.2.3.
4.3.3
Investigational Medicinal Product Accountability
As an IMP, atezolizumab will be provided by the Sponsor.  Vinflunine, paclitaxel, and 
docetaxel will be provided by the Sponsor if considered an IMP by local regulations.  The 
investigational site will acknowledge receipt of atezolizumab, vinflunine, paclitaxel, and 
docetaxel (if provided by the Sponsor) with use of the IxRS to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed upon 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
The Sponsor will offer post-trial access to the study drug atezolizumab free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 

There are no appropriate alternative treatments available to the patient


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
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met:

The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for locally advanced or metastatic UBC

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for locally advanced or metastatic UBC

Provision of study drug is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
4.4.1
Permitted Therapy 
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the date of informed 
consent and the date of clinical or radiographic progression or study discontinuation.
Patients who experience infusion-associated symptoms may be treated symptomatically 
with anti-pyretics (ibuprofen preferred), diphenhydramine, and/or cimetidine 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).
Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician (for specific recommendations, see Appendix 9).  
For patients randomized to atezolizumab, alternatives to corticosteroids should be 
considered if feasible, but premedication may be administered for Cycles 2.  The use 
of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed.  
Megestrol administered as an appetite stimulant is acceptable while the patient is 
enrolled in the study.


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Patients who use hormonal therapy such as oral contraceptives, hormone-replacement 
therapy, prophylactic or therapeutic anticoagulation therapy (such as lowmolecular
weight heparin or warfarin at a stable dose level), or other allowed ongoing therapies or 
medications (see Section 4.1.2) should continue their use.  Female patients of 
reproductive potential should use a highly effective means of contraception.  
All concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.
4.4.2
Excluded Therapy
Any concomitant therapy intended for the treatment of cancer, whether health 
authorityapproved or experimental, is prohibited.  This includes but is not limited to the 
following:

Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational 
agents, or herbal therapy
After the completion of Cycle 1, certain forms of radiotherapy may be 
considered for palliation if patients are deriving benefit (e.g., treatment of known 
bony metastases, symptomatic hematuria).  
Study drug administration may be continued during radiotherapy for patients 
being treated with atezolizumab.  Study drug should be suspended for patients 
being treated with vinflunine, paclitaxel, or docetaxel per institutional guidelines.
Patients experiencing a mixed response requiring local therapy (e.g., surgery, 
stereotactic radiosurgery, radiotherapy, radiofrequency ablation) for control of 
three or fewer lesions may still be eligible to continue study treatment, at the 
discretion of the investigator.  Patients who receive local therapy directed at a 
target lesion will no longer be evaluable for radiographic response but will 
remain evaluable for progression.  Such cases should be discussed with the 
Medical Monitor.
4.4.2.1
Excluded and Cautionary Therapy for Atezolizumab-Treated 
Patients
The following guidance applies only to patients randomized to receive atezolizumab.  
The following medications are excluded while the patient is receiving study treatment:

Traditional herbal medicines; these therapies are not fully studied and their use may 
result in unanticipated drug-drug interactions that may cause or confound the 
assessment of toxicity.

RANKL inhibitor (denosumab)

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.


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Influenza vaccinations (inactivated forms only) should be given during influenza season 
only (approximately October to March in the Northern hemisphere; April to September in 
the Southern Hemisphere).  Patients must agree not to receive live, attenuated influenza 
vaccines (such as FluMist) 28 days prior to randomization, during treatment or within 
5 months following the last dose of atezolizumab (for patients randomized to 
atezolizumab).
Initiation or increased dose of granulocyte colony-stimulating factors (e.g., granulocyte 
colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, and/or 
pegfilgrastim) is prohibited.
Systemic corticosteroids and antiTNF-agents may also attenuate potential beneficial 
immunologic effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician.  If feasible, alternatives to these agents should be 
considered.
In addition, patients treated with atezolizumab (including those who discontinue the 
study early) should not receive other immunomodulatory agents for 10 weeks after study 
treatment discontinuation.
4.4.3
Concomitant Medications with Paclitaxel
The metabolism of paclitaxel is catalyzed by CYP isoenzymes CYP2C8 and CYP3A4. 
Caution should be exercised when paclitaxel is concomitantly administered with known 
inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) and inducers (e.g., 
rifampin and carbamazepine) of CYP3A4.
Granulocyte colony-stimulating factor treatment is permitted for patients in the paclitaxel 
arm.  The primary prophylaxis should be administered per the American Society of 
Clinical Oncology (ASCO), EORTC, and ESMO guidelines; namely, in patients who are
60 years of age and/or with comorbidities (Smith et al. 2006; Crawford et al. 2009; 
Aapro et al. 2011).
Anti-emetics, anti-allergic measures, and other treatments for concomitant paclitaxel 
toxicities may be used at the discretion of the investigator, taking into account 
precautions from the Summary of Product Characteristics.
See the Summary of Product Characteristics (Package Insert) for paclitaxel for all boxed 
warnings and contraindications.


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4.4.4
Concomitant Medications with Docetaxel
Docetaxel is a CYP3A4 substrate.  Patients randomized to receive docetaxel must avoid 
using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, and voriconazole).  There are no clinical data with a dose adjustment in 
patients receiving strong CYP3A4 inhibitors.
In addition, concomitant treatment with CYP3A4 inducers may decrease plasma 
concentrations of docetaxel.  Therefore, concomitant medications that are CYP3A4 
inducers should be used with caution.
Granulocyte colony-stimulating factor treatment is permitted for patients in the docetaxel 
arm.  The primary prophylaxis should be administered per the ASCO, EORTC, and 
ESMO guidelines; namely, in patients who are 60 years of age and/or with 
comorbidities (Smith et al. 2006; Crawford et al. 2009; Aapro et al. 2011).
Anti-emetics, anti-allergic measures, and other treatments for concomitant docetaxel 
toxicities may be used at the discretion of the investigator, taking into account 
precautions from the Summary of Product Characteristics.
See the Summary of Product Characteristics (Package Insert) for docetaxel for all boxed 
warnings and contraindications.
4.4.5
Concomitant Medications with Vinflunine
Patients randomized to receive vinflunine must avoid using concomitant strong CYP3A4 
inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) or inducers 
(e.g., rifampicin, St John’s wort) since they may increase or decrease plasma 
concentration of vinflunine and its metabolite 4Odeacetyl-vinflunine, respectively.
In addition, the concomitant use of vinflunine with other QT/QTc intervalprolonging
drugs should be avoided.
Laxatives and dietary measures including oral hydration for concomitant vinflunine 
toxicities may be used at the discretion of the investigator, taking into account 
precautions from the Summary of Product Characteristics.
See the Summary of Product Characteristics (Package Insert) for vinflunine for all boxed 
warnings and contraindications.
4.5
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.


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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.
4.5.1
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.
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
Description of Study Assessments
4.5.2.1
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 the date of informed consent.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.2.2
Physical Examinations
A complete physical examination should include a weight measurement and 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.
4.5.2.3
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. 


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For patients assigned to both treatment arms, at all infusions, vital signs (heart rate, 
respiratory rate, blood pressures, and temperature) should be determined within 
60 minutes before and 30 (10) minutes after the infusion.  For the atezolizumab arm, 
vital signs will also be collected during the first infusion (every 15 [5] minutes.  Patients 
will be informed about the possibility of delayed post-infusion symptoms and instructed 
to contact their study physician if they develop such symptoms.
4.5.2.4
Tumor and Response Evaluations
Measurable and nonmeasurable disease must be documented at screening and 
reassessed at each subsequent tumor evaluation.  Tumor assessments are to be 
performed at the timepoints specified in Appendix 1, 3 business days regardless of 
drug delays or interruptions.
Results of standard of care tests or examinations performed prior to obtaining Informed 
Consent and 28 days prior to study entry may be used for the purposes of Screening 
rather than repeating such tests.
Screening assessments must include CT scans (with oral/IV contrast unless 
contraindicated) or MRI of the chest, abdomen, and pelvis.  A spiral CT scan of the chest 
may be obtained but is not a requirement.  In patients for whom CT scans with contrast 
are contraindicated (e.g. patients with contrast allergy or impaired renal clearance), 
MRIs of the chest, abdomen, and pelvis with a non-contrast spiral CT scan of the chest 
may be used.
A CT (with contrast if not contraindicated) or MRI scan of the head must be done at 
screening to evaluate CNS metastasis in all patients.  An MRI scan of the brain is 
required to confirm or refute the diagnosis of CNS metastases at baseline in the event of 
an equivocal scan.  Patients with active or untreated CNS metastases are not eligible for 
this study (see Section 4.1.2.1 for CNS-related exclusions).
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for 
a full-contrast diagnostic CT scan.
Bone scans (Technetium-99m [TC-99m]) or sodium fluoride PET (NaF-PET) should be 
performed at screening if clinically indicated.  If bone metastases are present at 
screening and cannot be seen on CT or MRI scans, or if clinically indicated, TC-99m and 
NaF-PET bone scans should be repeated when complete response is identified in target 
disease or when progression in bone is suspected. 
CT scans of the neck or extremities should also be performed if clinically indicated and 
followed throughout the study if there is evidence of disease at screening.  At the 
investigator’s discretion, other methods of assessment of measurable disease as per 
RECIST v1.1 may be used.


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For subsequent tumor assessments, procedures for tumor assessment should be 
performed as clinically indicated. The same radiographic procedure used to assess 
disease sites at screening should be used throughout the study (e.g., the same contrast 
protocol for CT scans).  All known sites of disease must be documented at screening 
and reassessed at each subsequent tumor evaluation.  For patients randomized to the 
atezolizumab arm, response will be assessed by the investigator with use of 
RECIST v1.1 and modified RECIST (see Appendix 3 and Appendix 4).  For patients 
randomized to the chemotherapy arm, response will be assessed by the investigator 
with use of RECIST v1.1 only.  Assessments should be performed by the same 
evaluator if possible to ensure internal consistency across visits.
Patients assigned to atezolizumab who continue treatment beyond radiographic disease
progression (see Section 4.6.1) will be monitored with a follow-up scan at the next 
scheduled tumor assessment when the scan frequency is every 9 weeks.  If the scan 
frequency is every 12 weeks (see Appendix 1), the follow-up scan must be performed at 
9 (2) weeks as an unscheduled tumor assessment, or earlier if clinically indicated.
At the investigator’s discretion, CT scans may be repeated at any time if progressive 
disease is suspected.
Primary imaging data used for tumor assessment may be collected by the Sponsor to 
enable centralized, independent review of response endpoints if needed.
4.5.2.5
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, Epstein-Barr virus (EBV) testing, C-reactive 
protein (CRP) testing, 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)


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
Serum pregnancy test during screening and serum or urine pregnancy tests (a 
positive urine test result will be confirmed with a serum pregnancy test) 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)

All patients will be tested for HIV within 3 months prior to the inclusion into the study, 
and HIV-positive patients will be excluded from the clinical trial.

All patients will have a tuberculin (PPD) skin test or IGRA performed locally within 
3 months prior to the inclusion into the study, and patients with active TB 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:

EBV serology (screening sample collection only; serology tests to be performed on 
the screening sample only in patients who experience an acute inflammatory event 
such as systemic inflammatory response syndrome while receiving study treatment)

CRP

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. 
Any remaining samples collected for PK and ATAs may be used for exploratory 
biomarker profiling, identification, and pharmacodynamic assay development 
purposes and additional safety assessments (e.g., ATA assay) as appropriate.

Vitamin D assays
25(OH)D

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


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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).

Archival or fresh tumor tissue samples for eligibility
Representative tumor specimens in paraffin blocks (preferred) or at least 
15 unstained slides, with an associated pathology report, must be submitted 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, 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 UBC 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.
For fresh biopsy specimens (i.e., after the initiation of the screening period), 
acceptable samples include core-needle biopsies for deep tumor tissue 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.


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
Optional biopsies 
Patients may agree to provide optional tumor biopsies by providing consent on 
the Optional RCR Informed Consent Form, which is separate from the main 
study Informed Consent Form.  For patients who agree to optional biopsies, 
tissue samples for biopsy may be collected per investigator discretion, 
preferably of growing lesions pre-treatment (unless a sample collection was 
performed during screening to meet tissue eligibility requirements) and at the 
time of radiographic progression (atezolizumab-treated patients only).
Optional biopsies should consist of core-needle biopsies for deep tumor tissue 
or organs or excisional, incisional, punch, or forceps biopsies for cutaneous, 
subcutaneous, or mucosal lesions.

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 4.5.6), the samples will be destroyed no 
later than 15 years after the date of final closure of the clinical database.
See the laboratory manual for additional details on laboratory assessments and sample 
handling.
4.5.3
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 and Worobec 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.
4.5.4
Cardiac and Pulmonary Function Tests
4.5.4.1
Electrocardiograms
A 12-lead ECG is required at screening and when clinically indicated.  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.


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For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.
4.5.5
Patient-Reported Outcomes
The EORTC QLQ-C30 is a validated and reliable self-report measure 
(Aaronson et al. 1993, Hjermstad et al. 1995, Osoba et al. 1997), that consists of 
30 questions assessing global healthrelated quality of life, five aspects of patient 
functioning (physical, emotional, role, cognitive, and social), three symptom scales 
(fatigue, nausea and vomiting, and pain), and six single-items (dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties; see Appendix 5).  Scale 
scores can be obtained for the multi-item scales.
The EQ-5D (3L) is generic preference-based HRQoL questionnaire that provides a 
single index value for health status (see Appendix 5 and is used to inform 
pharmacoeconomic evaluations.  The EQ-5D (3L) consists of two parts; the first part, 
health state classification, contains five dimensions of 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, will not be used in this study.
A paper instrument or electronic PRO (ePRO) data collection modality may be employed.  
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 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.
The PRO questionnaires (EORTC QLQ-C30 and EQ-5D [3L]) will be completed on 
Cycle 1, Day 1 (prior to any health care interaction), on Day 1 of each subsequent cycle, 
and at the treatment discontinuation visit, which is within 30 days after the last treatment 
dose.  In addition, the EQ-5D (3L) only will be collected at 6, 12, and 24 weeks after the 
CT/MRI scan date from which disease progression per RECIST v1.1 is determined.  The 
EQ-5D (3L) post-disease progression will be collected via 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 (3L) during 
the telephone interview as record of source documentation.  For patients assigned to 
atezolizumab who continue treatment beyond radiographic disease progression (see 


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Section 4.6.1), only EQ-5D (3L) will be collected on Day 1 of each subsequent cycle and 
after eventual treatment discontinuation until collection at 6, 12, and 24 weeks after 
disease progression is fulfilled.
4.5.6
Optional Biopsies and Samples for RCR (Optional Future 
Research)
4.5.6.1
Overview of the Roche Clinical Repository
The RCR is a centrally administered group of facilities 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 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.6.2
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 will not be applicable at that site.
4.5.6.3
Optional Samples for Roche Clinical Repository
The following samples will be collected for the identification of 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 before 
treatment and at the time of radiographic progression)


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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 
Blood sample for genetic biomarker analysis:  a whole blood sample for DNA 
isolation will be collected from patients who have consented to optional RCR 
sampling at baseline as shown in the schedule of activities 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.
4.5.6.4
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.


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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 only 
be disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data 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.
4.5.6.5
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 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.
4.5.6.6
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.  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 with use of the RCR Subject Withdrawal Form 
and, if the trial is ongoing, must enter the date of withdrawal on the appropriate 
Research Sample Withdrawal of Informed Consent eCRF.  The patient will be provided 
with instructions on how to withdraw consent after the trial is closed.  A patient's 
withdrawal from Study GO29294 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 GO29294.


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4.5.6.7
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.
4.5.7
Timing of Study Assessments
4.5.7.1
Screening and Pre-Treatment Assessments
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.
Written informed consent can be obtained up to 42 days prior to randomization.  Tumor 
tissue may be submitted up to 42 days prior to randomization.  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.
4.5.7.2
Assessments during Treatment
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 
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 period assessments.


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The following assessments may be performed 96 hours before Day 1 of each cycle 
(including Cycle 1):  ECOG performance status, limited physical examination, local 
laboratory tests, CRP test, adverse event evaluation, and concomitant medication 
evaluation.  
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.  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.
After five cycles, one of three cycles may be delayed by 1 week (28 days instead of 
21 days for one cycle) to allow for vacations.
Blood samples for pharmacodynamic biomarker analysis and pharmacokinetics will be 
obtained according to the schedules in Appendix 2.
4.5.7.3
Assessments at Treatment Discontinuation Visit
Patients who discontinue from treatment 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 progression is 
determined or confirmed) may be used as the treatment discontinuation visit.
See Appendix 1 and Appendix 2 for the schedule of activities performed at the treatment 
discontinuation visit.
4.5.7.4
Follow-Up Assessments
Ongoing Tumor Assessments
Patients who discontinue study drug for reasons other than disease progression 
(e.g., toxicity) should continue to undergo scheduled tumor assessments at the same 
frequency as would have been followed if the patient had remained on study drug until 
death, disease progression (see exceptions for atezolizumab arm in Section 3.1 and
Appendix 1, withdrawal of consent, or until the study is terminated by Sponsor, 
whichever occurs first.  Patients who start a new anti-cancer therapy in the absence of 
disease progression should continue to undergo tumor assessments according to the 
protocol schedule until disease progression, withdrawal of consent, study termination by 
Sponsor, or death whichever occurs first.


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4.5.7.5
Adverse Events
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study drug.  All adverse 
events regardless of relationship to study drug will be reported until 30 days after the last 
dose of study drug.
After the treatment discontinuation visit, adverse events should be followed as outlined 
in Appendix 9.
4.5.7.6
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.
4.5.7.7
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 treatment 
discontinuation visit until death, loss to follow-up, or study termination by the Sponsor.  
All patients will be followed for survival and 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.
4.6
PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  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 noncompliance
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.


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4.6.1.1
Discontinuation from Study Drug
Patients must discontinue study drug if they experience any of the following:

Intolerable toxicity related to study treatment

Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment

Use of another systemic anti-cancer therapy (see Section 4.4.2)

Pregnancy

Radiographic disease progression per RECIST v1.1 
Exception:  Patients will be permitted to continue atezolizumab after RECIST v1.1 
criteria for progressive disease are met if they meet all of the following criteria (see
Figure 2 for schematic representation):
Evidence of clinical benefit (defined as the stabilization or improvement of 
disease-related symptoms) as assessed by the investigator
Absence of symptoms and signs (including worsening of laboratory values 
[e.g., new or worsening hypercalcemia]) indicating unequivocal progression of 
disease
No decline in ECOG performance status that can be attributed to disease 
progression
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be readily managed and stabilized by protocol-allowed 
medical interventions prior to repeat dosing
Patients who demonstrate confirmed radiographic disease progression may be 
considered for continued study treatment at the discretion of the investigator, 
provided they continue to meet all the criteria above.
The primary reason for study drug discontinuation should be documented on the 
appropriate eCRF.


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Figure 2
Conditions for Continuing Atezolizumab in the Presence of 
Increased Radiographic Tumor Size
ECOG PSEastern Cooperative Oncology Group performance status; ICFInformed Consent 
Form; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1.
4.6.2
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 study is placed on hold or if the Sponsor 
decides to discontinue the study or development program.
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include but are not limited to the following:

Excessively slow recruitment


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
Poor protocol adherence

Inaccurate or incomplete data recording

Noncompliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice
5.
ASSESSMENT OF SAFETY
Atezolizumab is approved in the United States for the treatment of locally advanced or 
metastatic urothelial carcinoma.   Clinical 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 on similar molecules.
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.  
Guidelines for managing patients who experience anticipated adverse events, including 
criteria for dosage modification and treatment interruption or discontinuation, are 
provided in Appendix 9.  Refer to Sections 5.25.6 for details on safety reporting 
(e.g., adverse events, pregnancies) for this study.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-related hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, and 
myocarditis.  In addition, systemic immune activation is a potential risk when 
atezolizumab is given in combination with other immunomodulating agents.  Refer to 
Appendix 9 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure 
for a detailed description of anticipated safety risks for atezolizumab.
5.1.2
Risks Associated with Vinflunine, Paclitaxel, and Docetaxel
For adverse reactions, warnings, and precautions for vinflunine, paclitaxel, and 
docetaxel see local prescribing information.  Other specific instructions can be found in 
Sections 4.4.3 and 5.1.6 for paclitaxel, Sections 4.4.4 and 5.1.7 for docetaxel, and 
Sections 4.4.5 and 5.1.8 for vinflunine.


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5.1.3
General Plan to Manage Safety Concerns
5.1.3.1
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 for additional details).
5.1.3.2
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 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 and investigators will review and evaluate observed adverse events on a 
regular basis.
Patients will be followed for safety for 90 days following their last dose of study drug.
Patients who have an ongoing study drugrelated adverse event upon study completion 
or at discontinuation from the study 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.
5.1.4
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 withheld.  If atezolizumab is withheld because 
of adverse events for 42 days beyond the last dose, then the patient will be 
discontinued from atezolizumab and will be followed up for safety and efficacy as 
specified in Section 4.5.7.4.


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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 
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.
Management of atezolizumab-specific adverse events is presented below (Section 5.1.5)
and in Appendix 9.
5.1.5
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 holding 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.
Management of systemic immune activation is presented below.  See Appendix 9 for 
details on management of infusion-related reactions, gastrointestinal, dermatologic, 
endocrine, pulmonary toxicity, hepatotoxicity, neurologic disorders, potential pancreatic 


 
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or eye toxicity, and other immune-mediated adverse events.  See Appendix 7 for  
precautions for anaphylaxis. 
5.1.5.1 
Systemic Immune Activation 
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation 
is considered a potential risk when given in combination with other immunomodulating 
agents.  Systemic immune activation should be included in the differential diagnosis for 
patients who, in the absence of an alternative etiology, develop a sepsis-like syndrome 
after administration of atezolizumab and the initial evaluation should include the 
following: 
• 
CBC with peripheral smear 
• 
PT, PTT, fibrinogen, and D-dimer  
• 
Ferritin 
• 
Triglycerides 
• 
AST, ALT, and total bilirubin  
• 
LDH 
• 
Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 
Language regarding early identification and management of systemic immune activation 
may be found in the Atezolizumab Investigator’s Brochure.  If systemic immune 
activation is still suspected after the initial evaluation, contact the Medical Monitor for 
additional recommendations. 
5.1.6 
Paclitaxel Dose Modification and Management of Specific 
Adverse Events  
Paclitaxel should be held for any Grade 3−4 toxicity attributable to paclitaxel 
(e.g., neutropenia, anemia, thrombocytopenia, peripheral neuropathy, myalgia/arthralgia, 
and nausea/vomiting) until symptoms resolve to Grade ≤ 1 or baseline grade.  When 
treatment is resumed, the paclitaxel dose may be reduced to 135 mg/m2 (see Table 4).  
No dose re-escalation will be allowed.  Subsequent Grade 3−4 toxicities at the reduced 
dose will result in discontinuation of paclitaxel.  If Grade ≥ 3 toxicities persist for more 
than 21 days after the last administered dose or recur after dose reduction, the patient 
will be permanently discontinued from paclitaxel treatment. 
See the local prescribing information/institution guidelines for paclitaxel for further 
guidance on adverse event management and dose modifications. 


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Table 4
Dose Levels for Paclitaxel
Starting Dose
First Dose-Level 
Reduction
Indication for Further 
Dose-Level Reduction
Paclitaxel 
175 mg/m2
135 mg/m2
Discontinue
5.1.7
Docetaxel Dose Modification and Management of Specific 
Adverse Events
Guidelines for docetaxel dose modifications to manage general toxicities are shown in
Table 5.  Guidelines for the management of hepatotoxicity for docetaxel-treated patients 
are shown in Table 6.  Guidelines for the management of edema for docetaxel-treated 
patients are shown in Table 7.
Patients who are dosed initially at 75 mg/m2 and who experience either febrile 
neutropenia, neutrophils 500 cells/ mm3 for more than 1 week, severe or cumulative 
cutaneous reactions, or other Grade 34 non-hematological toxicities during docetaxel 
treatment should have treatment withheld until resolution of the toxicity and then have 
treatment resumed at 55 mg/m2.  Patients who develop Grade 3 peripheral neuropathy 
should have docetaxel treatment discontinued entirely.
Table 5
Guidelines for Management of Specific Docetaxel-Related 
Adverse Events
Adverse Event
(Worst Grade in Previous Cycle)
Action to Be Taken

Febrile neutropenia/Grade 4 AGC 7 days

Hold docetaxel until symptoms resolve a

Reduce docetaxel to 75% of previous dose 
(e.g., from 75 mg/m2 to 55 mg/m2)

Grade 3 skin/neuropathy/major organ/ 
non-hematologic toxicity

Hold docetaxel until symptoms resolve

Reduce docetaxel to 75% of previous dose

Grade 4 skin/neuropathy/major organ/ 
non-hematologic toxicity
OR

Recurrence of Grade 3 toxicity after prior 
dose reduction

Discontinue docetaxel treatment
AGCabsolute granulocyte count.
a
Do not retreat until AGC 1.5109/L, platelets 100109/L, and toxicity Grade 2.


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Table 6
Guidelines for Management of Hepatotoxicity in 
Docetaxel-Treated Patients
AST/ALT
Alkaline 
Phosphatase
Bilirubin
Docetaxel Dose
Mild to 
moderate
1.5ULN
AND
2.5ULN
75%
Severe
3.5ULN
AND
6ULN
OR
ULN
Do not treat.  
Discontinue if 
treatment already 
started.
ULNupper limit of normal.
5.1.7.1
Other Specific Toxicities Not Requiring Dose Adjustment
Hypersensitivity Reactions
Patients should be observed closely for hypersensitivity reactions, especially during the 
first and second infusions.  Severe hypersensitivity reactions characterized by 
generalized rash/erythema, hypotension, and/or bronchospasm, or very rarely, fatal 
anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids.  
Severe hypersensitivity reactions require immediate discontinuation of the docetaxel 
infusion and aggressive therapy.  Patients with a history of severe hypersensitivity 
reactions should not be rechallenged with docetaxel.
Hypersensitivity reactions may occur within a few minutes following initiation of 
docetaxel infusion.  If minor reactions such as flushing or localized skin reactions occur, 
interruption of therapy is not required.
Fluid Retention
Severe fluid retention has been reported following docetaxel therapy.  Patients should be 
pre-medicated with oral corticosteroids prior to each docetaxel infusion to reduce the 
incidence and severity of fluid retention (see Section 4.3.2.3).  Patients with preexisting 
effusions should be closely monitored from the first dose for the possible exacerbation of 
the effusions.  See Table 7 for the management of edema.


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Table 7
Guidelines for the Management of Edema in Docetaxel-Treated 
Patients
Edema
Severity
Effusion
Asymptomatic
Mild, Grade 1
Asymptomatic, no intervention 
needed
Symptomatic
Moderate, Grade 2
Symptomatic, may require 
intervention
Symptomatic, resulting in 
interruption of treatment
Severe, Grade 2
Symptomatic, urgent 
intervention required
5.1.8
Vinflunine Dose Modification and Management of Specific 
Adverse Events
Criteria for vinflunine dose delay and dose reduction are listed in Table 8 and Table 9, 
respectively.  Criteria for dose reduction in patients with renal impairment or elderly 
patients are listed in Table 10.  See local prescribing information/institution guidelines for 
vinflunine for further guidance on adverse event management and dose modifications.
Table 8
Dose Delay Guidelines for Vinflunine
Toxicity 
Day 1 Treatment Administration
Neutropenia 
(ANC 1000/mm3)
OR
Thrombocytopenia (platelets 
100,000/mm3)
Delay until recovery (ANC 1000/mm3 and platelets 100,000 
cells/ mm3) and adjust the dose if necessary (see Table 9).
Discontinuation if recovery has not occurred within 2 weeks.
Organ toxicity:  moderate, 
severe, or life-threatening
Delay until recovery to mild toxicity or none, or to initial 
baseline status and adjust the dose if necessary (see Table 9).
Discontinuation if recovery has not occurred within 2 weeks.
Cardiac ischemia in patients 
with prior history of myocardial 
infarction or angina pectoris
Discontinuation


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Table 9
Dose Modification Guidelines for Vinflunine
Toxicity
Dose Modification
Vinflunine Initial Dose of 320 mg/m2
Vinflunine Initial Dose of 280 mg/m2
First Event
Second 
Consecutive Event
Third Consecutive 
Event
First Event
Second 
Consecutive Event
Neutropenia Grade 4 
(ANC 500/mm3) 7 days
280 mg/m2
250 mg/m2
Definitive treatment 
discontinuation
250 mg/m2
Definitive treatment 
discontinuation
Febrile neutropenia
(ANC 1000/mm3 and fever 
38.5C)
Mucositis or constipation 
Grade 2 5 days or Grade 3 
any duration
Any other toxicity Grade 3 
(severe or life-threatening; 
except Grade 3 vomiting or 
nausea)


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Table 10 Dose Modification Guidelines for Vinflunine in Patients with Renal Impairment or Elderly Patients
Toxicity
Dose Modification
Vinflunine Initial Dose of 280 mg/m2
Vinflunine Initial Dose of 250 mg/m2
First Event
Second Consecutive 
Event
First Event
Second Consecutive 
Event
Neutropenia Grade 4
(ANC 500/mm3) 7 days
250 mg/m2
Definitive treatment 
discontinuation
225 mg/m2
Definitive treatment 
discontinuation
Febrile neutropenia
(ANC 1000/mm3 and fever 
38.5C)
Mucositis or constipation 
Grade 2 5 days or Grade 3 
any duration
Any other toxicity Grade 3 
(severe or life threatening; 
except Grade 3 vomiting or 
nausea)


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of the monitoring and recording of adverse events, 
including serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether 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 5.3.5.8

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.9)


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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to 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 (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:

The following conditions which may be suggestive of an autoimmune disorder:
Pneumonitis
Hypoxia or dyspnea Grade 3
Colitis
Endocrinopathies:  diabetes mellitus, pancreatitis, or adrenal insufficiency
Vasculitis
Hepatitis
Transaminitis:  Grade 2 (AST or ALT 3ULN and bilirubin 2ULN) OR 
AST/ALT 10ULN
Systemic lupus erythematosus
Guillain-Barré syndrome
Myasthenia gravis
Skin reactions:  vitiligo, pemphigoid


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
Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response syndrome, or infusion reaction syndromes

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 

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.
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, 5.5, and 5.6.
For each adverse event, 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) on the Adverse Event eCRF.
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as biopsies).
After initiation of study drug, any serious adverse events and adverse events of 
special interest will be reported until 90 days after the last dose of study drug.  All 
adverse events, regardless of relationship to study drug, will be reported until 30 days 
after the last dose of study drug.  After this period, investigators should only report any 
serious adverse events or other adverse events of concern that are believed to be 
related to prior treatment with study drug (see Section 5.3.5.6 for reporting of deaths).


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5.3.2
Eliciting Adverse Event Information
A consistent methodology of nondirective questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of nondirective 
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 11 will be used for assessing the severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 11 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:  Based on 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_8.5x11.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 
adverse event is considered related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug


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
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF; colloquialisms and abbreviations should be avoided.
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) rather than individual signs and symptoms 
should be recorded on the Adverse Event eCRF (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.
5.3.5.1.1
Infusion-Related Reactions
An exception to the above is symptoms that occur during or within 24 hours after an 
atezolizumab infusion.  These may be part of an acute infusion reaction and should not 
be recorded under the diagnosis of “infusion-related reaction.”  Rather, non-serious 
symptoms should be recorded as separate adverse events on the Adverse Event eCRF.
5.3.5.2
Adverse Events Occurring Secondary to Other Events
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause.  For example, if chest pain 
is known to have resulted in myocardial infarction, it is sufficient to record only 
myocardial infarction as an adverse event on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.


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5.3.5.3
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 
separately on the Adverse Event eCRF.
5.3.5.4
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:

Worsened from baseline

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding if an isolated laboratory abnormality 
should be classified as an adverse event.
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).
5.3.5.4.1
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.  
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


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
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).
5.3.5.5
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:

Worsened from baseline

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 if an isolated vital sign abnormality should be 
classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded 
on the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of UBC should be recorded only on the Study 
Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).
If the patient withdraws from the study, study staff may use a public information source 
(e.g., county records) to obtain information about survival status only.


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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.  The term “sudden death” should only be used for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the 
case of an unwitnessed death, within 24 hours after the patient was last seen alive and 
stable.  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.
During survival follow-up, deaths attributed to progression of UBC should be recorded 
only on the Survival eCRF.
5.3.5.7
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”).
5.3.5.8
Worsening of Urothelial Bladder Cancer
The term disease progression (i.e., worsening and/or progression of UBC) should not be 
recorded as an adverse event.  The underlying symptoms should be captured as 
adverse events and assessed accordingly for seriousness, severity, and causality.  Data 
for disease progression will be captured as efficacy assessment data only.
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST criteria.  In rare cases, the determination of clinical 
progression will be on the basis of symptomatic deterioration.  However, every effort 
should be made to document progression with use of objective criteria.
5.3.5.9
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization 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.  


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The following hospitalization scenarios are not considered to be serious adverse events:

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 suffered an adverse event.
The following hospitalization scenarios are not considered to be serious adverse events 
but should be reported as adverse events instead:

Hospitalization for outpatient care outside of normal clinic operating hours that is 
required per protocol or per local standard of care
5.3.5.10
Adverse Events Associated with an Overdoses 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).
5.3.5.11
Patient-Reported Outcome Data
The PRO measurements are described in Section 3.4.4.  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.  The 
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 


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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

Adverse events of special interest

Pregnancies
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 on the basis of new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor (Roche Medical Responsible) Contact Information
Medical Monitor:
, M.D.
E-mail:
Telephone Nos.:

 (mobile)

 (office)
Back-up Medical Monitor:
, M.D.
E-mail:
m 
Telephone Nos.:

 (mobile)

 (office)
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk, as 
well as Medical Monitor contact information, will be distributed to all investigators.
5.4.2
Reporting Requirements for Serious Adverse Events and
Adverse Events of Special Interest
5.4.2.1
Events that Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  


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The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to Roche 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 with use of the fax number or email address provided 
to investigators.
5.4.2.2
Events that Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study drug.  All adverse 
events regardless of relationship to study drug will be reported until 30 days after the last 
dose of study drug.  Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the Adverse Event eCRF 
and submit the report via the EDC system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Adverse Event of Special Interest Case Report Form (CRF) and Fax Coversheet 
should be completed and faxed to Roche Safety Risk Management or its designee 
immediately (i.e., no more than 24 hours after learning of the event), with use of the fax 
numbers provided to investigators (see "Protocol Administrative and Contact Information 
& List of Investigators").  Once the EDC system is available, all information will need to 
be entered and submitted via the EDC system.
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 atezolizumab, 3 months after the last dose of vinflunine, and 6 months after the 
last dose of docetaxel or paclitaxel.  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.  Pregnancies 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 the 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 Roche 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 with use of the fax number or 


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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
Pregnancies in Female Partners of Male Patients
There are no known reproductive risks to the female partner of a male patient receiving 
atezolizumab.  Male patients will be instructed through the Informed Consent Form to 
immediately inform the investigator if their partner becomes pregnant during the study or 
within 3 months after the last dose of vinflunine, and 6 months after the last dose of 
docetaxel or paclitaxel.  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.  Attempts should be made to collect and report 
details of the course and outcome of any pregnancy in the partner of a male patient 
exposed to study drug.  The pregnant partner will need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
Once the authorization has been signed, the investigator will update the Pregnancy 
Report eCRF with additional information on the course and outcome of the pregnancy.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus to support 
an informed decision in cooperation with the treating physician and/or obstetrician.
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1.
5.4.3.3
Abortions
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), 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).
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, new 
anti-cancer treatment is initiated, the patient is lost to follow-up, or the patient withdraws 
consent, or it has been determined that study treatment or participation is not the cause 
of the adverse event.  Every effort should be made to follow all serious adverse events 
considered related to study drug or trial-related procedures until a final outcome can be 
reported.


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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 5.4.3.1.
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 (see Section 5.3.5.6 for reporting of 
deaths).
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 on the basis of applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events with use of the Atezolizumab IB as a reference 
and with the use of vinfluinine, paclitaxel or docetaxel local label as a reference.
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.


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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
This is a Phase III, global, multicenter, open-label, randomized, two-arm, controlled 
study designed to evaluate the efficacy and safety of atezolizumab compared with 
chemotherapy in patients with locally advanced or metastatic UBC who have progressed 
during or following a platinum-containing regimen.  Within the chemotherapy control arm, 
the percentage of patients who are treated with a taxane (paclitaxel or docetaxel) will be 
capped at 40%.  Until that cap is reached, the selection of the specific chemotherapy 
(vinflunine or taxane) for patients who are randomized to the chemotherapy arm will be 
per investigator’s choice.
Primary efficacy analysis of OS and PFS will be performed on randomized patients, 
irrespective of whether the assigned treatment was actually received.  ORR analyses will 
be performed on all randomized patients who have measureable disease at baseline.  
DOR analyses will be performed on the subset of patients who achieve an objective 
response.  For all efficacy analyses, patients will be grouped according to the treatment 
assigned at randomization.
Safety analyses will be performed on all randomized patients who received any amount 
of study treatment (i.e., atezolizumab or chemotherapy), with patients grouped according 
to whether any amount of atezolizumab was received including the case when 
atezolizumab was received in error.
6.1
DETERMINATION OF SAMPLE SIZE
This study will enroll approximately 931 patients, including a minimum of 230 patients 
with a PD-L1 IHC score of IC2/3 and a minimum of 537 patients with a PD-L1 IHC score 
of IC1/2/3.
The numbers of events required to demonstrate efficacy of the atezolizumab 
experimental arm over the chemotherapy arm (i.e., vinflunine, paclitaxel, or docetaxel) 
with regard to OS are estimated based on the following assumptions:

Two-sided significance level of 5%

94% for the primary analysis of OS in the population of patients with an IHC score of 
IC2/3 with an HR of 0.57, corresponding to an improvement in median OS from 
7.5 months to 13.2 months 

98% power for the primary analysis of OS in the population of patients with an 
IHC score of IC1/2/3 with an HR of 0.68, corresponding to an improvement in 
median OS from 7.5 months to 11 months


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
97% power for the primary analysis of OS in the ITT population with an HR of 0.74, 
corresponding to an improvement in median OS from 7.5 months to 10.1 months

1:1 randomization ratio

Dropout rate of 5% per year over 24 months
6.2
ANALYSES TIMING
The primary analyses of OS will occur when approximately 152, 403, and 652 deaths 
have been observed in the following populations:  patients with an IHC score of IC2/3, 
patients with an IHC score of IC1/2/3, and ITT populations, respectively, whichever 
occurs later.  This is expected to occur approximately 25 months after FPI.  No interim 
analysis is planned for this study.
The timing of the primary analyses of OS will depend on the actual accrual rate and will 
be driven by the occurrence of number of deaths as indicated above.
6.3
SUMMARIES OF CONDUCT OF STUDY
Study enrollment, study drug administration, reasons for discontinuation from study drug, 
and reasons for study termination will be summarized by treatment arm for the following 
populations:  patients with an IHC score of IC2/3, patients with an IHC score of IC1/2/3, 
and overall ITT population.  Major protocol violations will be reported and summarized by 
treatment arm for the overall ITT population.
6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic characteristics, such as age, sex, race/ethnicity, baseline disease 
characteristics (e.g., ECOG performance status), and number of prior cancer treatments, 
will be summarized by treatment arm for the following populations:  patients with an 
IHC score of IC2/3, patients with an IHC score of IC1/2/3, and the overall ITT population 
individually.  Descriptive statistics (mean, median, SD, and range) will be presented for 
continuous data, and frequencies and percentages will be presented for categorical data.
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of study drug.
6.5
EFFICACY ANALYSES
6.5.1
Primary Efficacy Endpoint
The primary efficacy endpoint is OS.  OS is defined as the time between the date of 
randomization and death due to any cause.  Data for patients who are not reported as 
having died by the time of the data cutoff date for primary analysis will be censored at 
the date when they were last known to be alive.  Patients who do not have post-baseline 
information will be censored at the date of randomization plus 1 day.


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The primary analysis will occur when approximately 152, 403, and 652 deaths have 
been observed in the following populations:  patients with an IHC score of IC2/3, patients 
with an IHC score of IC1/2/3, and ITT populations respectively, whichever occurs later.
Comparisons with respect to OS between the treatment and control arms will be tested 
using a hierarchical fixed-sequence procedure based on a stratified log-rank test at 
two-sided level of 5% significance within the following populations:  patients with an 
IHC score of IC2/3, patients with an IHC score of IC1/2/3, and in the ITT population as 
follows:
1.
Test to reject the null hypothesis of no difference in OS between the two arms in the 
population of patients with an IHC score of IC2/3.  If the estimate of the HR is 1 
and the two-sided p-value corresponding to the stratified log-rank test is 0.05, the 
null hypothesis will be rejected and it will be concluded that atezolizumab prolongs 
OS relative to chemotherapy (i.e., vinflunine, paclitaxel, or docetaxel) in the 
population of patients with an IHC score of IC2/3.
2.
If the null hypothesis from Step 1 is rejected, then test to reject the null hypothesis of 
no difference in OS between the two arms in the population of patients with an 
IHC score of IC1/2/3.  If the estimate of the HR is 1 and the two-sided p-value 
corresponding to the stratified log-rank test is 0.05, the null hypothesis will be 
rejected and it will be concluded that atezolizumab prolongs OS relative to 
chemotherapy (i.e., vinflunine, paclitaxel, or docetaxel) in the population of patients 
with an IHC score of IC1/2/3.
3.
If the null hypothesis from Step 2 is rejected, then test to reject the null hypothesis of 
no difference in OS between the two arms in the ITT population.  If the estimate of 
the HR is 1 and the two-sided p-value corresponding to the stratified log-rank test 
is 0.05, the null hypothesis will be rejected and it will be concluded that 
atezolizumab prolongs OS relative to chemotherapy (i.e., vinflunine, paclitaxel, or 
docetaxel) in the ITT population.
The stratification factors will be those specified for randomization (i.e., chemotherapy, 
PD-L1 IHC status, prognostic factors, and liver metastases).  Results from an 
unstratified analysis will also be presented.
Kaplan−Meier methodology will be used to estimate median OS for each treatment arm 
and to construct survival curves for the visual description of the difference between the 
treatment arms.  Brookmeyer−Crowley methodology will be used to construct the 95% CI 
for the median OS for each treatment arm (Brookmeyer and Crowley 1982).
6.5.2
Secondary Efficacy Endpoints
If the primary endpoint of OS is statistically significant in the population of patients with 
an IHC score of IC2/3, the population of patients with an IHC score of IC1/2/3, and in the 
ITT population, the secondary endpoints of ORR and PFS will be tested in order (i.e., 
ORR followed by PFS), each at the two-sided 5% significance level in each respective 
population (i.e., test for an ORR difference between the two arms in the population of 


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patients with an IHC score of IC2/3, and if the preceding null hypothesis is rejected, test 
for an ORR difference in the population of patients with an IHC score of IC1/2/3.  If the 
preceding null hypothesis is rejected, test for an ORR difference in the ITT population, 
and if the preceding null hypothesis is rejected, test for a PFS difference between the 
two arms in the population of patients with an IHC score of IC2/3, and if the preceding 
null hypothesis is rejected, test for a PFS difference between the two arms in the 
population of patients with an IHC score of IC1/2/3, and if the preceding null hypothesis 
is rejected, test for a PFS difference in the ITT population).
6.5.2.1
Objective Response Rate
An objective response is defined as either a CR or PR, as determined by the investigator 
with use of RECIST v1.1.  Objective response in this study does not need to be a 
confirmed response.  Patients not meeting these criteria including patients including 
patients without any post-baseline tumor assessment will be considered non-responders.
ORR is defined as the proportion of patients who had an objective response.  The 
analysis population for ORR will be all randomized patients with measurable disease at 
baseline.  An estimate of ORR and its 95% CI will be calculated using the 
Clopper-Pearson method for each treatment arm.  CIs for the difference in ORRs 
between the two arms will be determined using the normal approximation to the binomial 
distribution.  The ORR will be compared between the two arms with use of the stratified 
Cochran-Mantel-Haenszel test.
6.5.2.2
Progression-Free Survival
PFS is defined as the time between the date of randomization and the date of first 
documented disease progression or death, whichever occurs first.  Disease progression 
will be determined on the basis of investigator assessment with use of RECIST v1.1.  
Patients who have not experienced disease progression or death at the time of analysis 
will be censored at the time of the last tumor assessment.  Patients with no 
post-baseline tumor assessment will be censored at the date of randomization plus 
1 day.  
The analyses that will be performed for OS as described in Section 6.5.1 will also be 
applied to PFS.
6.5.2.3
Duration of Objective Response
DOR is defined as the time between the date of the first occurrence of a complete or 
partial response (whichever status is recorded first) and the date of first documented 
progressive disease or death is documented, whichever occurs first.  Disease 
progression will be determined on the basis of investigator assessment with use of 
RECIST v1.1.  DOR based on the investigator assessment will be analyzed for the 
subset of patients who achieve an objective response as determined by the investigator 
with use of RECIST v1.1.


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Patients who have not progressed or who have not died by the data cutoff date for 
analysis will be censored at the time of last tumor assessment date.  If no tumor 
assessments were performed after date of the first occurrence of a complete or partial 
response, DOR will be censored at the date of the first occurrence of a complete or 
partial response plus 1 day.
The secondary endpoint of DOR as well as the exploratory efficacy endpoints will be 
analyzed but will not be part of the endpoints in the hierarchical fixed sequence.
DOR analysis is based on a non-randomized subset of patients (specifically, patients 
who achieve an objective response); therefore, formal hypothesis testing will not be 
performed for this endpoint.  DOR will be estimated using Kaplan-Meier methodology.  
Comparisons between treatment arms will be made for descriptive purposes only.
Further details on the analysis plan of secondary endpoints can be found in the 
Statistical Analysis Plan (SAP).
6.5.3
Handling of Missing Data
For OS, patients who are not reported as having died will be analyzed as censored 
observations on the date when they were last known to be alive.  If no post-baseline 
data are available, OS will be censored at the date of randomization plus 1 day.
For objective response, patients without a post-baseline assessment will be considered 
non-responders.
For PFS, patients without a date of disease progression and death will be analyzed as 
censored observations on the date of last tumor assessment.  If no post-baseline tumor 
assessment is available, PFS will be censored at the date of randomization plus 1 day.
For DOR, patients who have not progressed or who have not died at the time of analysis 
will be censored at the time of last tumor assessment date.  If no tumor assessments 
were performed after date of the first occurrence of a complete or partial response, DOR 
will be censored at the date of the first occurrence of a complete or partial response plus 
1 day.
6.6
SAFETY ANALYSES
Safety analyses will be performed on safety-evaluable population, defined as all 
randomized patients who receive any amount of the study drug, with patients grouped 
according to whether any amount of atezolizumab was received, including the case 
when atezolizumab was received in error.  Summaries will be presented for the 
safety-evaluable populations by treatment arm.


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Drug exposure will be summarized to include treatment duration, number of doses, and 
dose intensity.
Verbatim description of adverse events will be mapped to MedDRA thesaurus terms and 
graded according to NCI CTCAE v4.0.  All adverse events occurring during or after the 
first study drug dose will be summarized by treatment arm and NCI CTCAE grade.  In 
addition, serious adverse events, severe adverse events (Grade 3), adverse events 
of special interest, and adverse events leading to study drug discontinuation or 
interruption will be summarized accordingly.  Multiple occurrences of the same event will 
be counted once at the maximum severity.  The proportion of patients experiencing at 
least one adverse event will be reported by toxicity term and treatment arm.
Laboratory data with values outside the normal ranges will be identified.  In addition, 
selected laboratory data will be summarized by treatment arm and grade.
Changes in vital signs will be summarized by treatment arm and grade.
Deaths reported during the study treatment period and those reported during the 
follow-up period after treatment completion/discontinuation will be summarized by 
treatment arm.
6.7
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, 4, 8, and 16 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.
6.8
OUTCOME ANALYSES
The EORTC QLQ-C30 data will be scored according to the EORTC scoring manual
(Fayers 2001).  For all questionnaire subscales, if more than 50% of the constituent 
items are completed, a pro-rated score will be computed consistent with the scoring 
manuals and validation papers.  For subscales with less than 50% of the items 
completed, the subscale will be considered as missing.  All PRO data analyses will be 
performed on patients with baseline assessments and at least one post-baseline 
assessment by treatment arm for the following populations (individually):  patients with 
an IHC score of IC2/3, patients with an IHC score of IC1/2/3, and the ITT population.
HRQoL will be summarized using items from the EORTC QLQ-C30.  A responder 
analysis will be used to assess improvement in function between treatment arms.  
Responders are defined as patients with a 10-point improvement in mean scale score 


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from baseline and will be assessed in the fatigue and physical function scales.  
Patient-reported bothersomeness of treatment-related symptoms, including constipation, 
nausea and vomiting, diarrhea, and pain, will be summarized descriptively as absolute 
mean scores and change from baseline for each post-baseline assessment.
6.9
EXPLORATORY ANALYSES
Analyses using modified RECIST criteria (atezolizumab arm only with no comparison to 
the chemotherapy arm for PFS, ORR, and DOR) will also be performed 
(see Appendix 3).  The investigator-assessed ORR is defined as the proportion of 
patients whose best overall response is either a PR or CR per modified RECIST.
DCR is defined as the rate of patients with complete or partial response as best 
response or stable disease maintained for 18 weeks per RECIST v1.1.  The analysis 
methods for DCR will be the same as those for the analysis of ORR.
Exploratory biomarker analyses will be performed in order to understand the association 
of these markers with study drug response, including efficacy and/or adverse events.  
Exploratory biomarker analyses will include assessments of biomarkers in both tumor 
tissue and blood.  Changes in biomarkers will be listed by cohort and response status.
The pharmacodynamic biomarker analyses will include patients with at least one 
predose and one postdose biomarker assessment, with patients grouped according to 
the treatment actually received.  Blood samples for biomarker assessments will be 
assayed using analytically qualified methods (e.g., enzyme-linked immunosorbent assay, 
quantitative real-time polymerase chain reaction).
EQ-5D (3L) health status data will be used for obtaining utility measures for economic 
modeling.  For the EQ-5D (3L), further scoring and analysis may be reported in a 
separate document.
All items from the EORTC QLQ-C30 that are not included in the main PRO outcomes 
analyses will be summarized descriptively with summary statistics (mean, SD, median, 
25th and 75th percentiles, and range) of absolute scores of the EORTC QLQ-C30 scales 
and their changes from baseline at each assessment timepoint for both treatment arms.
6.10
SENSITIVITY ANALYSES
6.10.1
Loss to Follow-Up
The impact of loss to follow-up on OS will be assessed depending on the number of 
patients who are lost to follow-up.  If 5% of patients are lost to follow-up for survival in 
either treatment arm, a sensitivity analysis (“worst-case” analysis) will be performed in 
which patients who are lost to follow-up will be considered as having died at the last date 
they were known to be alive.


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6.10.2
Subsequent Anti-Cancer Therapy
The impact of non-protocol specified anti-cancer therapy use on OS will also be 
assessed.
6.11
SUBGROUP ANALYSIS
To assess the consistency of the study results in subgroups defined by demographics 
(e.g., age, sex, and race/ethnicity) and baseline prognostic characteristics (e.g., PD-L1 
IHC status, ECOG performance status, number of risk factors, hemoglobin, vinflunine vs. 
taxane, visceral involvement, liver metastasis, etc.), OS in these subgroups will be 
examined.  It is expected that accrual in subgroups defined by these baseline 
characteristics may not be large enough for definitive treatment comparisons to be made
between these subgroups.
Summaries of survival, including unstratified hazard ratios estimated from Cox 
proportional hazards models and Kaplan-Meier estimates of median survival time, will be 
produced separately for each level of the categorical variables. 
6.12
INTERIM ANALYSES
No interim efficacy analyses are planned for this study.
An iDMC will be set up to evaluate safety results approximately every 6 months after FPI.  
All summaries/analyses by treatment arm for the iDMC’s review will be prepared by an 
external iDCC.  Members of the iDMC will be external to the Sponsor and will follow a 
charter that outlines their roles and responsibilities.
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 with 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.


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7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training 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, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, 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 investigational site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational 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 


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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, ePRO data, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for at least 
15 years after completion or discontinuation of the study, or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug application (IND) will comply with U.S. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union or European Economic Area will comply with the E.U. 
Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Caregiver's 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.
The Informed Consent Form will contain a separate section that addresses the collection 
of optional samples and the use of remaining mandatory samples (plasma, serum, whole 


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blood, and tissue) for optional exploratory research.  The investigator or authorized 
designee will explain to each patient the objectives of the exploratory research.  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 allow the collection of optional 
samples and to use any remaining specimens for exploratory research.  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.
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. 


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


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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, which includes 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.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  
Approximately 250 sites globally will participate in the study and approximately 
931 patients will be randomized.
Randomization will occur through an IxRS.  Central facilities will be used for study 
assessments throughout the study (e.g., specified laboratory tests, and PK analyses).  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
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, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results. 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.


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The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENT SECTIONS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Assessments
Assessment Window (Days)
Screening a
All Cycles 
Treatment 
Discontinuation b 
Follow-Up
Days –28
to –1
Day 1 (3 Days for 
Cycles 2)
30 Days after Last 
Dose
Signed Informed Consent Form(s) a
x
Review of eligibility criteria
x
Medical, surgical, and cancer histories, including 
demographic information c
x
HIV, HBV, HCV, EBV serology d
x
TB test e
x
Concomitant medications f
x
x
x
Tumor assessment g
x
Every 9 weeks 3 business days for 54 weeks and every 
12 weeks 6 business days thereafter until disease 
progression, death, or loss of follow-up
Patient-reported outcomes h
x
x
x
Complete physical examination i
x
x
Limited physical examination i
x j
x
ECOG performance status
x
x j
x
Vital signs k
x
x
x
12-lead ECG l
x
x l
x l
Weight
x
x
x
Height
x
Hematology m
x
x j
x
Serum chemistry n
x
x j
x


Appendix 1
Schedule of Assessments (cont.)
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Assessment Window (Days)
Screening a
All Cycles 
Treatment 
Discontinuation b 
Follow-Up
Days –28
to –1
Day 1 (3 Days for 
Cycles 2)
30 Days after Last 
Dose
Coagulation panel (aPTT, INR) n
x
x
Vitamin D assay
x
C-reactive protein testing
x
x o
Urinalysis p
x
x q
x
Serum pregnancy test r
x
TSH, free T3, free T4
x
x s
x
Auto-antibody testing (atezolizumab patients only) t
x
Serum sample for ATA assessment (atezolizumab 
patients only) u
x
x
Serum sample for PK sampling (atezolizumab patients 
only) u
x
x
Blood samples for pharmacodynamics biomarkers v
x
x
Optional whole blood sample for RCR DNA w
x
Adverse events x
x
x
x
Study drug infusion y
x
Archival/screening FFPE tumor tissue specimen or 
15 unstained slides z
x


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
127/Protocol GO29294, Version 8
Assessment Window (Days)
Screening a
All Cycles 
Treatment 
Discontinuation b 
Follow-Up
Days –28
to –1
Day 1 (3 Days for 
Cycles 2)
30 Days after Last 
Dose
Fresh biopsy (optional RCR)
x aa
Per investigator discretion, 
biopsy(ies) to be performed 
preferably at the time of radiographic 
progression (atezolizumab-treated 
patients only) z
Survival and anti-cancer therapy follow-up bb
x
anti-HBc antibody against hepatitis B core antigen; ATAanti-therapeutic antibody; EBVEpstein-Barr virus; ECOG Eastern Cooperative 
Oncology Group;  EORTCEuropean Organisation for Research and Treatment of Cancer; EQ-5D (3L)EuroQoL 5 Dimensions; 
FFPEformalin fixed paraffin embedded; HBVhepatitis B virus; HCVhepatitis C virus; MUGAmultiple-gated acquisition; 
PD-L1programmed death-ligand 1; PKpharmacokinetic; PRO patient-reported outcome; QLQ-C30Quality-of-life Questionnaire Core 30; 
RCRRoche Clinical Repository; RECIST Response Evaluation Criteria in Solid Tumors; TSH thyroid-stimulating hormone.
Note:  Assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise noted.
a Written informed consent is required for performing any study-specific tests or procedures.  Signing of the Informed Consent Form can occur 
outside the 28-day screening period.  Results of standard-of-care tests or examinations performed prior to obtaining informed consent and 
within 28 days prior to study entry (except where otherwise specified) may be used for screening assessments rather than repeating such 
tests.
b Patients will be asked to return to the clinic not more than 30 days after the last treatment for a treatment discontinuation visit. 
c Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment.  Demographic information includes age, sex, 
and self-reported race/ethnicity.  Reproductive status and smoking history should also be captured.
d All patients will be tested for HIV locally prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical trial.  
Hepatitis B surface antigen, anti-HBc antibody and anti-HBs antibody should be collected during screening and tested locally.  In patients 
who have positive serology for the anti-HBc antibody, HBV DNA should be collected prior to Cycle 1, Day 1.  EBV serology tests will be 
performed centrally on the samples collected during screening only in patients who experience an acute inflammatory event such as 
systemic inflammatory response syndrome while receiving study treatment.


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
128/Protocol GO29294, Version 8
e All patients will have a tuberculin (PPD) skin test or IGRA done locally prior to the inclusion into the study, and patients with active TB will be 
excluded from the clinical trial. 
f
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 the date of informed consent should be documented.  At subsequent visits, changes to current medications 
or medications used since the last documentation of medications will be recorded.
g Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of Cycle 1, Day 1 may be used 
rather than repeating tests.   All measurable and evaluable lesions should be assessed and documented at the screening visit.  The same 
radiographic procedure must be used throughout the study for each patient.  Results must be reviewed by the investigator before dosing at 
the next cycle.  Tumor assessments will be performed at baseline, every 9 weeks (approximately every three cycles) following randomization 
for 54 weeks, and every 12 weeks thereafter, with additional scans as clinically indicated.  For patients randomized to vinflunine or taxane, 
assessments will continue until disease progression per RECIST v1.1 (see Appendix 4), regardless of whether treatment has been 
discontinued.  Patients randomized to atezolizumab will undergo assessments until disease progression or until treatment discontinuation (for 
patients who continue to receive atezolizumab following disease progression).  Tumor assessments should continue regardless of whether 
patients start new anti-cancer therapy in the absence of disease progression unless they withdraw consent.  If an optional biopsy is to be 
performed at approximately the same timepoint of a tumor assessment or as a result of the radiographic determination (e.g., response or 
progression), samples should be acquired after all imaging scans have been performed, if at all possible.  Patients assigned to atezolizumab 
who continue treatment beyond radiographic disease progression (see Section 4.6.1.1) will be monitored with a follow-up scan at the next 
scheduled tumor assessment when the scan frequency is every 9 weeks.  If the scan frequency is every 12 weeks, the follow-up scan must be 
performed at 9 weeks (2 weeks) as an unscheduled tumor assessment, or earlier if clinically indicated.  Investigators may perform additional 
scans or more frequent assessments if clinically indicated.   
h The PRO questionnaires (EORTC QLQ-C30, and EQ-5D [3L]) will be completed by the patients at the investigational site.  All PRO 
questionnaires are required to be administered prior to administration of study treatment 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.  In addition, 
the EQ-5D only will be collected at 6, 12, and 24 weeks after disease progression per RECIST 1.1 through 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 (3L) during the telephone interview as record of source documentation.
i
Complete and limited physical examinations are defined in Section 4.5.2.2. 


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
129/Protocol GO29294, Version 8
j
ECOG performance status, limited physical examination, local laboratory assessments, and C-reactive protein assessment may be obtained 
96 hours before Day 1 of each cycle (including Cycle 1).   
k Vital signs include heart rate, respiratory rate, blood pressures, and temperature.  At all infusions of study drug (atezolizumab, vinflunine, 
paclitaxel, or docetaxel), the patient’s vital signs should be determined up to 60 minutes before and 30 (10) minutes after the infusion.  For 
the atezolizumab arm, vital signs will also be collected during the first infusion (every 15 [5] minutes).
l
ECG recordings will be obtained during screening and when clinically indicated.  Patients should be resting and in a supine position for at 
least 10 minutes prior to each ECG collection.
m Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils, and other cells), and platelet count.  A manual differential can be done if clinically indicated.  See 
Section 4.1.1 for a list of laboratory results obtained within 14 days prior to the first study treatment.
n Serum chemistry includes BUN, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, 
total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.  See Section 4.1.1 for a list of laboratory results obtained 
within 14 days prior to the first study treatment.
o On Day 1 of Cycle 4 and every four cycles thereafter until Cycle 16.
p Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood). 
q On Day 1 of Cycle 3 and every two cycles thereafter. 
r
Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and 
documented as negative within 14 days prior to Day 1. 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.
s On Day 1 of Cycle 5 and every four cycles thereafter.
t
For patients assigned to atezolizumab only.  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. 
u For patients assigned to atezolizumab only.  See Appendix 2 for details of the ATA and PK collection schedule.  Blood samples should be 
processed to obtain serum.  A post-treatment ATA and PK sample should be collected 120 (30) days after the last dose of atezolizumab 
unless the patient withdraws consent or the study closes.
v See Appendix 2 for details of the pharmacodynamic sampling schedule.


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
130/Protocol GO29294, Version 8
w Whole blood for DNA isolation will be collected from patients who have consented to optional RCR sampling at baseline.  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. 
x After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, any serious adverse events and adverse events of special interest will be 
reported until 90 days after the last dose of study drug.  All adverse events, regardless of relationship to study drug, will be reported until 
30 days after the last dose of study drug.  After this period, investigators should only report any serious adverse events or other adverse 
events of concern that are believed to be related to prior treatment with study drug (see Section 5.3.5.6 for reporting of deaths).  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.
y Patients should 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 3 days after randomization.  For atezolizumab, the 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 as long as the patient continues 
to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease 
progression as determined by the investigator after an integrated assessment of radiographic data, biopsy results (if available), and clinical 
status.  For vinflunine, paclitaxel, and docetaxel, study drug will be administered according to the local prescribing information, including 
premedication for paclitaxel (see Section 4.3.2) and docetaxel.  Vinflunine, paclitaxel, and docetaxel treatment will continue until disease 
progression per standard RECIST v1.1 or unacceptable toxicity.
z 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, bone metastases, and 
lavage samples are not acceptable.  For core-needle biopsy specimens, at least three cores should be submitted for evaluation.  After signing 
of the Informed Consent Form, retrieval and submission of archival tumor sample can occur outside the 28-day screening period.
aa 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.  Preferably, growing 
lesions should be selected, and samples collected at the time of radiographic progression.  Optional biopsy tissue will be stored in the RCR. 
Not applicable for a site that has not been granted approval for RCR sampling.


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
131/Protocol GO29294, Version 8
bb Starting from treatment discontinuation visit, survival follow-up information will be collected via telephone calls, patient medical records, and/or 
clinic visits approximately every 3 months until death, loss to follow-up, or study termination by Roche.  All patients will be followed for survival 
and new anti-cancer therapy (including targeted therapy and immunotherapy) 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.   


Atezolizumab—F. Hoffmann-La Roche Ltd
132/Protocol GO29294, Version 8
Appendix 2
Anti-Therapeutic Antibody, Pharmacodynamic, 
and Pharmacokinetic Sampling Schedule
Study Visit
Time
Sample
Patients 
Randomized to 
Vinflunine, 
Paclitaxel, or 
Docetaxel
Patients Randomized 
to Atezolizumab
Cycle 1,
Day 1
Predose
Pharmacodynamics a
ATA
Atezolizumab
pharmacokinetics and
pharmacodynamics. a
30 (10) minutes 
after end of 
atezolizumab 
infusion
Atezolizumab
pharmacokinetics
Cycles 2, 3,
and 4, Day 1 
Predose
Pharmacodynamics a
ATA
Atezolizumab
pharmacokinetics and
pharmacodynamics. a
Cycles 8, Day 1
Predose
ATA (every 8 cycles).
Atezolizumab
pharmacokinetics
(every 8 cycles).
At time of fresh 
biopsy (before 
treatment, on 
treatment, or at 
progression)
Pharmacodynamics a
Pharmacodynamics a
Treatment 
discontinuation 
visit
At visit
Pharmacodynamics a
ATA
Atezolizumab
pharmacokinetics and
pharmacodynamics. a
120 (30) days 
after last dose of 
atezolizumab
At visit
ATA
Atezolizumab
pharmacokinetics and
pharmacodynamics. a
ATAanti-therapeutic antibody.
a Pharmacodynamic samples may include plasma, serum, and whole blood (see 
laboratory manual for details on sample collection).


Atezolizumab—F. Hoffmann-La Roche Ltd
133/Protocol GO29294, Version 8
Appendix 3
Modified Response Evaluation Criteria in Solid Tumors
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents like atezolizumab, which can produce delayed 
responses that may be preceded by initial apparent radiological progression, including 
the appearance of new lesions.  Therefore, modified response criteria have been 
developed that account for the possible appearance of new lesions and allow 
radiological progression to be confirmed at a subsequent assessment.
Modified Response Evaluation Criteria in Solid Tumors (RECIST) is derived from 
RECIST, Version 1.1 (RECIST v1.1) conventions1, 2, 3 and immune-related response 
criteria 3, 4, 5 (irRC).  When not otherwise specified, RECIST v1.1 conventions will apply.
Modified RECIST and RECIST, Version 1.1:  Summary of Changes
RECIST v1.1
Modified RECIST
New lesions after baseline
Define progression.
New measurable lesions are 
added into the total tumor 
burden and followed.
Nontarget lesions
May contribute to the 
designation of overall 
progression
Contribute only in the 
assessment of a complete 
response
Radiographic progression
First instance of 20% 
increase in the sum of 
diameters or unequivocal 
progression in nontarget 
disease
Determined only on the basis 
of measurable disease; may 
be confirmed by a consecutive 
assessment 4 weeks from 
the date first documented 
RECIST Response Evaluation Criteria in Solid Tumors.
                                           
1
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
2
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
antiPD-1 antibody in cancer. N Engl J Med 2012;366:244354.
3
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Can Res 2009;15:741220.
4
Nishino M, Gargano M, Suda M, et al. Optimizing immune-related tumor response 
assessment: does reducing the number of lesions impact response assessment in 
melanoma patients treated with ipilimumab. J Immunother Can 2014;2:17.
5
Nishino M, Giobbie-Hurder A, Gargano M, et al. Developing a common language for tumor 
response to immunotherapy: immune-related response criteria using unidimensional 
measurements. Clin Can Res 2013;19:393643.


Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
134/Protocol GO29294, Version 8
DEFINITIONS OF MEASURABLE/NONMEASURABLE LESIONS
All measurable and nonmeasurable lesions should be assessed at screening and at the 
protocol-specified tumor assessment timepoints.  Additional assessments may be 
performed, as clinically indicated for suspicion of progression.  The investigator will 
evaluate response to treatment with use of modified RECIST.
MEASURABLE LESIONS
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable)
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, 
a lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and follow-up, 
only the short axis will be measured and followed.  
NONMEASURABLE LESIONS
Nonmeasurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 but 15 mm), as well as truly 
nonmeasurable lesions.  Lesions considered truly nonmeasurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
BONE LESIONS
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions.


Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
135/Protocol GO29294, Version 8
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.
Blastic bone lesions are nonmeasurable.
CYSTIC LESIONS
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they are, 
by definition, simple cysts.
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions.
LESIONS WITH PRIOR LOCAL TREATMENT
Tumor lesions situated in a previously irradiated area or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable.
TUMOR RESPONSE EVALUATION
DEFINITIONS OF TARGET/NONTARGET LESIONS
Target Lesions
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be recorded as nonmeasurable lesions (even if the size is 10 mm by CT 
scan).  


Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
136/Protocol GO29294, Version 8
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition, should lend 
themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, in 
which circumstance, the next largest lesion that can be measured reproducibly should 
be selected.
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  As noted above, 
pathological nodes that are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of 15 mm by CT scan.  Only the short 
axis of these nodes will contribute to the baseline sum.  The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor.  
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  For 
example, an abdominal node that is reported as being 20 mm30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 
short axis 10 mm but 15 mm) should be considered nontarget lesions.  Nodes that 
have a short axis of 10 mm are considered non-pathological and should not be 
recorded or followed. 
Lesions irradiated within 3 weeks prior to Cycle 1, Day 1 may not be counted as target 
lesions.
Nontarget Lesions
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as nontarget lesions and should also be recorded at baseline.  Measurements 
are not required.
It is possible to record multiple nontarget lesions involving the same organ as a single 
item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”). 
After baseline, changes in nontarget lesions will contribute only in the assessment 
of complete response (i.e., a complete response is attained only with the complete 
disappearance of all tumor lesions, including nontarget lesions) and will not be used 
to assess progressive disease.


Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
137/Protocol GO29294, Version 8
New Lesions
During the study, all new lesions identified and recorded after baseline must be 
assessed at all tumor assessment timepoints.  New lesions will be evaluated for 
measurability with use of the same criteria applied to prospective target lesions at 
baseline per RECIST v1.1 (e.g., nonlymph node lesions must be 10mm; see note for 
new lymph node lesions below).  Up to a maximum of five new lesions total (and a 
maximum of two lesions per organ), all with measurements at all timepoints, can be 
included in the tumor response evaluation.  New lesion types that would not qualify as 
target lesions per RECIST v1.1 cannot be included in the tumor response evaluation.
New lesions that are not measurable at first appearance but meet measurability criteria 
at a subsequent timepoint may be measured from that point forward and contribute to 
the tumor response evaluation.
CALCULATION OF SUM OF THE DIAMETERS
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated as a measure of tumor burden.  
The sum of the diameters is calculated at baseline and at each tumor assessment for 
the purpose of classification of tumor responses.
Sum of the Diameters at Baseline:  The sum of the diameters for all target lesions 
identified at baseline prior to treatment on Day 1.
Sum of the Diameters at Tumor Assessment:  For every on-study tumor assessment 
collected per protocol or as clinically indicated, the sum of the diameters at tumor 
assessment will be calculated using tumor imaging scans.  All target lesions selected at 
baseline and allup to fivenew measurable lesions (with a maximum of two new 
lesions per site) that have emerged after baseline will contribute to the sum of the 
diameters at tumor assessment.  Hence, each net percentage change in tumor burden 
per assessment with use of modified RECIST accounts for the size and growth kinetics 
of both old and new lesions as they appear.
Note:  In the case of new lymph nodes, RECIST v1.1 for measurability (equivalent to 
baseline target lesion selection) will be followed.  That is, if at first appearance the short 
axis of a new lymph node lesion is 15 mm, it will be considered a measureable new 
lesion and will be tracked and included in the sum of diameters.  Thereafter, the lymph 
node lesion will be measured at subsequent timepoints and measurements will be 
included in the sum of diameters, even if the short axis diameter decreases to 15 mm 
(or even 10 mm).  However, if it subsequently decreases to 10 mm and all other 


Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
138/Protocol GO29294, Version 8
lesions (including nontarget lesions) are no longer detectable (or have also decreased to 
a short axis diameter of 10 mm if lymph nodes) then a response assessment of CR 
may be assigned.
If at first appearance the short axis of a new lymph node is 10 mm and 15 mm, the 
lymph node will not be considered measurable but will still be considered a new lesion.  
It will not be included in the sum of diameters unless it subsequently becomes 
measurable (short axis diameter 15 mm).
The appearance of new lymph nodes with a diameter of 10 mm should not be 
considered pathological and not be considered a new lesion.
RESPONSE CRITERIA
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Lymph nodes that 
shrink to 10 mm short axis are considered normal.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of all 
target and all new measurable lesions, taking as reference the baseline sum of 
diameters, in the absence of CR.
Note:  The appearance of new measurable lesions is factored into the overall tumor 
burden but does not automatically qualify as progressive disease until the sum of the 
diameters increases by 20% when compared with the sum of the diameters at nadir.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of the diameters while 
on study.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of all 
target and all new measurable lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
Impact of New Lesions on Modified RECIST
New lesions alone do not qualify as progressive disease.  However, their contribution 
to total tumor burden is included in the sum of the diameters, which is used to determine 
the overall modified RECIST tumor response. 


Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
139/Protocol GO29294, Version 8
EVALUATION OF BEST OVERALL RESPONSE USING MODIFIED RECIST
TIMEPOINT RESPONSE
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
MISSING ASSESSMENTS AND INEVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is 
not evaluable (NE) at that timepoint.  If only a subset of lesion measurements are made 
at an assessment, usually the case is also considered NE at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned timepoint response.  This would be most likely 
to happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm 
with three measured lesions and at follow-up only two lesions were assessed but those 
gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion.
Table 1
Modified RECIST Timepoint Response Definitions
% Change in Sum of the Diameters 
(Including Measurable New Lesions 
When Present)
Nontarget Lesion 
Response
Overall Modified RECIST 
Timepoint Response
100% a
CR
CR
100% a
Non-CR or not all 
evaluated
PR
30%
Any
PR
30% to 20%
Any
SD
Not all evaluated
Any
NE
20%
Any
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; RECIST Response Evaluation Criteria in Solid Tumors; SDstable disease.
a When lymph nodes are included as target lesions, the % change in the sum of the 
diameters may not be 100% even if complete response criteria are met since a normal 
lymph node is defined as having a short axis of 10 mm.  Any pathological lymph 
nodes (whether target or nontarget) must have reduction in short axis to 10 mm in 
order to meet the definition of CR.


Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
140/Protocol GO29294, Version 8
BEST OVERALL RESPONSE:  ALL TIMEPOINTS
The best overall response is determined once all the data for the patient are known.
The best overall response according to modified RECIST is interpreted as below:

CR:  Complete disappearance of all tumor lesions (target and nontarget) and no 
new measurable or unmeasurable lesions, confirmed by a consecutive assessment 
4 weeks from the date first documented.  All lymph nodes short axes must be 
10 mm.

PR:  Decrease in the sum of the diameters of all target and all new measurable 
lesions 30% relative to baseline, in the absence of CR, confirmed by a consecutive 
assessment 4 weeks from the date first documented.  

SD: Criteria for CR, PR, and PD are not met. 

PD:  Increase in the sum of the diameters of all target and all new measurable 
lesions 20% relative to the nadir, which may be confirmed by a consecutive 
assessment 4 weeks from the date first documented as follows: 
The confirmatory assessment shows an additional measurable increase in 
tumor burden as measured by the sum of the diameters of all target and all new 
measurable lesions.
This protocol allows patients to continue to receive study treatment even after confirmed 
radiographic PD per modified RECIST, and patients may achieve a best overall 
response of PR or CR based on tumor regression achieved at any time prior to study 
treatment discontinuation.


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Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1 1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
nonmeasurable as follows:
Measurable Tumor Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable)

20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Nontarget Lesions” for information on lymph node 
measurement.
Nonmeasurable Tumor Lesions
Nonmeasurable tumor lesions encompass small lesions (longest diameter 10 mm 
or pathological lymph nodes with 10 to 15 mm short axis), as well as truly 
nonmeasurable lesions.  Lesions considered truly nonmeasurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
                                           
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
Revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47.
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


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


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is suggested.
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a noncontrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether noncontrast CT or MRI (enhanced or nonenhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease and should be 
optimized to allow for comparison with the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of nontarget disease or new lesions since the same lesion may appear 
to have a different size with use of a new modality.
Ultrasound.  Ultrasound is not useful in the assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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TUMOR RESPONSE EVALUATION
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above.
BASELINE DOCUMENTATION OF TARGET AND NONTARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means in instances where patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be recorded as nonmeasurable lesions (even if the size is 10 mm by 
CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but additionally, should lend 
themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, 
in which circumstance the next largest lesion that can be measured reproducibly should 
be selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, this 
is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, 
or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 
but 15 mm) should be considered nontarget lesions.  Nodes that have a short axis 
10 mm are considered nonpathological and should not be recorded or followed.


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as nontarget lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple nontarget lesions involving the same organ as 
a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
RESPONSE CRITERIA
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  disappearance of all target lesions
Any pathological lymph nodes (whether target or nontarget) must have 
reduction in short axis to 10 mm.

Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  at least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest sum on study (nadir), 
including baseline
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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Special Notes on the Assessment of Target Lesions
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be 
zero even if CR criteria are met since a normal lymph node is defined as having a short 
axis 10 mm.
Target Lesions That Become Too Small to Measure.  While on study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on the CT scan that the radiologist may not feel comfortable assigning 
an exact measure and may report them as being too small to measure.  When this 
occurs, it is important that a value be recorded on the CRF as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and below measurable limit (BML) should 
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well and BML should also be ticked.) 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may 
be maintained that would aid in obtaining maximal diameter measurements of 
each individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the coalesced lesion.
Evaluation of Nontarget Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of nontarget lesions.  Whereas some nontarget lesions may actually be 


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
147/Protocol GO29294, Version 8
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the timepoints specified in the protocol.

CR:  disappearance of all nontarget lesions and (if applicable) normalization of 
tumor marker level)
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  persistence of one or more nontarget lesion(s) and/or (if 
applicable) maintenance of tumor marker level above the normal limits

PD:  unequivocal progression of existing nontarget lesions
The appearance of one or more new lesions is also considered progression.
Special Notes on Assessment of Progression of Nontarget Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the nontarget disease, there must be an overall 
level of substantial worsening in nontarget disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more nontarget lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in nontarget 
disease in the face of SD or PR of target disease will therefore be extremely rare.
When the Patient Has Only Nonmeasurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance, there 
is no measurable disease assessment to factor into the interpretation of an increase in 
nonmeasurable disease burden.  Because worsening in nontarget disease cannot be 
easily quantified (by definition:  if all lesions are truly nonmeasurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if 
the increase in overall disease burden based on the change in nonmeasurable disease 
is comparable in magnitude to the increase that would be required to declare PD for 
measurable disease, that is, an increase in tumor burden representing an additional 
73% increase in volume (which is equivalent to a 20% increase in diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from “trace” 
to “large” or an increase in lymphangitic disease from localized to widespread or may 
be described in protocols as “sufficient to require a change in therapy.”  If unequivocal 
progression is seen, the patient should be considered to have had overall PD at that 
point.  Whereas it would be ideal to have objective criteria to apply to nonmeasurable 
disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial.


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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When the patient has bone lesions at baseline.  When a bone scan is the sole 
indicator of progression, progression in bone will be defined as when at least two or 
more new lesions are seen on bone scan compared with screening.  In situations where 
the scan findings are suggestive of a flare reaction, or apparent new lesion(s) which may 
represent trauma, these results must be confirmed with other imaging modalities such as 
MRI or fine-cut CT to constitute progression.  Only a single new bone lesion on bone 
scan is required for progression if the lesion can be correlated on CT, MRI or plain film.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a CT 
scan report as a “new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
New osteoblastic bone lesions identified on plain films, CT, or MRI will not be considered 
progression in an otherwise stable or responding subject, if, in the opinion of the 
physician, the osteoblastic lesion appears to be healing or a response to therapy.
EVALUATION OF RESPONSE
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have nonmeasurable (therefore nontarget) disease only, Table 2 is to be 
used.


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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Table 1
Timepoint Response:  Patients with Target Lesions (with or 
without Nontarget Lesions)
Target Lesions
Nontarget Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not 
all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; 
PRpartial response; SDstable disease.
Table 2
Timepoint Response:  Patients with Nontarget Lesions Only
Nontarget Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for nontarget 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some trials; thus, assigning “stable disease” 
when no lesions can be measured is not advised.
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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would not change the assigned timepoint response.  This would be most likely to happen 
in the case of PD.  For example, if a patient had a baseline sum of 50 mm with three 
measured lesions and, during the study, only two lesions were assessed, but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more nontarget lesions are not assessed, the response for 
nontarget lesions should be “unable to assess” except where there is clear progression.  
Overall response would be “unable to assess” if either the target response or the 
nontarget response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that timepoint.


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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Table 3
Best Overall Response When Confirmation Is Required
Overall Response at 
First Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration for 
SD was met; otherwise, PD
CR
PD
SD, provided minimum duration for 
SD was met; otherwise, PD
CR
NE
SD, provided minimum duration for 
SD was met; otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration for 
SD was met; otherwise, PD
PR
NE
SD, provided minimum duration for 
SD was met; otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR).  Best response would depend on whether 
the minimum duration for SD was met.  However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR, at the first timepoint.  Under these circumstances, the original CR should be 
changed to PR and the best response is PR.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and nontarget disease as shown in Table 1, Table 2, and Table 3.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or nontarget 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or nontarget lesion.


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Appendix 5
Patient-Reported Outcomes Instruments


Appendix 5
Patient-Reported Outcomes Instruments (Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 5
Patient-Reported Outcomes Instruments (Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
155/Protocol GO29294, Version 8


Appendix 5
Patient-Reported Outcomes Instruments (Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
156/Protocol GO29294, Version 8


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 6
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).  Please contact the Medical Monitor regarding any uncertainty over 
autoimmune exclusions.
Acute disseminated 
encephalomyelitis
Addison’s disease
Ankylosing spondylitis
Antiphospholipid antibody
syndrome
Aplastic anemia
Autoimmune hemolytic anemia
Autoimmune hepatitis
Autoimmune hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune thrombocytopenic
purpura
Behcet’s disease
Bullous pemphigoid
Chronic fatigue syndrome
Chronic inflammatory
demyelinating polyneuropathy
Chung-Strauss syndrome
Crohn’s disease 
Dermatomyositis
Dysautonomia
Epidermolysis bullosa acquista
Gestational pemphigoid
Giant cell arteritis
Goodpasture’s syndrome
Graves’ disease
Guillain-Barre 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 7
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.


Atezolizumab—F. Hoffmann-La Roche Ltd
159/Protocol GO29294, Version 8
Appendix 8
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


Atezolizumab—F. Hoffmann-La Roche Ltd
160/Protocol GO29294, Version 8
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-related 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-related 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-related 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. 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab in this study.
TREATMENT INTERRUPTION
Atezolizumab treatment may be temporarily suspended in patients experiencing 
toxicity considered to be related to study treatment.  If corticosteroids are initiated for 
treatment of the toxicity, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.  If atezolizumab is 
withheld for 42 days after event onset, the patient will be discontinued from 
atezolizumab.  However, atezolizumab may be withheld for 42 days to allow for 
patients to taper off corticosteroids prior to resuming treatment.  Atezolizumab can be 
resumed after being withheld for 42 days if the Medical Monitor agrees that the 
patient is likely to derive clinical benefit.  Atezolizumab treatment may be suspended 
for reasons other than toxicity (e.g., surgical procedures) with Medical Monitor 
approval.  The investigator and the Medical Monitor will determine the acceptable 
length of treatment interruption.


Appendix 9
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
161/Protocol GO29294, Version 8
MANAGEMENT GUIDELINES
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have computed 
tomography (CT) scans of the chest performed at every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, 
pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or 
pulmonary hypertension.  Management guidelines for pulmonary events are provided 
in Table 1.


Appendix 9
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
162/Protocol GO29294, Version 8
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-related 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
163/Protocol GO29294, Version 8
HEPATIC EVENTS
Immune-related 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 tests.
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-related 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
164/Protocol GO29294, Version 8
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 tests.
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-related 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-related 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
165/Protocol GO29294, Version 8
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea 
or Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate
treatment with 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.
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-related 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. 
b If corticosteroids have been initiated, they must be tapered over 1 month to 


Appendix 9
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
166/Protocol GO29294, Version 8
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea 
or Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical
Monitor. c

Refer patient to GI specialist for evaluation and confirmation
biopsy.

Initiate treatment with 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-related 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 
167/Protocol GO29294, Version 8 
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
168/Protocol GO29294, Version 8
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-related 
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-related 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
169/Protocol GO29294, Version 8
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-related 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
170/Protocol GO29294, Version 8
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-related 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
171/Protocol GO29294, Version 8
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-related 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
172/Protocol GO29294, Version 8
IMMUNE-RELATED MYOCARDITIS
Immune-related myocarditis has been associated with the administration of 
atezolizumab.  Immune-related myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not 
limited to, dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or 
syncope.  Immune-related myocarditis needs to be distinguished from myocarditis 
resulting from infection (commonly viral, e.g., in a patient who reports a recent history 
of gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing 
cardiac enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac 
MRI as appropriate per institutional guidelines.  A cardiologist should be consulted.  
An endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.


Appendix 9
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(Cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
173/Protocol GO29294, Version 8
Table 6
Management Guidelines for Immune-Related Myocarditis
Event
Management
Immune-related 
myocarditis, Grade 1

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines.
Immune-related 
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.

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-related 
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.

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-related 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
174/Protocol GO29294, Version 8
INFUSION-RELATED REACTIONS
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) with Cycle 1 of 
atezolizumab may receive premedication with antihistamines or antipyretics/analgesics 
(e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in 
treating atezolizumab-associated IRRs because of its potential for causing 
agranulocytosis.
Guidelines for medical management of IRRs during Cycle 1 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
175/Protocol GO29294, Version 8
Table 7
Management Guidelines for Infusion-Related Reactions
Event
Management
IRR, Grade 1 

Reduce infusion rate to half the rate being given at the time of 
event onset.

After the event has resolved, the investigator should wait for 30 
minutes while delivering the infusion at the reduced rate.

If the infusion is tolerated at the reduced rate for 30 minutes 
after symptoms have resolved, the infusion rate may be increased 
to the original rate.
IRR, Grade 2

Interrupt atezolizumab infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, 
epinephrine, bronchodilators, oxygen).

After symptoms have resolved to baseline, resume infusion at half 
the rate being given at the time of event onset.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics and monitor closely for IRRs.
IRR, Grade 3 or 4

Stop infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen).

Permanently discontinue atezolizumab and contact Medical 
Monitor. a
IRR infusion-related reaction.
a Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related 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
176/Protocol GO29294, Version 8
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate work-up should include an evaluation for ductal obstruction, as well as 
serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 8.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2

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-related 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
177/Protocol GO29294, Version 8
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-related 
pancreatitis, Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event 
onset. a

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV 
methylprednisolone or equivalent and convert to
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
Immune-related 
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-related 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
178/Protocol GO29294, Version 8
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-related 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
179/Protocol GO29294, Version 8
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-related 
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-related 
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-related 
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-related 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
180/Protocol GO29294, Version 8
IMMUNE-RELATED MENINGOENCEPHALITIS
Immune-related meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-related 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-Related 
Meningoencephalitis
Event
Management
Immune-related 
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-related 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.


Clinical Study Report: RO5541267 - F. Hoffmann-La Roche Ltd
Protocol GO29294     Report Number 1074426
6181
 
Name
Reason for Signing
Date and Time
(UTC)
03-Aug-2016 17:59:31
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 GO29294 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE III, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB 
(MPDL3280A) (ANTI−PD-L1 ANTIBODY) 
COMPARED WITH CHEMOTHERAPY IN 
PATIENTS WITH LOCALLY ADVANCED OR 
METASTATIC UROTHELIAL BLADDER CANCER 
AFTER FAILURE WITH PLATINUM-CONTAINING 
CHEMOTHERAPY 
PROTOCOL NUMBER: 
GO29294 
STUDY DRUG: 
Atezolizumab (MPDL3280A; RO5541267) 
VERSION NUMBER 
1 
IND NUMBER: 
120827 
EUDRACT NUMBER 
2014-003231-19 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, Ph.D. 
DATE FINAL 
See electronic date stamp below. 


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2/Statistical Analysis Plan GO29294 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 5 
2. 
STUDY DESIGN ........................................................................................... 5 
2.1 
Protocol Synopsis.................................................................... 8 
2.2 
Outcome Measures ................................................................. 8 
2.2.1 
Efficacy Outcome Measures.................................................... 8 
2.2.1.1 
Primary Efficacy Outcome Measure ........................................ 8 
2.2.1.2 
Secondary Efficacy Outcome Measures.................................. 8 
2.2.2 
Safety Outcome Measures ...................................................... 8 
2.2.3 
Pharmacokinetic Outcome Measures...................................... 8 
2.2.4 
Patient-Reported Outcome Measure ....................................... 9 
2.2.5 
Exploratory Outcome Measures .............................................. 9 
2.3 
Determination of Sample Size ................................................. 9 
2.4 
Analyses Timing .................................................................... 10 
2.5 
Interim Analyses .................................................................... 10 
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 
Pharmacokinetic-Evaluable Population ................................. 11 
4.1.3 
Safety 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 
Objective Response Rate...................................................... 13 
4.4.2.2 
Progression-Free Survival ..................................................... 13 
4.4.2.3 
Duration of Objective Response............................................ 14 


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4.4.3 
Exploratory Efficacy Endpoints.............................................. 14 
4.4.3.1 
Objective Response Rate, Progression-Free 
Survival, and Duration of Objective Response 
per Modified RECIST............................................................. 14 
4.4.3.2 
Disease Control Rate ............................................................ 15 
4.4.3.3 
Assessment of Tumor Burden ............................................... 15 
4.4.3.4 
Exploratory Analyses on Primary Efficacy 
Endpoint ................................................................................ 15 
4.4.3.5 
Exploratory Analyses on Secondary Efficacy 
Endpoints............................................................................... 17 
4.4.3.6 
Biomarker Analyses............................................................... 17 
4.5 
Patient-Reported Outcome Analyses .................................... 17 
4.6 
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 18 
4.7 
Safety Analyses..................................................................... 18 
4.7.1 
Exposure to Study Medication............................................... 18 
4.7.2 
Adverse Events ..................................................................... 19 
4.7.3 
Laboratory Data..................................................................... 19 
4.7.4 
Vital Signs.............................................................................. 19 
4.7.5 
Anti-Therapeutic Antibodies................................................... 19 
4.8 
Missing Data.......................................................................... 20 
5. 
REFERENCES ........................................................................................... 21 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema............................................................................... 6 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 22 
Appendix 2 
Schedule of Assessments........................................................... 35 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ATA 
anti-therapeutic antibody 
CR 
complete response 
DCR 
disease control rate 
DOR 
duration of objective response 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EORTC QLQ-C30 
European Organization for Research and Treatment of 
Cancer Quality-of-Life Questionnaire Core 30 
EQ-5D-3L 
Euro QoL 5 Dimension 3 Level 
FDA 
U.S. Food and Drug Administration 
FPI 
first patient in 
GC 
gemcitabine and cisplatin 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
iDCC 
independent Data Coordinating Center 
iDMC 
independent Data Monitoring Committee 
IHC 
immunohistochemistry 
ITT 
intent-to-treat 
MVAC 
methotrexate, vinblastine, doxorubicin, and cisplatin 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
ORR 
objective response rate 
OS 
overall survival 
PD 
pharmacodynamic 
PD-1 
programmed death-1 
PD-L1 
programmed death-ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PRO(s) 
patient-reported outcome(s) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 
SLD 
sum of longest diameter 
TCC 
transitional cell carcinoma 
UBC 
urothelial bladder cancer 


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1. 
BACKGROUND 
Urothelial bladder cancer (UBC, also termed transitional cell carcinoma [TCC] or 
urothelial cell carcinoma [UCC] of the urinary tract) is the most common cancer of the 
urinary system worldwide with UBC of the bladder being the predominant histologic type 
and location.  Although less common, urothelial cancers may originate in the renal 
pelvis, ureter, or urethra.  The overall 5-year survival rate for metastatic UBC is 
approximately 5.4%.  Although several chemotherapeutic agents have been studied in 
the second-line setting over the last two decades, the overall response rates are low and 
associated with considerable toxicity.  No survival benefit has been demonstrated with 
second-line chemotherapy.   
Atezolizumab is a humanized IgG1 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.  Atezolizumab is 
being investigated as a potential therapy against solid tumors and hematologic 
malignancies in humans.  On 18 May 2016, atezolizumab was granted accelerated 
approval by the US Food and Drug Administration (FDA) for the treatment of metastatic 
urothelial carcinoma in patients who had progressed following prior platinum-containing 
chemotherapy. 
The Ventana anti−PD-L1 (SP142) immunohistochemistry (IHC) assay will be used to 
determine programmed death−ligand 1 (PD-L1) expression. Using this assay, the PD-L1 
IHC score will have three categories:  IC0, IC1, and IC2/3 which are defined as PD-L1 
stained tumor-infiltrating immune cells (ICs) covering < 1%, ≥ 1% to < 5%, and ≥ 5% of 
the tumor area, respectively. 
This Statistical Analysis Plan (SAP) specifies the planned analyses and statistical 
methods used for Study GO29294, and will supersede those specified in study protocol. 
2. 
STUDY DESIGN 
Study GO29294 is a Phase III, global, multicenter, open-label, two-arm, randomized, 
controlled study designed to evaluate the efficacy and safety of atezolizumab compared 
with chemotherapy in patients with locally advanced or metastatic UBC who have 
progressed during or following a platinum-containing regimen.  Prior to randomization, 
the investigator will have the option of choosing one of three chemotherapy regimens 
(vinflunine, paclitaxel, or docetaxel) for each patient.  Figure 1 illustrates the study 
design. 


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 Figure 1 Study Schema 
 
IHC = immunohistochemistry; PD-L1 = programmed death−ligand 1; q3w = every 3 weeks; RECIST 
v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1; UBC = urothelial bladder cancer. 
a Patients randomized to Arm A may continue atezolizumab treatment after disease progression 
according to RECIST v1.1 if they meet criteria specified in Protocol Section 4.6.1.1. 
 


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The primary endpoint of this study is overall survival (OS).  Secondary endpoints of the 
study include objective response rate (ORR), progression-free survival (PFS), and 
duration of objective response (DOR).  Other endpoints include safety, pharmacokinetic 
(PK), patient-reported outcome (PRO), and exploratory outcome measures (see 
Section 2.2). 
Male and female patients aged ≥ 18 years with Eastern Cooperative Oncology Group 
(ECOG) performance status of 0 or 1 who have histologically or cytologically proven 
locally advanced or metastatic UBC and who have experienced disease progression 
during or following treatment for advanced disease consisting of platinum-based therapy 
are eligible.  Patients who experience disease progression during or within 12 months 
following completion of a platinum-based adjuvant or neoadjuvant regimen will also be 
eligible for enrollment into the study.  Patients must have received at least 
one platinum-containing regimen (e.g., gemcitabine and cisplatin [GC], methotrexate, 
vinblastine, doxorubicin, and cisplatin [MVAC], carboplatin and gemcitabine [CarboGem], 
etc.) for locally advanced or metastatic UBC.  The maximum number of prior therapies in 
the locally advanced or metastatic setting is restricted to two.  Tumor specimens from 
eligible patients will be prospectively tested for PD-L1 expression by a central laboratory.  
Patients, investigators and Sponsor will be blinded to the PD-L1 expression status.  The 
study will enroll all patients whose tissue is evaluable for expression testing, regardless 
of PD-L1 expression status. 
Eligible patients will be randomized in a 1:1 ratio to receive either atezolizumab or 
chemotherapy (vinflunine, paclitaxel, or docetaxel) and stratified by the following criteria: 
• 
Chemotherapy (vinflunine vs. taxane [paclitaxel or docetaxel]) 
• 
PD-L1 immunohistochemistry (IHC) status (IC0/1 vs. IC2/3) 
• 
Number of baseline prognostic risk factors (0 vs. 1/2/3) 
Time from prior chemotherapy (TFPC) < 3 months 
ECOG performance status > 0 
Hemoglobin < 10 g/dL 
• 
Liver metastasis (yes vs. no) 
 
Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle.  Patients will receive atezolizumab as long as they continue to 
experience clinical benefit in the opinion of the investigator until unacceptable toxicity or 
symptomatic deterioration attributed to disease progression (i.e., pain secondary to 
disease or unmanageable ascites, etc.) as determined by the investigator after an 
integrated assessment of radiographic data, biopsy results (if available), and clinical 
status. 
No crossover will be allowed from the control arm to the experimental arm. 


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An external independent Data Monitoring Committee (iDMC) will evaluate study safety 
data approximately every 6 months after first-patient-in (FPI) in accordance with the 
iDMC Charter. 
A total of approximately 931 patients will be enrolled into the study, including a minimum 
of 230 patients with a PD-L1 IHC score of IC2/3 and a minimum of 537 patients with a 
PD-L1 IHC score of IC1/2/3.  The primary analyses of OS will occur when approximately 
152, 403, and 652 deaths have been observed in the following populations:  patients 
with an IHC score of IC2/3, patients with an IHC score of IC1/2/3, and intent-to-treat (ITT) 
populations, respectively, whichever occurs later.  
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2. 
2.2 
OUTCOME MEASURES 
2.2.1 
Efficacy Outcome Measures 
2.2.1.1 
Primary Efficacy Outcome Measure 
• 
OS, defined as the time between the date of randomization and death due to any 
cause 
 
2.2.1.2 
Secondary Efficacy Outcome Measures 
• 
ORR, defined as the proportion of patients with an objective response (either a 
complete response [CR] or partial response [PR]) as determined by the investigator 
with use of Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
• 
PFS, defined as the time between the date of randomization and the date of first 
documented disease progression as determined by the investigator with use of 
RECIST v1.1 or death due to any cause, whichever occurs first 
• 
DOR, defined as the time between the date of first documented response and the 
date of first documented disease progression as determined by the investigator with 
use of RECIST v1.1 or death due to any cause, whichever occurs first 
 
2.2.2 
Safety Outcome Measures 
• 
Incidence, nature, and severity of adverse events graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
Version 4.0 
• 
Changes in selected vital signs, physical findings, and clinical laboratory results 
• 
Incidence of anti-therapeutic antibody (ATA) response to MPDL3280A and potential 
correlation with PK, pharmacodynamic, safety, and efficacy parameters 
 
2.2.3 
Pharmacokinetic Outcome Measures 
• 
Maximum observed serum atezolizumab concentration (Cmax) after infusion on 
Day 1 of Cycle 1 


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• 
Minimum observed serum atezolizumab concentration (Cmin) prior to infusion on 
Day 1 of Cycles 1, 2, 3, 4, 8, and 16, at treatment discontinuation, and at 120 days 
(± 30 days) after the last dose of atezolizumab 
 
2.2.4 
Patient-Reported Outcome Measure 
• 
UBC cancer symptoms, patient functioning, and health-related quality of life 
(HRQoL) as measured by the European Organisation for Research and Treatment 
of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) 
 
2.2.5 
Exploratory Outcome Measures 
• 
ORR, PFS, and DOR with use of modified RECIST for patients randomized to 
atezolizumab 
• 
Disease control rate (DCR), defined as the rate of patients with CR or PR as best 
response or stable disease maintained for ≥ 24 weeks per RECIST v1.1 
• 
Tumor burden:  change over time in the sum of the longest diameters (SLD) 
computed from RECIST-defined target lesions identified at baseline 
• 
Status of tumor immune-related or disease type-related exploratory biomarkers in 
archival and/or freshly obtained tumor tissues and association with disease status 
and/or response to atezolizumab 
• 
Status of exploratory biomarkers in plasma, whole blood, or serum (including but not 
limited to cytokines such as interleukin 6 [IL-6]) collected before or during treatment 
with atezolizumab or at progression and association with disease status and/or 
response to atezolizumab 
• 
Utility scores of the EuroQoL 5 Dimension 3 Level (EQ-5D-3L) questionnaire for use 
in economic models 
• 
Items from the EORTC QLQ-C30 that are not included in the main PRO outcome 
measure  
 
2.3 
DETERMINATION OF SAMPLE SIZE 
This study will enroll approximately 931 patients, including a minimum of 230 patients 
with a PD-L1 IHC score of IC2/3 and a minimum of 537 patients with a PD-L1 IHC score 
of IC1/2/3 (enrollment of all patients will continue until the minimum requirement of 
patients with PD-L1 IC2/3 and IC1/2/3 are reached). 
The number of events required to demonstrate efficacy of the atezolizumab treatment 
arm over the chemotherapy arm (i.e., vinflunine, paclitaxel, or docetaxel) with regard to 
OS (see Section 4.4.1) are estimated on the basis of the following assumptions: 
• 
Two-sided significance level of 5% 
• 
94% power for the primary analysis of OS in the IC2/3 population with an HR of 0.57, 
corresponding to an improvement in median OS from 7.5 months to 13.2 months 
• 
98% power for the primary analysis of OS in the IC1/2/3 population with an HR of 
0.68, corresponding to an improvement in median OS from 7.5 months to 


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11 months 
• 
97% power for the primary analysis of OS in the ITT population with an HR of 0.74, 
corresponding to an improvement in median OS from 7.5 months to 10.1 months 
• 
1:1 randomization ratio 
• 
Dropout rate of 5% per year over 24 months 
 
2.4 
ANALYSES TIMING 
The primary analyses of OS will occur when approximately 152, 403, and 652 deaths 
have been observed in the following populations:  patients with an IHC score of IC2/3, 
patients with an IHC score of IC1/2/3, and ITT populations, respectively, whichever 
occurs later.  This is expected to occur approximately 25 months after FPI. 
The timing of the primary analyses of OS will depend on the actual accrual rate and will 
be driven by the occurrence of number of deaths as indicated above. 
2.5 
INTERIM ANALYSES 
No interim analyses of efficacy are planned for this study. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
Eligible patients will be randomized in a 1:1 ratio to receive either atezolizumab or 
chemotherapy (vinflunine, paclitaxel, or docetaxel) on a 21-day cycle.  A permuted-block 
randomization scheme will be used to ensure balanced assignments to each treatment 
arm with respect to the following stratification factors: 
• 
Chemotherapy (vinflunine vs. taxane) 
• 
PD-L1 IHC status (IC0/1 vs. IC2/3) 
• 
Number of baseline prognostic risk factors (0 vs. 1/2/3) 
TFPC < 3 months 
ECOG performance status > 0 
Hemoglobin < 10 g/dL 
• 
Liver metastasis (yes vs. no) 
 
3.2 
DATA MONITORING 
The iDMC, consisting of independent, external experts, will monitor all accumulated 
patient safety data approximately every 6 months during the course of the study after 
FPI.  All summaries and analyses by treatment arm for the iDMC review will be prepared 
by an external independent Data Coordinating Center (iDCC).  Members of the iDMC will 
follow a charter that outlines their roles and responsibilities.  Additional details will be 
provided in the iDMC Charter. 


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4. 
STATISTICAL METHODS 
4.1 
ANALYSIS POPULATIONS 
4.1.1 
Intent-to-Treat Population 
The intent-to-treat (ITT) population is defined as all randomized patients, irrespective of 
whether the assigned treatment was actually received.  The IC2/3 population for efficacy 
analyses is defined as ITT patients with a PD-L1 IHC score of IC2/3 at the time of 
randomization, and the IC1/2/3 population for efficacy analyses is defined as ITT 
patients with a PD-L1 IHC score of IC1 or IC2/3 at the time of randomization.  For each 
patient, the sample(s) with highest IC score prior to the start of study drug treatment will 
be used to determine the PD-L1 IC score for the patient.  
For all efficacy analyses, patients will be grouped according to the treatment assigned at 
randomization by the interactive voice/web response system (IxRS).  
4.1.2 
Pharmacokinetic-Evaluable Population 
The PK-evaluable population will include all randomized patients who received 
atezolizumab. 
4.1.3 
Safety Population 
The safety population will include all randomized patients who received any amount of 
study drug, with patients grouped according to whether any amount of atezolizumab was 
received, including the case when atezolizumab was received in error.  Patients who are 
randomized into the study but do not receive any amount of study drug will not be 
included in the safety population. 
4.2 
ANALYSIS OF STUDY CONDUCT 
Study enrollment, major protocol violations and reasons for discontinuation from the 
study will be summarized overall and by treatment arm for the IC2/3, IC1/2/3 and overall 
ITT populations.  Study drug administration and reasons for discontinuation from the 
study drug will be summarized for the Safety Population.  
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic characteristics, such as age, sex, race/ethnicity, and baseline disease 
characteristics (e.g., ECOG performance status), number of Bellmunt risk factors (ECOG 
performance status ≥ 1, liver metastases [yes vs. no], and hemoglobin < 10 g/dL) and 
number of prior cancer treatments will be summarized by treatment arm for the IC2/3, 
IC1/2/3 and overall ITT populations individually.  Descriptive statistics (mean, median, 
SD, and range) will be presented for continuous data, and frequencies and percentages 
will be presented for categorical data. 
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of study drug on Cycle 1, Day 1. 


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4.4 
EFFICACY ANALYSES 
4.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is OS.  OS is defined as the time between the date of 
randomization and death due to any cause.  Patients who are not reported as having 
died by the date of data cutoff for primary analysis will be censored at the date when 
they were last known to be alive.  Patients who do not have post-baseline information 
will be censored at the date of randomization plus one day. 
Comparisons with respect to OS between the treatment and control arms within the 
IC2/3, IC1/2/3 and ITT populations will be tested using a hierarchical fixed-sequence 
procedure based on a stratified log-rank test at two-sided level of 5% significance: 
Step 1. Test to reject the null hypothesis of no difference in OS between the two arms 
in the IC2/3 population.  If the estimate of the HR is < 1 and the two-sided 
p-value corresponding to the stratified log-rank test is < 0.05, the null 
hypothesis will be rejected and it will be concluded that atezolizumab prolongs 
OS relative to chemotherapy (i.e., vinflunine, paclitaxel, or docetaxel) in the 
IC2/3 population. 
Step 2. If the null hypothesis from Step 1 is rejected, then test to reject the null 
hypothesis of no difference in OS between the two arms in the IC1/2/3 
population.  If the estimate of the HR is < 1 and the two-sided p-value 
corresponding to the stratified log-rank test is < 0.05, the null hypothesis will be 
rejected and it will be concluded that atezolizumab prolongs OS relative to 
chemotherapy (i.e., vinflunine, paclitaxel, or docetaxel) in the 
IC1/2/3 population. 
Step 3. If the null hypothesis from Step 2 is rejected, then test to reject the null 
hypothesis of no difference in OS between the two arms in the ITT population.  
If the estimate of the HR is < 1 and the two-sided p-value corresponding to the 
stratified log-rank test is < 0.05, the null hypothesis will be rejected and it will be 
concluded that atezolizumab prolongs OS relative to chemotherapy (i.e., 
vinflunine, paclitaxel, or docetaxel) in the ITT population. 
 
The null and alternative hypotheses for OS analysis can be phrased in terms of the 
survival functions SA (t) and SB(t) in the atezolizumab arm (Arm A) and chemotherapy 
arm (Arm B), respectively: 
H0: SA(t) = SB(t) versus H1: SA(t) ≠ SB(t) 
Kaplan-Meier methodology will be used to estimate the median OS for each treatment 
arm and to construct survival curves for the visual description of the difference between 
the treatment arms.  The Brookmeyer-Crowley methodology will be used to construct the 
95% CI for the median OS for each treatment arm (Brookmeyer and Crowley 1982). 
The hazard ratio, λA/λB, where λA  and λB represent the hazard of death in Arm A and 
Arm B, respectively, will be estimated using a stratified Cox regression model with the 


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same stratification variables used in the stratified log-rank test, including 95% CIs.  The 
stratification factors will be those specified for randomization (i.e., chemotherapy, 
prognostic factors, and liver metastases as recorded on the electronic Case Report 
Forms [eCRFs), and PD-L1 IHC status as recorded on the central laboratory form).  
Results from an unstratified analysis will also be presented. 
4.4.2 
Secondary Efficacy Endpoints 
If the primary endpoint of OS is statistically significant in all the IC2/3, IC1/2/3 and 
ITT populations, the secondary endpoints of ORR and PFS will be tested in order 
(i.e., ORR followed by PFS), each at 5% significance level in the IC2/3, IC1/2/3 and ITT 
populations individually as follows.  First, test for an ORR difference between the two 
arms (i.e., H0: ORRA = ORRB versus H1: ORRA ≠ ORRB) in the IC2/3 population.  If the 
null hypothesis is rejected, test for an ORR difference in the IC1/2/3 population.  If the 
preceding null hypothesis is rejected, test for an ORR difference in the ITT population.  If 
the preceding null hypothesis is rejected, test for a PFS difference between the two arms 
(i.e., the null hypothesis of no difference in PFS between the two arms) in the 
IC2/3 population.  If the preceding null hypothesis is rejected, test for a PFS difference in 
the IC1/2/3 population, and if the preceding null hypothesis is rejected, test for a PFS 
difference in the ITT population. 
4.4.2.1 
Objective Response Rate 
An objective response is defined as either a CR or PR, as determined by the investigator 
with use of RECIST v1.1.  Objective response in this study does not need to be a 
confirmed response.  Patients not meeting these criteria, including patients without any 
post-baseline tumor assessment, will be considered non-responders. 
ORR is defined as the proportion of patients who had an objective response.  The 
analysis population for ORR will be all randomized patients with measurable disease at 
baseline per investigator assessment using RECIST v1.1.  An estimate of ORR and its 
95% CI will be calculated using the Clopper-Pearson method for each treatment arm.  
CIs for the difference in ORRs between the two arms will be determined using the 
normal approximation to the binomial distribution.  The ORR will be compared between 
the two arms with use of the stratified Cochran-Mantel-Haenszel test without using the 
continuation correction factor. 
4.4.2.2 
Progression-Free Survival 
PFS is defined as the time between the date of randomization and the date of first 
documented disease progression or death, whichever occurs first.  Disease progression 
will be determined on the basis of investigator assessment with use of RECIST v1.1.  
Patients who have not experienced disease progression or death at the time of analysis 
will be censored at the time of the last tumor assessment.  Patients with no 
post-baseline tumor assessment will be censored at the date of randomization plus one 
day. 


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For U.S. registrational purposes, PFS will be defined as described above with an 
additional censoring rule for missed visits.  Patients with a PFS event who missed two or 
more consecutive assessments immediately prior to the PFS event will be censored at 
the last tumor assessment prior to the missed visits. 
PFS will be analyzed using the same methods as OS. 
4.4.2.3 
Duration of Objective Response 
DOR is defined as the period measured from the date of the first occurrence of a CR or 
PR (whichever status is recorded first) to the date that progressive disease or death is 
first documented.  Disease progression will be determined on the basis of investigator 
assessment with use of RECIST v1.1.  DOR based on the investigator assessment will 
be analyzed for the subset of patients who achieve an objective response as determined 
by the investigator with use of RECIST v1.1.  Patients who have not progressed or who 
have not died by the data cutoff date for analysis will be censored at the time of last 
tumor assessment date.  If no tumor assessments were performed after the date of the 
first occurrence of a CR or PR, DOR will be censored at the date of the first occurrence 
of a CR or PR plus one day. 
DOR analysis is on the basis of a non-randomized subset of patients (specifically, 
patients who achieve an objective response); therefore, formal hypothesis testing will not 
be performed for this endpoint.  DOR will be estimated using Kaplan-Meier methodology. 
4.4.3 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints will be analyzed using the same methodology specified in 
Section 4.4.2 for their respective endpoints.  The exploratory efficacy endpoints are not 
part of the endpoints tested in the hierarchical fixed sequence specified in Section 4.4.1. 
ORR, PFS, and DOR analyses using modified RECIST criteria (see Protocol) will be 
performed on patients in the MPDL3280A arm only, with no comparison with the 
chemotherapy arm. 
4.4.3.1 
Objective Response Rate, Progression-Free Survival, and 
Duration of Objective Response per Modified RECIST 
ORR, PFS, and DOR per modified RECIST have the same definitions as the secondary 
efficacy endpoints except that disease progression is determined by the modified 
RECIST criteria as described below. 
ORR per modified RECIST is defined as either a CR or PR, as determined by the 
investigator with use of modified RECIST. 


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PFS per modified RECIST is defined as the time between the date of randomization and 
the date of first documented disease progression per modified RECIST or death, 
whichever occurs first.  A patient is considered to have disease progression by modified 
RECIST if either of the following conditions is met: 
• 
(a) Modified RECIST criteria for progression were met at a tumor assessment and 
no subsequent tumor assessment was performed. 
• 
(b) Modified RECIST criteria for progression were met at a tumor assessment and at 
the subsequent tumor assessment the criteria for confirmed progression by modified 
RECIST were also met. 
 
For patients who meet criterion (a), the date of progression is the date of the tumor 
assessment that met the criteria for modified RECIST.  For patients who meet 
criterion (b), the date of progression is the date of the tumor assessment at which the 
modified RECIST criteria for progression were first met.  Patients who do not meet either 
of the above criteria are not considered to have had disease progression by 
modified RECIST. 
DOR per modified RECIST is defined as the period measured from the date of the first 
occurrence of a CR or PR (whichever status is recorded first) until the first date that 
progressive disease per modified RECIST or death is documented.  Analysis 
methodology for ORR, PFS, and DOR per modified RECIST are the same as those used 
for these endpoints per RECIST v1.1. 
4.4.3.2 
Disease Control Rate 
DCR is defined as the proportion of patients with CR or PR as best response or stable 
disease maintained for ≥ 24 weeks per RECIST v1.1.  The analysis methods for DCR will 
be the same as those for the analysis of ORR. 
4.4.3.3 
Assessment of Tumor Burden 
The change in the sum of longest diameter (SLD) computed from the RECIST-defined 
target lesions identified at baseline will be plotted for each patient by visit.  Per RECIST 
v1.1, up to five target lesions, not more than two per organ, will be designated as target 
lesions at baseline and followed at subsequent tumor assessments. 
4.4.3.4 
Exploratory Analyses on Primary Efficacy Endpoint 
Overall Survival Rate at Landmark Timepoints 
The OS rate at various timepoints (i.e., 6, 12, 18, and 24 months after randomization) 
within the IC2/3, IC1/2/3, and ITT populations will be estimated with use of the 
Kaplan-Meier methodology for each treatment arm with 95% CIs calculated using 
Greenwood’s formula.  The 95% CI for the difference in OS rates between the two 
treatment arms will be estimated using the normal approximation method with the 
standard errors computed using Greenwood’s formula. 


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Sensitivity Analyses 
Loss to Follow-Up:  The impact of loss-to-follow-up on OS will be assessed depending 
on the number of patients who are lost to follow-up.  If > 5% of patients are lost to 
follow-up for survival in either treatment arm, a sensitivity analysis (“worst case” analysis) 
will be performed in which patients who are lost to follow-up will be considered to have 
died at the last date they were known to be alive.  Kaplan-Meier methods will be used to 
estimate median OS.  OS between the two treatment arms will be compared using 
unstratified and stratified log-rank tests within the IC2/3, IC1/2/3 and ITT populations 
individually.  Stratified and unstratified Cox models will be used to estimate the HR for 
OS between the two treatment arms. 
Subsequent Anti-Cancer Therapy:  The impact of non-protocol specified anti-cancer 
therapy use on OS will be assessed depending on the number of patients who receive 
non-protocol anti-cancer therapy before an OS event.  If  > 10% of patients have received 
a non-protocol anti-cancer therapy before an OS event in any treatment arm, one 
sensitivity analysis will be performed for the comparisons between atezolizumab and 
chemotherapy in which patients who have received non-protocol therapy before an OS 
event will be censored on the date they were last alive before receipt of non-protocol 
anti-cancer therapy. 
Stratification Factors:  A sensitivity analysis of OS will be performed using the 
stratification factors (i.e., chemotherapy, PD-L1 IHC status, prognostic factors, and liver 
metastases) as recorded on IxRS.  
Subgroup Analyses 
The consistency of OS results in subgroups defined by demographics (e.g., age 
[ < 65, ≥ 65], sex, and race/ethnicity, etc.) and baseline characteristics including 
PD-L1 IHC status (IC0/1, IC2/3, IC1/2/3, IC0, IC1), ECOG performance status, number 
of Bellmunt risk factors, hemoglobin ( < 10 g/dL vs. ≥ 10 g/dL), chemotherapy (vinflunine 
vs. taxane), visceral metastasis, and liver metastasis, etc., will be examined.  It is 
expected that accrual in subgroups defined by these baseline characteristics may not be 
large enough for definitive treatment comparisons to be made between these subgroups. 
Within each IHC subpopulations (IC2/3, IC1/2/3 and ITT populations), descriptive 
summaries of survival, including unstratified HRs estimated from Cox proportional 
hazards models and Kaplan-Meier estimates of median survival time, will be produced 
separately for each level of the categorical variables listed above and displayed on a 
forest plot (Lewis and Clarke 2001). 
Multivariate Modeling 
The impact of each of the baseline variables and potential interaction on the estimate of 
treatment effect for OS will be assessed using the Cox proportional hazards model.  For 
each variable, the Cox model will include factors for treatment and the individual variable.  
An initial multivariate model that includes the effects of treatment and all variables that 


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were individually significant will be examined.  The final multivariate model will exclude 
variables that are not significant at a 0.05 significance level in the initial multivariate 
model, and the final model will contain only significant variables. 
4.4.3.5 
Exploratory Analyses on Secondary Efficacy Endpoints 
Objective Response Rate 
Exploratory analyses of ORR based on confirmed CR or PR per RECIST v1.1 will be 
performed using the same analysis methods described for the unconfirmed ORR 
analyses in Section 4.4.2.1. 
Duration of Objective Response 
Exploratory analyses of DOR based on confirmed CR or PR per RECIST v1.1 will be 
performed using the same analysis methods described for the DOR based on 
unconfirmed CR or PR in Section 4.4.2.3. 
4.4.3.6 
Biomarker Analyses 
Efficacy analyses, including OS, PFS, and ORR, will be performed in subgroups defined 
by gene or gene signature expression in tumor tissue and/or in peripheral blood 
mononuclear cells.  The analyses will include a comparison of the atezolizumab arm to 
the chemotherapy arm.  The gene or gene signatures used for the analyses may include 
PD-L1, IFNG, T-effector, and/or a combination thereof.  
The association between efficacy and other predictive biomarkers in blood and tumor 
tissue (e.g., tumor mutation status and burden, T-cell markers, plasma cytokines) may 
also be analyzed.  
The exploratory biomarker analyses may not be included in the Clinical Study Report 
(CSR). 
4.5 
PATIENT-REPORTED OUTCOME ANALYSES 
The EORTC QLQ-C30 data will be scored according to the EORTC scoring manual 
(Fayers et al. 2001).  For all questionnaire subscales, if > 50% of the constituent items 
are completed, a pro-rated score will be computed consistent with the scoring manuals 
and validation papers.  For subscales with < 50% of the items completed, the subscale 
will be considered missing.  All PRO data analyses will be performed on randomized 
patients with non-missing baseline assessments and at least one non-missing 
post-baseline assessment by treatment arm for the IC2/3, IC1/2/3 and ITT populations 
individually unless otherwise stated. 
EORTC QLQ-C30 standardized scores at each visit and change from baseline will be 
summarized with descriptive statistics (mean, median, SD, and range).  In addition, the 
standardized scores will be displayed in a shift table for each response category (0 to 24, 
25 to 49, 50 to 74, and 75 to 100).  


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Compliance with EORTC QLQ-C30 assessment, defined as the proportion of the 
number of forms received to the number of forms expected, will be documented at each 
visit by treatment arm.  When available, reasons for non-completion will be provided. 
A responder analysis will be used to assess improvement in the physical function score, 
the fatigue scale, and the global health status scores between treatment arms at each 
visit and at time of progression.  Responders are defined as patients with a ≥ 10-point 
improvement in mean scale score from baseline.  
Time to deterioration (TTD) on the EORTC scale (the physical function score, the fatigue 
scale, and the global health status scores) is defined as the time from baseline to the 
first time the patient’s score shows a ≥ 10-point increase above baseline.  In order for the 
symptom to be considered “deteriorated,” a score increase of ≥ 10 points above 
baseline must be held for at least two consecutive cycles or an initial score increase 
of ≥ 10 points is followed by death within 3 weeks from the last assessment.  A ≥ 10-point 
change in the score is perceived by patients as clinically significant (Osoba et al. 1998).  
Patients who have not deteriorated before the last PRO assessment is completed will be 
censored at this timepoint.  Patients with no assessment post-baseline will be censored 
at randomization date plus one day.  TTD analyses will be performed in the IC2/3, 
IC1/2/3 and ITT populations with non-missing baseline measurement.  
4.6 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
The PK analyses will be performed on the PK-evaluable population (see Section 4.1.2).  
Atezolizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized for each cycle for which pharmacokinetics are to be measured (Cmax will be 
reported for Cycle 1 only; Cmin will be evaluated at Cycles 1, 2, 3, 4, 8, and 16, 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 PD analyses will be conducted as appropriate and may not be 
included in the CSR. 
4.7 
SAFETY ANALYSES 
Safety analyses will be performed on the safety population (see Section 4.1.3).  
Summaries will be presented for the safety-evaluable populations by treatment arm. 
4.7.1 
Exposure to Study Medication 
Study drug exposure, including treatment duration, number of doses, and dose intensity, 
will be summarized for each treatment arm using descriptive statistics. 


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4.7.2 
Adverse Events 
Verbatim description of adverse events will be mapped to the Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded according to NCI CTCAE 
v4.0.  Adverse events will be summarized by treatment arm and NCI CTCAE grade.  
Multiple occurrences of the same event will be counted once at the maximum severity. 
Safety summaries for adverse events, except for summaries of treatment-related serious 
adverse events, adverse events of special interest, and adverse events requiring the use 
of systemic corticosteroids with no clear alternate etiology (immune-mediated adverse 
events), will include all treatment-emergent adverse events defined as adverse events 
occurring on or after the first dose of study drug until the earliest of the following: 
• 
30 days after the last administration of study drug 
• 
Initiation of another non-protocol anti-cancer therapy after the last administration of 
study drug  
• 
Clinical cutoff date 
 
Summaries of treatment-related serious adverse events, adverse events of special 
interest, immune-mediated adverse events, and all listings of adverse events will include 
adverse events with an onset date on or after the date of the first dose of study drug up 
to the data cutoff date.  The adverse events of special interest will be derived from 
Sponsor-defined adverse event group terms consisting of preferred terms representing 
immune-mediated reactions.   
In addition, serious adverse events, severe adverse events (Grade ≥ 3), adverse events 
of special interest, immune-mediated adverse events, and adverse events leading to 
study drug discontinuation or interruption will be summarized separately.   
Deaths reported during the study treatment period and those reported during the 
follow-up period after treatment completion or discontinuation and causes of death will 
be summarized by treatment arm. 
4.7.3 
Laboratory Data 
Laboratory data during study treatment and for 30 days after the last dose of study drug 
with values outside the normal ranges will be identified.  In addition, selected laboratory 
data will be summarized by treatment arm and grade. 
4.7.4 
Vital Signs 
Changes in vital signs will be summarized by treatment arm and grade. 
4.7.5 
Anti-Therapeutic Antibodies 
The number and percentage of patients with positive serum antibodies to atezolizumab 
at baseline and post-baseline during the study period will be summarized.  Adverse 
events occurring in patients with positive serum antibodies to atezolizumab will be 


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reviewed.  The relationship of the immunogenicity response with pharmacokinetics, 
safety, and efficacy may also be evaluated when appropriate. 
4.8 
MISSING DATA 
For OS, patients who are not reported as having died will be analyzed as censored 
observations on the date when they were last known to be alive.  If no post-baseline 
data are available, OS will be censored at the date of randomization plus one day. 
For PFS, patients without a date of disease progression and death will be analyzed as 
censored observations on the date of last tumor assessment.  If no post-baseline tumor 
assessment is available, PFS will be censored at the date of randomization plus one day.  
In the analysis of PFS for U.S. registrational purposes, data for patients with a PFS 
event who missed two or more scheduled assessments immediately prior to the PFS 
event will be censored at the last tumor assessment prior to the missed visits. 
For objective response, patients without any post-baseline assessment will be 
considered non-responders. 
For DOR, patients who have not progressed or who have not died at the time of analysis 
will be censored at the time of last tumor assessment date.  If no tumor assessments 
were performed after date of the first occurrence of a CR or PR, DOR will be censored at 
the date of the first occurrence of a complete or partial response plus one day. 


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5. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29−41. 
Fayers PM, Aaronson NK, Bjordal K, et al. On behalf of the EORTC Quality of Life 
Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published by: 
European Organisation for Research and Treatment of Cancer, Brussels 2001. 
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-
related quality-of-life scores. J Clin Oncol 1998;16:139−44. 
Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ 
2001;322:1479−80. 
 


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Appendix 1  
Protocol Synopsis 
TITLE: 
A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED 
STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB (ANTI−PD-L1 ANTIBODY) COMPARED WITH 
CHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED OR 
METASTATIC UROTHELIAL BLADDER CANCER AFTER 
FAILURE WITH PLATINUM-CONTAINING CHEMOTHERAPY 
PROTOCOL NUMBER: 
GO29294 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2014-003231-19 
IND NUMBER: 
120827 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
PHASE: 
III 
INDICATION: 
Urothelial bladder cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
Objectives 
Efficacy Objectives 
For the primary and secondary efficacy objectives, a comparison of the treatment arms will be 
performed in different patient subpopulations according to tumor PD-L1 expression as 
evaluated by IHC.  The IHC scores will have three categories (IC0, IC1, and IC2/3), which will 
also be used for stratification (IHC score of IC0/1 vs. IHC score of IC2/3). 
Primary Efficacy Objective 
The primary efficacy objective for this study is as follows: 
• 
To evaluate the efficacy of atezolizumab treatment compared with chemotherapy treatment 
with respect to overall survival (OS) in patients with locally advanced or metastatic urothelial 
bladder cancer (UBC) who have progressed during or following a platinum-containing 
regimen 
 
Secondary Efficacy Objectives 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate the efficacy of atezolizumab compared with chemotherapy with respect to 
anti-tumor effects as measured by objective response rate (ORR) per investigator with use 
of Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
• 
To evaluate the efficacy of atezolizumab compared with chemotherapy with respect to 
anti-tumor effects as measured by progression-free survival (PFS) per investigator with use 
of RECIST v1.1 
• 
To evaluate the efficacy of atezolizumab compared with chemotherapy with respect to 
anti-tumor effects as measured by duration of objective response (DOR) per RECIST v1.1 
 


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Appendix 1  
Protocol Synopsis (cont.)  
 
Safety Objectives 
The safety objectives for this study are as follows: 
• 
To evaluate the safety and tolerability of atezolizumab compared with chemotherapy 
• 
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 in patients with locally advanced or 
metastatic UBC who have progressed during or following a platinum-containing regimen 
 
Patient-Reported Outcome Objective 
The patient-reported outcome (PRO) objective for this study is as follows: 
• 
To evaluate and compare PROs of patient health-related quality of life (HRQoL) between 
treatment arms as measured by the European Organisation for Research and Treatment of 
Cancer (EORTC) Quality-of-Life Questionnaire  
 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate the efficacy of atezolizumab with respect to anti-tumor effects as measured by 
PFS, ORR, and DOR per modified RECIST 
• 
To evaluate and compare disease control rate (DCR) between the two treatment arms 
• 
To evaluate the relationship between tumor tissue programmed death−ligand 1 (PD-L1) 
expression and measures of efficacy 
• 
To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival 
and/or fresh tumor tissue and blood and their association with disease status and/or 
response to study treatment 
• 
To assess health status as measured using the EuroQol 5-Dimension, 3-level version 
(EQ-5D [3L]) questionnaire for health economic modeling 
 
Study Design 
Description of Study 
This is a Phase III, global, multicenter, open-label, two-arm, randomized, controlled study 
designed to evaluate the efficacy and safety of atezolizumab compared with chemotherapy in 
patients with locally advanced or metastatic UBC who have progressed during or following a 
platinum-containing regimen.  Within the chemotherapy control arm, the percentage of patients 
who are treated with a taxane (paclitaxel or docetaxel) will be capped at 40%.  Until that cap is 
reached, the selection of the specific chemotherapy (vinflunine or taxane) for patients who are 
randomized to the chemotherapy arm will be per investigator’s choice. 
Male and female patients aged ≥ 18 years with Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1 who have histologically or cytologically proven, locally advanced or 
metastatic UBC and who have experienced disease progression during or following treatment 
for advanced disease consisting of platinum-based therapy are eligible. 
Patients who experience disease progression during or within 12 months following completion 
of a platinum-based adjuvant or neoadjuvant regimen will also be eligible for enrollment into the 
study.  
 


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Appendix 1  
Protocol Synopsis (cont.)  
Patients must have received at least one platinum containing regimen (e.g., gemcitabine and 
cisplatin [GC], methotrexate, vinblastine, doxorubicin, and cisplatin [MVAC], carboplatin and 
gemcitabine [CarboGem], etc.) for locally advanced or metastatic UBC.  The maximum number 
of prior therapies in the locally advanced or metastatic setting is restricted to two. 
Tumor specimens from eligible patients will be prospectively tested for PD-L1 expression by a 
central laboratory.  Both patients and investigators will be blind to the PD-L1 expression status.  
The study will enroll all patients whose tissue is evaluable for expression testing, regardless of 
PD-L1 expression status. 
This study will enroll approximately 931 patients, including a minimum of 230 patients with a 
PD-L1 IHC score of IC2/3 and a minimum of 537 patients with a PD-L1 IHC score of IC1/2/3 
(enrollment of all patients will continue to reach the minimum requirement of patients with a 
PD-L1 IHC score of IC2/3).  Patients will be randomized in a 1:1 ratio to receive either 
atezolizumab or chemotherapy (vinflunine, paclitaxel, or docetaxel; see protocol for stratification 
factors): 
• 
Arm A (experimental arm):  Atezolizumab 1200 mg every 3 weeks (q3w) 
• 
Arm B (control arm):  Vinflunine 320 mg/m2 q3w, paclitaxel 175 mg/m2 q3w, or docetaxel 
75 mg/m2 q3w 
 
Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on Day 1 of each 
21-day cycle.  Patients will receive atezolizumab as long as they continue to experience clinical 
benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration 
attributed to disease progression (i.e., pain secondary to disease or unmanageable ascites, etc.) 
as determined by the investigator after an integrated assessment of radiographic data, biopsy 
results (if available), and clinical status. 
During treatment, patients will be permitted to continue atezolizumab treatment after 
RECIST v1.1 criteria for progressive disease are met if they meet all of the following criteria: 
• 
Evidence of clinical benefit as assessed by the investigator 
• 
Absence of symptoms and signs (including worsening of laboratory values [e.g., new or 
worsening hypercalcemia]) indicating unequivocal progression of disease 
• 
No decline in ECOG performance status that can be attributed to disease progression 
• 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed and stabilized by protocol-allowed medical interventions (see protocol) 
 
Patients treated with atezolizumab for whom radiographic disease progression is confirmed at a 
subsequent tumor assessment may be considered for continued study treatment at the 
discretion of the investigator if they continue to meet the criteria above. 
Patients randomized to the chemotherapy arm will receive vinflunine, paclitaxel, or docetaxel 
per the investigator’s choice.  Vinflunine 320 mg/m2, paclitaxel 175 mg/m2, or docetaxel 
75 mg/m2 will be administered intravenously on Day 1 of each 21-day cycle until disease 
progression per standard RECIST v1.1 or unacceptable toxicity. 
Given the unique characteristics associated with the chemotherapy arm, including toxicities (i.e., 
mucositis, neutropenia, febrile neutropenia, and alopecia) and the premedications required (i.e., 
steroid, anti-emetics, and potentially growth factor support), this will be an open-label study. 
No crossover will be allowed from the control arm to the experimental arm. 
Patients will undergo scheduled tumor assessment at baseline and every 9 weeks thereafter for 
54 weeks following randomization.  After 54 weeks from randomization, patients will undergo 
tumor assessment every 12 weeks until disease progression per modified RECIST (see 
protocol) or until treatment discontinuation (for patients who continue to receive atezolizumab 
following disease progression).  For patients randomized to the chemotherapy arm, 
assessments will continue until disease progression per RECIST v1.1 (see protocol), regardless 
of whether treatment has been discontinued.  In the absence of disease progression, tumor  


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Appendix 1  
Protocol Synopsis (cont.)  
assessments should continue, regardless of whether patients start new anti-cancer therapy, 
until death, loss of follow-up, withdrawal of consent, or study termination by Sponsor.  Follow-up 
data capture, including subsequent anti-cancer therapies (including targeted therapies and 
immunotherapies), will continue for each patient until death, loss of follow-up, withdrawal of 
consent, or study termination by Sponsor. 
For patients randomized to the atezolizumab arm, response will be assessed by the investigator 
with use of RECIST v1.1 and modified RECIST.  For patients randomized to the chemotherapy 
arm, response will be assessed by the investigator with use of RECIST v1.1 only. 
Primary imaging data used for tumor assessment may be collected by the Sponsor to enable 
centralized, independent review of response endpoints if needed. 
Safety assessments will include the incidence, nature, and severity of adverse events and 
laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 4.0 (NCI CTCAE v4.0).  Laboratory safety assessments will include 
the regular monitoring of hematology and blood chemistry.  Serum samples will be collected to 
monitor atezolizumab pharmacokinetics and to detect the presence of antibodies to 
atezolizumab.  Patient samples, including archival tumor tissues, as well as serum and plasma 
and whole blood, 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 protocol). 
Number of Patients 
This study will enroll approximately 931 patients, including a minimum of 230 patients with a 
PD-L1 IHC score of IC2/3 and a minimum of 537 patients with a PD-L1 IHC score of IC1/2/3. 
Target Population 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for study entry: 
• 
Signed Informed Consent Form 
• 
Ability to comply with protocol 
• 
Age ≥ 18 years 
• 
Histologically or cytologically documented locally advanced (T4b, any N; or any T, N 2−3) or 
metastatic (M1, Stage IV) UBC (also termed transitional cell carcinoma [TCC] or urothelial 
cell carcinoma [UCC] of the urinary tract; including renal pelvis, ureters, urinary bladder, 
and urethra) 
Patients with mixed histologies are required to have a dominant transitional cell pattern. 
Locally advanced bladder cancer must be inoperable on the basis of involvement of 
pelvic sidewall or adjacent viscera (clinical stage T4b) or bulky nodal metastasis 
(N2−N3). 
• 
Patients with a history of treated asymptomatic CNS metastases are eligible, provided they 
meet all of the following criteria: 
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, 
pons, medulla or spinal cord) 
No ongoing requirement for corticosteroids as therapy for CNS disease 
No stereotactic radiation within 7 days 
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study  
Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases.  Following treatment, 
these patients may then be eligible without the need for an additional brain scan prior 
to enrollment [or randomization], if all other criteria are met. 
 


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Appendix 1  
Protocol Synopsis (cont.)  
• 
Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens 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 on the basis of 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. 
TURBT specimens must contain a muscle invasive component (i.e., T2 or greater) of 
the bladder tumor as verified by local pathology review.  If the TURBT specimens do 
not contain a muscle invasive component, then specimens obtained at the time of 
cystectomy or nephroureterectomy or metastatic spread (i.e., sample from a metastatic 
lesion) will be required prior to randomization.  An archival specimen, if available, 
should also be submitted. 
Patients who do not have tissue specimens meeting eligibility requirements may 
undergo a biopsy during the screening period.  Acceptable samples include core 
needle biopsies for deep tumor tissue (minimum three cores) or excisional, incisional, 
punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. 
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is 
therefore not acceptable. 
Patients having additional tissue samples from procedures performed at different times 
during the course of their UBC 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.  In situations where 
multiple specimens were received from different sites or at different times, the highest 
score will be used for both primary and secondary analyses. 
• 
Disease progression during or following treatment with at least one platinum-containing 
regimen (e.g., GC, MVAC, CarboGem, etc.) for inoperable, locally advanced or metastatic 
UBC or disease recurrence 
A regimen is defined as patients receiving at least two cycles of a platinum-containing 
regimen. 
Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed within 
12 months of treatment with a platinum-containing adjuvant/neoadjuvant regimen will 
be considered as second-line patients. 
Patients may have received no more than two prior regimens of treatment (including 
the required platinum-based regimen) for their advanced UBC. Patients must have 
demonstrated disease progression during or following all prior regimen(s). 
Patients who have received one cycle of a platinum-containing regimen but 
discontinued because of a Grade 4 hematologic toxicity or a Grade 3/4 
non-hematologic toxicity may also be eligible. 
Patients with disease progression following chemoradiotherapy must demonstrate 
progression outside the prior radiotherapy port. 
• 
ECOG performance status of 0 or 1  
• 
Life expectancy ≥ 12 weeks 
• 
Measurable disease, as defined by RECIST v1.1 
Previously irradiated lesions should not be counted as target lesions. 
• 
Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 14 days prior to the first study treatment: 


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Appendix 1  
Protocol Synopsis (cont.)  
ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 
2 weeks prior to Cycle 1, Day 1) 
WBC counts > 2500/μL  
Lymphocyte count ≥ 500/μL 
Platelet count ≥ 100,000/μL (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 times the upper limit of normal (ULN), with 
the following exceptions: 
Patients with documented liver metastases:  AST and/or ALT ≤ 5 × ULN 
Patients with documented liver or bone metastases:  alkaline phosphatase 
≤ 5 × ULN 
Serum bilirubin ≤ 1.0 × ULN 
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may 
be enrolled. 
INR and aPTT ≤ 1.5 × 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 ≥ 30 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 90 days after the last dose of 
atezolizumab, 3 months after the last dose of vinflunine and 6 months from the last dose of 
paclitaxel or docetaxel. 
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. 
• 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined below: 
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
< 1% per year during the treatment period and for at least 3 months after the last dose 
of vinflunine and 6 months from the last dose of paclitaxel or docetaxel.  Men must 
refrain from donating sperm during this same period. 
With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for at least 28 days after the last dose of vinflunine, paclitaxel, or 
docetaxel. 
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  


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Appendix 1  
Protocol Synopsis (cont.)  
(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 Exclusions 
• 
Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 
3 weeks prior to initiation of study treatment; the following exceptions are allowed: 
Palliative radiotherapy for bone metastases or soft tissue lesions should be completed 
> 7 days prior to baseline imaging 
Hormone-replacement therapy or oral contraceptives 
• 
Treatment with any other investigational agent or participation in another clinical trial with 
therapeutic intent within 28 days prior to enrollment 
• 
Active or untreated CNS metastases as determined by computed tomography (CT) or 
magnetic resonance imaging (MRI) evaluation during screening and prior radiographic 
assessments 
Patients with treated asymptomatic CNS metastases are eligible, provided they meet all 
of the following criteria: 
Evaluable or measurable disease outside the CNS 
No metastases to midbrain, pons, medulla, cerebellum, or within 10 mm of the optic 
apparatus (optic nerves and chiasm) 
No history of intracranial or spinal cord hemorrhage 
No ongoing requirement for dexamethasone as therapy for CNS disease; 
anti-convulsants at a stable dose are allowed 
No evidence of significant vasogenic edema 
No stereotactic radiation, whole-brain radiation or neurosurgical resection with 
4 weeks prior to Cycle 1, Day 1 
Radiographic demonstration of interim stability (i.e., no progression) between the 
completion of CNS-directed therapy and the screening radiographic study 
Screening CNS radiographic study ≥ 4 weeks since completion of radiotherapy or 
surgical resection and ≥ 2 weeks since discontinuation of corticosteroids 
• 
Leptomeningeal disease 
• 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
• 
Patients with indwelling catheters (e.g., PleurX®) are allowed. 
• 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to enrollment. 
Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not presently associated 
with spinal cord compression) should be considered for loco-regional therapy if 
appropriate prior to enrollment. 
• 
Uncontrolled hypercalcemia (defined as any one or more of the following criteria: 
> 1.5 mmol/L ionized calcium 
Serum calcium > 12 mg/dL  
Corrected serum calcium > ULN (if serum albumin < 4.0 g/dL) 


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Appendix 1  
Protocol Synopsis (cont.)  
Symptomatic hypercalcemia requiring continued use of bisphosphonate therapy 
or denosumab 
Patients who are receiving bisphosphonate therapy or denosumab specifically to 
prevent skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible. 
Patients who are receiving denosumab prior to enrollment must be willing and eligible 
to discontinue its use and replace it with a bisphosphonate instead while on study. 
• 
Malignancies other than UBC within 5 years prior to Cycle 1, Day 1 
Patients with localized low risk prostate cancer (defined as Stage ≤ T2b, Gleason 
score ≤ 7, and PSA at prostate cancer diagnosis ≤ 20 ng/mL) 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 ≤ 6, and 
PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are 
eligible. 
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of 
metastasis or death < 5% at 5 years) are eligible provided they meet all of the following 
criteria: 
Malignancy treated with expected curative intent (such as adequately treated 
carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal 
carcinoma in situ treated surgically with curative intent) 
No evidence of recurrence or metastasis by follow-up imaging and any 
disease-specific tumor markers 
 
General Medical Exclusions 
• 
Pregnant and lactating 
• 
Evidence of significant uncontrolled concomitant disease that could affect compliance with 
the protocol or interpretation of results, including significant liver disease (such as cirrhosis, 
uncontrolled major seizure disorder, or superior vena cava syndrome) 
• 
Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction within 3 months prior to randomization, unstable 
arrhythmias, or unstable angina 
• 
Patients with a known left ventricular ejection fraction (LVEF) < 40% will be excluded. 
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or LVEF < 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. 
• 
Severe infections within 4 weeks prior to randomization including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
• 
Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
randomization 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection 
or chronic obstructive pulmonary disease) are eligible. 
• 
Major surgical procedure within 4 weeks prior to randomization or anticipation of need for a 
major surgical procedure during the course of the study other than for diagnosis 
• 
Inability to understand the local language(s) for which the EORTC QLQ-C30 and 
EQ-5D (3L) questionnaires are available 
 
Exclusion Criteria Related to Paclitaxel 
• 
Prior treatment with paclitaxel for assignment of paclitaxel in the chemotherapy control arm 
prior to randomization 


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Appendix 1  
Protocol Synopsis (cont.)  
• 
History of severe hypersensitivity to paclitaxel or to other drugs formulated with 
polyoxyethylated castor oil 
 
Exclusion Criteria Related to Docetaxel 
• 
Prior treatment with docetaxel for assignment of docetaxel in the chemotherapy control arm 
prior to randomization  
• 
History of severe hypersensitivity to docetaxel or to other drugs formulated with 
polysorbate 80 
• 
Grade ≥ 2 peripheral neuropathy as defined by NCI CTCAE v4.0 criteria 
• 
Inability to discontinue use of strong cytochrome P450 (CYP)3A4 inhibitors including but not 
limited to ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole 
 
Exclusion Criteria Related to Vinflunine 
• 
Prior treatment with vinflunine for assignment of vinflunine in the chemotherapy control arm 
prior to randomization 
• 
History of severe hypersensitivity to vinflunine or other vinca alkaloids 
Exclusion Criteria Related to Atezolizumab 
• 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
• 
Known hypersensitivity or allergy 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 1 diabetes mellitus on a stable insulin regimen may be 
eligible for this study. 
Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis) are permitted provided that 
they meet the following conditions: 
Rash must cover less than 10% of body surface area (BSA) 
Disease is well controlled at baseline and only requiring low potency topical 
steroids 
No acute exacerbations of underlying condition within the last 12 months (not 
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency or oral steroids) 
• 
Patients with prior allogeneic stem cell or solid organ transplantation 
• 
History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest 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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Appendix 1  
Protocol Synopsis (cont.)  
• 
Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen 
[HBsAg] test at screening) or hepatitis C  
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as having a negative HBsAg test and a positive antibody to hepatitis B core antigen 
[anti-HBc] antibody test) are eligible. 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV RNA. 
• 
Active tuberculosis (TB) 
• 
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 March 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®) 28 days prior to randomization, during 
treatment or within 90 days following the last dose of atezolizumab (for patients 
randomized to atezolizumab). 
• 
Prior treatment with CD137 agonists, anti−programmed death−1 (PD-1), or anti−PD-L1 
therapeutic antibody or pathway-targeting agents 
Patients who have had prior anti−cytotoxic T lymphocyte−associated antigen 4 
(CTLA-4) may be enrolled, provided the following requirements are met: 
Minimum of 12 weeks from the first dose of anti−CTLA-4 and > 6 weeks from the last 
dose 
No history of severe immune-related adverse effects from anti−CTLA-4 (NCI CTCAE 
Grade 3 and 4) 
• 
Treatment with systemic immunostimulatory agents (including but not limited to interferons 
or interleukin [IL]−2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior 
to randomization 
• 
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 [TNF] agents) within 2 weeks 
prior to randomization 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) may be enrolled in 
the study after discussion with and approval by the Medical Monitor. 
The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids 
(i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed. 
 
End of Study 
The end of the study is defined as the date when all patients have one of the following:  
• 
Experienced an OS event 
• 
Been lost to follow-up 
• 
Withdrawn consent 
 
In addition, the Sponsor may decide to terminate the study at any time. 
Outcome Measures 
Efficacy Outcome Measures 
Primary Efficacy Outcome Measure 


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Appendix 1  
Protocol Synopsis (cont.)  
The primary efficacy outcome measure for this study is as follows: 
• 
OS, defined as the time between the date of randomization and death due to any cause 
 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
ORR, defined as the proportion of patients with an objective response (either a complete 
response [CR] or partial response [PR]) as determined by the investigator with use of 
RECIST v1.1 
• 
PFS, defined as the time between the date of randomization and the date of first 
documented disease progression as determined by the investigator with use of 
RECIST v1.1 or death due to any cause, whichever occurs first 
• 
DOR, defined as the time between the date of first documented response and the date of 
first documented disease progression as determined by the investigator with use of 
RECIST v1.1 or death due to any cause, whichever occurs first 
 
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, physical findings, 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, 4, 8, and 16, 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: 
• 
UBC cancer symptoms, patient functioning, and HRQoL as measured by the EORTC 
QLQ-C30 
 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
PFS, ORR, and DOR with use of modified RECIST for patients randomized to atezolizumab 
• 
DCR, defined as the rate of patients with complete or partial response as best response or 
stable disease maintained for ≥ 18 weeks per RECIST v1.1 
• 
Status of tumor immune-related or disease type−related exploratory biomarkers in archival 
and/or freshly obtained tumor tissues and association with disease status and/or response 
to atezolizumab 
• 
Status of exploratory biomarkers in plasma, whole blood, or serum (including but not limited 
to cytokines such as interleukin 6 [IL-6]) collected before or during treatment with 
atezolizumab or at progression and association with disease status and/or response to 
atezolizumab 
• 
Utility scores of the EQ-5D (3L) for use in economic models 


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Appendix 1  
Protocol Synopsis (cont.)  
• 
Items from the EORTC QLQ-C30 that are not included in the main PRO outcome measure 
 
Investigational Medicinal Products 
Test Product 
Atezolizumab is administered at a dose of 1200 mg by IV infusion on Day 1 of each 21-day 
cycle. 
Comparators 
Vinflunine is administered at a dose of 320 mg/m2 by IV infusion on Day 1 of each 21-day cycle. 
Paclitaxel is administered at a dose of 175 mg/m2 over 3 hours by continuous IV infusion on 
Day 1 of each 21-day cycle. 
Docetaxel is administered at a dose of 75 mg/m2 on Day 1 of each 21-day cycle. 
Statistical Methods 
Primary Analysis 
The primary efficacy endpoint is OS.  OS is defined as the time between the date of 
randomization and death due to any cause.  Data for patients who are not reported as having 
died by the time of the data cutoff date for primary analysis will be censored at the date when 
they were last known to be alive.  Patients who do not have post-baseline information will be 
censored at the date of randomization plus 1 day. 
The primary analysis will occur when approximately 152, 403, and 652 deaths have been 
observed in the following populations:  patients with an IHC score of IC2/3, patients with an IHC 
score of IC1/2/3, and ITT populations respectively, whichever occurs later. 
Comparisons with respect to OS between the treatment and control arms will be tested using a 
hierarchical fixed-sequence procedure based on a stratified log-rank test at two-sided level of 
5% significance within the following populations:  patients with an IHC score of IC2/3, patients 
with an IHC score of IC1/2/3, and in the ITT population. 
Determination of Sample Size 
This study will enroll approximately 931 patients, including a minimum of 230 patients with a 
PD-L1 IHC score of IC2/3 and a minimum of 537 patients with a PD-L1 IHC score of IC1/2/3. 
The number of events required to demonstrate efficacy of the atezolizumab experimental arm 
over the chemotherapy arm (i.e., vinflunine, paclitaxel, or docetaxel) with regard to OS are 
estimated based on the following assumptions: 
• 
Two-sided significance level of 5% 
• 
94% for the primary analysis of OS in the population of patients with an IHC score of 
IC2/3 with an HR of 0.57, corresponding to an improvement in median OS from 
7.5 months to 13.2 months 
• 
98% power for the primary analysis of OS in the population of patients with an IHC score 
of IC1/2/3 with an HR of 0.68, corresponding to an improvement in median OS from 
7.5 months to 11 months 
• 
97% power for the primary analysis of OS in the ITT population with an HR of 0.74, 
corresponding to an improvement in median OS from 7.5 months to 10.1 months 
• 
1:1 randomization ratio 
• 
Dropout rate of 5% per year over 24 months 
 
Interim Analyses 
No interim efficacy analyses are planned for this study. 
An iDMC will be set up to evaluate safety results approximately every 6 months after FPI.  All 
summaries/analyses by treatment arm for the iDMC’s review will be prepared by an external  
 


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Appendix 1  
Protocol Synopsis (cont.)  
iDCC.  Members of the iDMC will be external to the Sponsor and will follow a charter that 
outlines their roles and responsibilities.  
 


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Appendix 2  
Schedule of Assessments 
 
Screening a 
All Cycles  
Treatment 
Discontinuation b  
Assessment Window (Days) 
Days –28 
to –1 
Day 1 (± 3 Days for 
Cycles ≥ 2) 
≤ 30 Days after Last 
Dose 
Follow-Up 
Signed Informed Consent Form(s) a 
x 
 
 
 
Review of eligibility criteria 
x 
 
 
 
Medical, surgical, and cancer histories, including 
demographic information c 
x 
 
 
 
HIV, HBV, HCV, EBV serology d 
x 
 
 
 
TB test e 
x 
 
 
 
Concomitant medications f 
x 
x 
x 
 
Tumor assessment g 
x 
Every 9 weeks ± 3 business days for 54 weeks and every 
12 weeks ± 6 business days thereafter until disease 
progression, death, or loss of follow-up 
Patient-reported outcomes h 
 
x 
x 
x 
Complete physical examination i 
x 
 
x 
 
Limited physical examination i 
 
x j 
 
x 
ECOG performance status  
x 
x j 
x 
 
Vital signs k 
x 
x 
x 
 
12-lead ECG l 
x 
x l 
x l 
 
Weight 
x  
x 
x 
 
Height 
x 
 
 
 
Hematology m 
x 
x j 
x 
 


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Appendix 2 
Schedule of Assessments (cont.) 
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36/Statistical Analysis Plan GO29294  
Screening a 
All Cycles  
Treatment 
Discontinuation b  
Assessment Window (Days) 
Days –28 
to –1 
Day 1 (± 3 Days for 
Cycles ≥ 2) 
≤ 30 Days after Last 
Dose 
Follow-Up 
Serum chemistry n 
x 
x j 
x 
 
Coagulation panel (aPTT, INR) n 
x 
 
x 
 
Vitamin D assay 
x 
 
 
 
C-reactive protein testing 
x 
x o 
 
 
Urinalysis p 
x 
x q 
x 
 
Serum pregnancy test r 
x 
 
 
 
TSH, free T3, free T4 
x 
x s 
x 
 
Auto-antibody testing (atezolizumab patients only) t 
 
x  
 
 
Serum sample for ATA assessment (atezolizumab 
patients only) u 
 
x 
x 
 
Serum sample for PK sampling (atezolizumab patients 
only) u 
 
x 
x 
 
Blood samples for pharmacodynamics biomarkers v 
 
x  
x 
 
Optional whole blood sample for RCR DNA w 
x 
 
 
 
Adverse events x 
 
x 
x 
x 
Study drug infusion y 
 
x 
 
 
Archival/screening FFPE tumor tissue specimen or 
15 unstained slides z 
x 
 
 
 


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Appendix 2 
Schedule of Assessments (cont.) 
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Screening a 
All Cycles  
Treatment 
Discontinuation b  
Assessment Window (Days) 
Days –28 
to –1 
Day 1 (± 3 Days for 
Cycles ≥ 2) 
≤ 30 Days after Last 
Dose 
Follow-Up 
Fresh biopsy (optional RCR) 
x aa 
Per investigator discretion, 
biopsy(ies) to be performed 
preferably at the time of radiographic 
progression (atezolizumab-treated 
patients only) z 
Survival and anti-cancer therapy follow-up bb 
 
 
 
x 
anti-HBc = antibody against hepatitis B core antigen; ATA = anti-therapeutic antibody; EBV = Epstein-Barr virus; ECOG = Eastern Cooperative 
Oncology Group;  EORTC = European Organisation for Research and Treatment of Cancer; EQ-5D (3L) = EuroQoL 5 Dimensions; 
FFPE = formalin fixed paraffin embedded; HBV = hepatitis B virus; HCV = hepatitis C virus; MUGA = multiple-gated acquisition; 
PD-L1 = programmed death-ligand 1; PK = pharmacokinetic; PRO = patient-reported outcome; QLQ-C30 = Quality-of-life Questionnaire Core 30; 
RCR = Roche Clinical Repository; RECIST = Response Evaluation Criteria in Solid Tumors; TSH = thyroid-stimulating hormone. 
Note:  Assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise noted. 
a Written informed consent is required for performing any study-specific tests or procedures.  Signing of the Informed Consent Form can occur 
outside the 28-day screening period.  Results of standard-of-care tests or examinations performed prior to obtaining informed consent and 
within 28 days prior to study entry (except where otherwise specified) may be used for screening assessments rather than repeating such 
tests. 
b Patients will be asked to return to the clinic not more than 30 days after the last treatment for a treatment discontinuation visit.  
c Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment.  Demographic information includes age, sex, 
and self-reported race/ethnicity.  Reproductive status and smoking history should also be captured. 
d All patients will be tested for HIV locally prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical trial.  
Hepatitis B surface antigen, anti-HBc antibody and anti-HBs antibody should be collected during screening and tested locally.  In patients 
who have positive serology for the anti-HBc antibody, HBV DNA should be collected prior to Cycle 1, Day 1.  EBV serology tests will be 
performed centrally on the samples collected during screening only in patients who experience an acute inflammatory event such as 
systemic inflammatory response syndrome while receiving study treatment. 
 


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Appendix 2 
Schedule of Assessments (cont.) 
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38/Statistical Analysis Plan GO29294  
e All patients will have a tuberculin (PPD) skin test or IGRA done locally prior to the inclusion into the study, and patients with active TB will be 
excluded from the clinical trial.  
f 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 the date of informed consent should be documented.  At subsequent visits, changes to current medications 
or medications used since the last documentation of medications will be recorded. 
g Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of Cycle 1, Day 1 may be used 
rather than repeating tests.   All measurable and evaluable lesions should be assessed and documented at the screening visit.  The same 
radiographic procedure must be used throughout the study for each patient.  Results must be reviewed by the investigator before dosing at 
the next cycle.  Tumor assessments will be performed at baseline, every 9 weeks (approximately every three cycles) following randomization 
for 54 weeks, and every 12 weeks thereafter, with additional scans as clinically indicated.  For patients randomized to vinflunine or taxane, 
assessments will continue until disease progression per RECIST v1.1 (see Appendix 4), regardless of whether treatment has been 
discontinued.  Patients randomized to atezolizumab will undergo assessments until disease progression or until treatment discontinuation (for 
patients who continue to receive atezolizumab following disease progression).  Tumor assessments should continue regardless of whether 
patients start new anti-cancer therapy in the absence of disease progression unless they withdraw consent.  If an optional biopsy is to be 
performed at approximately the same timepoint of a tumor assessment or as a result of the radiographic determination (e.g., response or 
progression), samples should be acquired after all imaging scans have been performed, if at all possible.  Patients assigned to atezolizumab 
who continue treatment beyond radiographic disease progression (see Section 4.6.1.1) will be monitored with a follow-up scan at the next 
scheduled tumor assessment when the scan frequency is every 9 weeks.  If the scan frequency is every 12 weeks, the follow-up scan must be 
performed at 9 weeks (± 2 weeks) as an unscheduled tumor assessment, or earlier if clinically indicated.  Investigators may perform additional 
scans or more frequent assessments if clinically indicated.    
h The PRO questionnaires (EORTC QLQ-C30, and EQ-5D [3L]) will be completed by the patients at the investigational site.  All PRO 
questionnaires are required to be administered prior to administration of study treatment 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.  In addition, 
the EQ-5D only will be collected at 6, 12, and 24 weeks after disease progression per RECIST 1.1 through 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 (3L) during the telephone interview as record of source documentation. 
i Complete and limited physical examinations are defined in Section 4.5.2.2.  
j ECOG performance status, limited physical examination, local laboratory assessments, and C-reactive protein assessment may be obtained 
≤ 96 hours before Day 1 of each cycle (including Cycle 1).    
 


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Appendix 2 
Schedule of Assessments (cont.) 
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k Vital signs include heart rate, respiratory rate, blood pressures, and temperature.  At all infusions of study drug (atezolizumab, vinflunine, 
paclitaxel, or docetaxel), the patient’s vital signs should be determined up to 60 minutes before and 30 (± 10) minutes after the infusion.  For 
the atezolizumab arm, vital signs will also be collected during the first infusion (every 15 [± 5] minutes). 
l ECG recordings will be obtained during screening and when clinically indicated.  Patients should be resting and in a supine position for at 
least 10 minutes prior to each ECG collection. 
m Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils, and other cells), and platelet count.  A manual differential can be done if clinically indicated.  See 
Section 4.1.1  for a list of laboratory results obtained within 14 days prior to the first study treatment. 
n Serum chemistry includes BUN, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, 
total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.  See Section 4.1.1  for a list of laboratory results obtained 
within 14 days prior to the first study treatment. 
o On Day 1 of Cycle 4 and every four cycles thereafter until Cycle 16. 
p Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood).  
q On Day 1 of Cycle 3 and every two cycles thereafter.  
r Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and 
documented as negative within 14 days prior to Day 1. 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. 
s On Day 1 of Cycle 5 and every four cycles thereafter. 
t For patients assigned to atezolizumab only.  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.  
u For patients assigned to atezolizumab only.  See Appendix 2  for details of the ATA and PK collection schedule.  Blood samples should be 
processed to obtain serum.  A post-treatment ATA and PK sample should be collected 120 (± 30) days after the last dose of atezolizumab 
unless the patient withdraws consent or the study closes. 
v See Appendix 2  for details of the pharmacodynamic sampling schedule. 
w Whole blood for DNA isolation will be collected from patients who have consented to optional RCR sampling at baseline.  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.  
 


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Schedule of Assessments (cont.) 
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40/Statistical Analysis Plan GO29294  
x After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 90 days after the last dose of study 
treatment, whichever occurs first.  After this period, investigators should report any deaths, serious adverse events, or other adverse events of 
concern that are believed to be related to prior treatment with study drug.  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. 
y Patients should 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 3 days after randomization.  For atezolizumab, the 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 as long as the patient continues 
to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease 
progression as determined by the investigator after an integrated assessment of radiographic data, biopsy results (if available), and clinical 
status.  For vinflunine, paclitaxel, and docetaxel, study drug will be administered according to the local prescribing information, including 
premedication for paclitaxel (see Section 4.3.2) and docetaxel.  Vinflunine, paclitaxel, and docetaxel treatment will continue until disease 
progression per standard RECIST v1.1 or unacceptable toxicity. 
z 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, bone metastases, and 
lavage samples are not acceptable.  For core-needle biopsy specimens, at least three cores should be submitted for evaluation.  After signing 
of the Informed Consent Form, retrieval and submission of archival tumor sample can occur outside the 28-day screening period. 
aa 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.  Preferably, growing 
lesions should be selected, and samples collected at the time of radiographic progression.  Optional biopsy tissue will be stored in the RCR. 
Not applicable for a site that has not been granted approval for RCR sampling. 
bb Starting from treatment discontinuation visit, survival follow-up information will be collected via telephone calls, patient medical records, and/or 
clinic visits approximately every 3 months until death, loss to follow-up, or study termination by Roche.  All patients will be followed for survival 
and new anti-cancer therapy (including targeted therapy and immunotherapy) 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.